JP2023511595A - Methods for treating cancer using anti-TIGIT antagonist antibodies - Google Patents

Abstract

Cancer (e.g., lung cancer; cervical cancer; breast cancer; head and neck cancer; liver cancer; bladder cancer; stomach cancer; esophageal cancer; pancreatic cancer; cancer; ovarian cancer; or colorectal cancer). More specifically, the invention relates to treatment of patients with cancer with anti-TIGIT antagonist antibodies, including treatment with anti-TIGIT antagonist antibodies in combination therapy. [Selection figure] None

Description

Cross-reference to related applications

No. 62/966,448, filed Jan. 27, 2020; U.S. Patent Application No. 62/985,822, filed Mar. 5, 2020; U.S. patent application Ser. No. 62/994,272 filed on 24th March; U.S. Patent Application No. 63/059,960 filed July 31, 2020; U.S. Patent Application No. 63/074,807 filed September 4, 2020; U.S. Patent Application No. 63/074,827 filed September 4; International Application PCT/US2020/049415 filed September 4, 2020; No. 63/085,890; U.S. Patent Application No. 63/105,198 filed Oct. 23, 2020; U.S. Patent Application No. 63/114,517 filed Nov. 16, 2020; Claiming priority from U.S. Patent Application No. 63/124,693, filed December 11, 2020; and U.S. Patent Application No. 63/127,109, filed December 17, 2020; is incorporated herein by reference in its entirety.

SEQUENCE LISTING This application has been submitted electronically in ASCII format and contains a Sequence Listing which is hereby incorporated by reference in its entirety. The name of the above ASCII copy created on January 25, 2021 is 50474-206WO2_Sequence_Listing_1_25_2021_ST25 and is 30,641 bytes in size.

FIELD OF THE INVENTION The present invention relates to methods, uses and compositions for treating cancer. More specifically, the invention relates to treatment of patients with cancer with anti-TIGIT antagonist antibodies (eg, treatment with anti-TIGIT antagonist antibodies as monotherapy or combination therapy).

BACKGROUND OF THE INVENTION Cancer is characterized by the uncontrolled proliferation of cell subpopulations. Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. there is Cancer care therefore represents a significant and growing social burden.

Accordingly, there is an unmet need in the area of developing effective immunotherapies and methods of administering them for the treatment of cancer.

SUMMARY OF THE INVENTION In one aspect, the invention provides a method of treating a subject with cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks; administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks including doing

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

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

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 with cancer according to the methods provided herein. do.

In another aspect, the invention provides anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in methods of treating a subject with cancer, the methods according to the methods provided herein is.

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

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

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

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

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

In another aspect, the invention provides a method of treating a subject with cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein pembrolizumab is , at doses between about 300 mg and about 500 mg every 6 weeks.

In another aspect, the invention provides a method for treating a subject with cancer, the method comprising between about 500 mg and about 700 mg every 3 weeks for 2 weeks on/1 week off. PD-1 axis binding antagonist at a dose between about 900 mg and about 1500 mg every 3 weeks, and about 10 mg/m2 and about 10000 mg/ ^m2 orally twice daily every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the antimetabolite at a dose between ^m2 .

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

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

In another aspect, the invention provides a method of treating a subject with cancer comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein (a) the induction phase is every 3 weeks an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum every 3 weeks (b) the maintenance phase is an anti-TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding antagonist every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks. Methods are provided that include one or more additional dosing cycles of a therapeutic agent and the maintenance phase does not include administration of a platinum-based chemotherapeutic agent.

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

In another aspect, the invention provides a method of treating a subject or population of subjects with lung cancer, comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor. The treatment comprises administering to the subject or subject population a dosing regimen comprising one or more dosing cycles of the agent, wherein the treatment is a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and topoisomerase II without an anti-TIGIT antagonist antibody. Prolongs progression-free survival (PFS) in subjects compared to treatment with an inhibitor.

In another aspect, the invention provides a method of treating a subject population having lung cancer, the method 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. The treatment comprises administering to the subject population a dosing regimen comprising one or more dosing cycles, wherein the treatment results in a median PFS for the subject population of from about 8.2 months to about 9.2 months.

In another aspect, the invention provides a method of treating a subject or population of subjects with lung cancer, comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor. The treatment comprises administering to the subject or subject population a dosing regimen comprising one or more dosing cycles of the agent, wherein the treatment is a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and topoisomerase II without an anti-TIGIT antagonist antibody. Prolongs the subject's OS compared to treatment with the inhibitor.

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

In another aspect, the invention provides a method for treating a subject or subject population with SCLC, comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on day 1 of each dosing cycle, each Atezolizumab at a dose of about 900 mg to about 1500 mg on Day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and 1 day of each dosing cycle administering to the subject or subject population one or more 21-day dosing cycles of etoposide at a dose of 100 mg/ ^m2 on each of Days 2, 2, and 3; Prolongs PFS and/or OS in a subject or subject population compared to treatment with atezolizumab, carboplatin and etoposide without.

In another aspect, the invention provides a method for treating a subject or population of subjects with ES-SCLC, wherein the method comprises administering to the subject or population of subjects four initial dosing cycles followed by one or more additional doses. (a) the four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle; a dose of atezolizumab, a dose of carboplatin sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle, and a dose of carboplatin on Days 1, 2, and 3 of each initial dosing cycle (b) one or ^more additional dosing cycles administering a dose of about 600 mg of tiragolumab on Day 1 of each additional dosing cycle; and administering atezolizumab at a dose of about 1200 mg on day 1 of each additional dosing cycle, wherein the four initial dosing cycles and one or more additional dosing cycles are each 21-day dosing cycles; Treatment prolongs PFS and/or OS in a subject or subject population compared to treatment with atezolizumab, carboplatin, and etoposide without tiragolumab.

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

In another aspect, the invention provides a method of treating a subject or subject population having advanced non-squamous NSCLC, wherein the subject or subject population is treated with four doses of tiragolumab, atezolizumab, carboplatin or cisplatin and pemetrexed. comprising administering a dosing regimen comprising 21-day dosing cycles, wherein tiragolumab is administered every 3 weeks at a dose of about 600 mg and atezolizumab is administered every 3 weeks on day 1 of each of the 4 21-day dosing cycles Carboplatin administered at a dose of about 1200 mg every 3 weeks at a dose sufficient to achieve AUC = 5 mg/ml/min or Cisplatin administered at a dose of 75 mg/m ² every 3 weeks. , pemetrexed is administered every 3 weeks at a dose of about 500 mg/m ² .

In another aspect, the invention provides a method of treating a subject or subject population having advanced non-squamous NSCLC, the method comprising administering to the subject or subject population: (i) a dose of about 600 mg every 3 weeks; Four run-in phases of tiragolumab, atezolizumab at a dose of approximately 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min, and ^pemetrexed at a dose of approximately 500 mg/m2 every 3 weeks. and (ii) one or more maintenance phases of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/ ^m2 every 3 weeks. one or more 21-day dosing cycles in the maintenance phase does not include administration of carboplatin, and the subject or subject population has not received prior systemic therapy for advanced non-squamous NSCLC .

In another aspect, the invention provides a method for treating a subject with resectable lung cancer, the method comprising an anti-TIGIT antagonist antibody at a dose of between about 500 mg and about 700 mg every 3 weeks and administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg per dose.

In another aspect, the invention provides a method for treating a subject with 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 an anti-TIGIT antagonist antibody at a dose between about 500 mg and about 700 mg every 3 weeks and a PD-1 axis binding antagonist at a dose between about 900 mg and about 700 mg every 3 weeks as a neoadjuvant treatment. including administering to the subject at a dose of between 1500 mg.

In another aspect, the invention provides a method for treating a subject with resectable lung cancer, the method comprising tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks and (a) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) about 75 mg/min every 3 weeks and (b)(i) pemetrexed at a dose of about 500 mg/ ^m2 every three weeks, or about 1000 mg/m2 or about 1250 mg/ ^m2 on days ¹ and 8 of each dosing cycle. or (ii) one or more dosing cycles of paclitaxel at a dose of about 175 mg/m ² or about 200 mg/ ^{m 2 every} three weeks.

In another aspect, the invention provides a method for treating a subject with lung cancer, the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) the dosing cycle is a neoadjuvant treatment, wherein the subject is administered (a) tiragolumab at a dose of about 1200 mg every 3 weeks, (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; ) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of approximately 1000 mg/ ^m2 on days 1 and 8 of each dosing cycle; or (iii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/ ^m2 or about 200 mg/ ^m2 every 3 weeks; (II) at least one ^{of the} dosing cycles comprises , as adjuvant treatment, administering to the subject tiragolumab at a dose of between about 500 mg and about 700 mg every three weeks and atezolizumab at a dose of between about 900 mg and about 1500 mg every three weeks.

In another aspect, the invention provides a method for treating a subject or subject population having cervical cancer with a detectable PD-L1 expression level, the method comprising about 500 mg and about 700 mg every 3 weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 900 mg and about 1500 mg every three weeks to the subject or population of subjects.

In another aspect, the invention provides a method of selecting a therapy for a subject with cervical cancer, the method comprising the steps of: (a) PD-L1 on tumor cells from a tumor sample from the subject; detecting protein expression levels by an IHC assay using an anti-PD-L1 antibody suitable for staining, and (b) for subjects with detectable PD-L1 expression levels, PD-L1 on detected tumor cells; Based on L1 expression, an anti-TIGIT antagonist antibody administered at a dose of between about 500 mg and about 700 mg every 3 weeks and a PD-1 axis binding administered at a dose of between about 900 mg and about 1500 mg every 3 weeks. selecting a therapy that includes one or more dosing cycles of the antagonist.

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

In another aspect, the invention provides a method of treating a subject or subject population with breast cancer comprising tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and Methods are provided comprising administering to a subject or population of subjects a dosing regimen comprising one or more dosing cycles of nab-paclitaxel at a dose of about 100 mg/m ² between on/one week off.

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

In another aspect, the invention provides a method of treating a subject with eTNBC comprising tiragolumab at a dose of about 420 mg every two weeks, atezolizumab at a dose of about 840 mg every two weeks, and (a)(i) nab-paclitaxel at a dose of about 125 mg/ ^m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks for the first 12 weeks of the dosing regimen, (ii) a dosing regimen doxorubicin at a dose of about 60 mg/ ^m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/ ^m2 every 2 weeks, and G-CSF or GM-CSF; or (b) (i) nab-paclitaxel at a dose of about 125 mg/m ² weekly for the first 12 weeks of the dosing regimen; (ii) every 2 weeks for weeks 13 through 19 of the dosing regimen. administering to the subject a doxorubicin at a dose of about 60 mg/m every ^two weeks, cyclophosphamide at a dose of about 600 mg/ ^m every two weeks, and G-CSF or GM-CSF every two weeks. wherein the method further comprises surgery between 2 weeks and 6 weeks after the last administration of the dosing regimen.

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

In another aspect, the invention provides a method of selecting a therapy for a subject or subject population with SCCHN, comprising: (a) by an IHC assay using an anti-PD-L1 antibody suitable for staining; , detecting a protein expression level of PD-L1 in a tumor sample from a subject or population of subjects; (b) for a subject or population of subjects having a detectable PD-L1 expression level, One or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of between about 500 mg and about 700 mg every 3 weeks on a daily basis. selecting a therapy comprising

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

In another aspect, the invention provides a method of treating a subject or subject population having hepatocellular carcinoma (HCC), wherein the subject or subject population is treated with one or more anti-TIGIT antagonist antibodies and a PD-1 axis binding antagonist. A method is provided comprising administering a dosing cycle, wherein the subject or subject population has not received prior systemic treatment for HCC.

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

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

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

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

In another aspect, the invention provides a method for treating a subject or subject population having MIBC, wherein the subject or subject population is administered tiragolumab at a dose of about 600 mg every three weeks and One or more subjects are cisplatin ineligible, including administering one or more dosing cycles of atezolizumab at a dose of about 1200 mg.

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

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

In another aspect, the invention provides a method for treating a subject or subject population having mUC, wherein the subject or subject population is administered tiragolumab at a dose of about 600 mg every three weeks and administering one or more dosing cycles of atezolizumab at a dose of about 1200 mg.

In another aspect, the invention provides a method for treating a subject or population of subjects with mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen (a) the first dosing regimen comprises tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and (b) the second dosing regimen is (i) enfortumab vedotin at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off or (ii) suctuzumab govitecan administered at a dose of 10 mg/kg weekly for 2 weeks on/1 week off, the second dosing regimen being the first dosing regimen It is administered to a subject or subject population during which the subject or subject population experiences disease progression or unacceptable toxicity.

In another aspect, the invention provides a method of treating a subject or subject population having pancreatic cancer, wherein the subject or subject population is administered about 420 mg on days 1 and 15 of each 28-day dosing cycle. atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle; gemcitabine at a dose of about 1000 mg/ ^m2 on days 1, 8 and 15 of each 28-day dosing cycle; and administering a dosing regimen comprising one or more 28-day dosing cycles of nab-paclitaxel at a dose of about 125 mg/m ² on days 1, 8 and 15 of each 28-day dosing cycle.

In another aspect, the invention provides a method for treating a subject or subject population with advanced or metastatic esophageal cancer, wherein the method comprises between about 500 mg and about 700 mg on day 1 of each dosing cycle. and one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle. Including administering to a population.

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

In another aspect, the invention provides a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein the method comprises administering to the subject or population of subjects about Tiragolumab at a dose of 600 mg, Atezolizumab at a dose of approximately 1200 mg on Day 1 of each dosing cycle, Cisplatin at ^a dose of approximately 80 mg/m2 on Day 1 of each dosing cycle, and Days 1-5 of each 21-day cycle. administering a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of 800 mg/m ² /24 hours on day 6 and omitting cisplatin from the dosing regimen after 6 doses.

In another aspect, the invention provides a method for treating a subject or subject population with advanced or metastatic esophageal cancer, the method comprising administering to the subject or subject population a first dosing regimen and a second (a) the first dosing regimen comprises cisplatin at a dose of about 80 mg/ ^m2 on day 1 of each dosing cycle and cisplatin on days 1-5 of each 21-day cycle; (b) a second dosing regimen comprising one or more 21-day dosing cycles with 5-fluorouracil at a dose of 800 mg/m ² /24 hrs and cisplatin omitted from the dosing regimen after 6 doses; One or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of the cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle.

In another aspect, the invention provides kits comprising PD-1 axis binding antagonists and/or anti-TIGIT antagonist antibodies for treating a subject with 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 with cancer according to the methods provided herein. do.

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 with cancer according to the methods provided herein. do.

In another aspect, the invention provides an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with cancer, the method provided herein It is due to the method used.

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

FIG. 1 is a flow chart showing a Phase Ib chemotherapy expansion and a Phase Ib Q4W dosing expansion. FIG. 2 is a flow chart of the Phase Ib Trial Schema. EOCG = US East Coast Cancer Clinical Trials Group; IHC = immunohistochemistry; PD-L1+ = programmed death ligand 1 positive; Q4W = every 4 weeks; RECIST v1.1 = response criteria in solid tumors, version 1.1; = treatment-free period; 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 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 yeah. Figure 4 is a flow chart of the Phase Ib tiragolumab and atezolizumab expansion cohort, serial biopsy cohort, and Q4W dosing expansion cohort study designs. CIT = cancer immunotherapy; DLT = dose limiting toxicity; HNSCC = head and neck squamous cell carcinoma, IV = intravenous, MAD = maximum 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 immunoreceptor with Ig and ITIM domains. Note: Restricted to patients with PD-L1-selected tumors and/or TIGIT-selected tumors. ^a Progressive incurable refractory solid tumor Tiragolumab IV and atezolizumab 1200 mg IV every 3 weeks. Enrollment only after IMC review of safety data from Phase Ia. 3+3 dose escalations with a 21 day DLT window. Other intermediate doses of tiragolumab may be tested if the MTD is not exceeded. To obtain additional safety, PK and PD data, patients may be enrolled in backfill if they consent to any serial biopsies. Evaluation of dose levels above 1200 mg tiragolumab would require modification of the protocol with a supporting rationale. ^bExpansion may begin at dose < MTD or MAD. ^c Up to about half of the patients in each cohort consent to voluntary serial biopsies. Patients with tumors for which anti-PD-L1/PD-1 agents have been approved by local regulatory authorities (e.g., NSCLC melanoma, renal cell carcinoma) are eligible for clinical trials of investigational agents in combination with anti-PD-L1 Enrollment in expansion cohorts (indication-specific or serial biopsies) can only occur if considered a viable treatment option. ^dRestricted to patients consenting to any serial biopsy (acceptable specimens include core needle, excision, incision, punch and/or foreceptor biopsy). ^e In the Q4W dose expansion cohort, approximately 3 patients will complete safety run-in. All relevant safety data from the safety run-in will be reviewed thoroughly by the IMC and investigators before enrollment continues. Figure 5 is a flow chart of the Phase Ib chemotherapy expansion cohort study design. Figure 6 is a flow chart of the Phase Ib non-chemotherapy expansion cohort study design. FIG. 7 is a flow chart showing the conditions for continuing trial treatment beyond progress. ECOG = US East Coast Cancer Clinical Trials Group; RECIST = Response Evaluation Criteria in Solid Tumors. FIG. 8 is a flow chart showing the crossover from phase Ia to phase Ib. AE = adverse event, DLT = dose limiting toxicity, PD = disease progression. Figure 9 is a graph showing the pharmacokinetics of tiragolumab. Figure 10 is a series of graphs showing the pharmacodynamics of tiragolumab. Figure 11 is a graph showing all adverse events of 10% or greater in the Phase Ia tiragolumab dose escalation study. *Grade 5 AEs were malignant neoplastic progression (n=3) and were not related to tiragolumab. Figure 12 is a graph showing all adverse events of 10% or greater in the Phase Ib tiragolumab and atezolizumab dose escalation study. *Grade 5 AEs were malignant neoplastic progression (n=12) and pulmonary embolism (n=2) and were not related to study drug. Figure 13 is a graph showing tumor size reduction in a Phase Ia tiragolumab dose escalation study. Figure 14 is a graph showing tumor size reduction in a Phase Ib tiragolumab and atezolizumab dose escalation study. FIG. 15 is a graph showing CIT-naive PD-L1-positive NSCLC tumor size reduction in a Phase Ib tiragolumab and atezolizumab dose escalation study. Figure 16 is a graph showing CIT naive PD-L1 positive NSCLC tumor size reduction over time in a Phase Ib tiragolumab and atezolizumab dose escalation study. Figure 17 is a flow chart of the Phase III trial schema. 1L = First Line; CE = Carboplatin and Etoposide; ECOG PS = US East Coast Cancer Clinical Trial Group Performance Status; ES-SCLC = Advanced Small Cell Lung Cancer; LDH = Lactase Dehydrogenase; RECIST = Response Evaluation Criteria in Solid Tumors; ITT = intent to treat; PP = primary population. Figure 18 is a schematic representation of the study design showing parameters for subject selection, stratification criteria, randomization into treatment groups and treatment endpoints. Figure 19 is a schematic showing the design of the GO42501 Phase II clinical trial. Resectable with no activating EGFR mutation (EGFR-), no ALK fusion oncogene (ALK-), and East Coast Cancer Trials Group (ECOG) performance status of 0 or 1 Patients with stage II, IIIA or select IIIB (T3N2) non-small cell lung cancer (NSCLC) are selected. Cohort A consists of PD-L1 high patients. Patients in Cohort A will be treated with atezolizumab (Atezo) and tiragolumab (Tira) every 3 weeks (Q3W) for 4 cycles. Cohort B consists of patients with any PD-L1 status. Patients in Cohort B are treated with Atezo, Tira and a platinum-based doublet chemotherapy (Chemo) Q3W for 4 cycles. Chest computed tomography (CT) is performed after the second and fourth cycles. Patients in both cohorts will undergo surgery to assess major pathologic response (MPR) and pathologic complete response (pCR). After surgery, patients in Cohort A are treated with 16 cycles of Atezo and Tira Q3W or 4 cycles of Chemo Q3W. Patients in Cohort B are treated with Atezo and Tira Q3W for 16 cycles. Postoperative radiotherapy (PORT) is optional for R1/R2 resection and/or ypN2 before adjuvant administration. Perform survival follow-up. Figure 20 is a flow chart showing patient enrollment in the GO42501 Phase II clinical trial. For Cohort A (PD-L1 high patients; PD-L1 Tumor Proportion Score (TPS) ≧50%), 6 patients will be used to perform a safety lead-in. Enrollment in Cohort A will be suspended if surgical safety criteria are not met. Enrollment in Cohort A will continue if surgical safety criteria are met. For Cohort B (patients with any PD-L1 status), 6 patients with PD-L1 TPS <50% will be used to perform a safety lead-in. Enrollment of Cohort B will be suspended if surgical safety criteria are not met. If surgical safety criteria are met, continue to enroll Cohort B, enrolling patients with PD-L1 TPS<50% and PD-L1 TPS≧50%. After 8 patients with tumors expressing PD-L1 ≧50% have been enrolled in Cohort B, patients with PD-L1 TPS ≧50% will continue to be enrolled in Cohort A. FIG. 21 is a flow chart of the Phase II trial schema. 1L = first choice; CDx = companion diagnostic; ECOG PS = US East Coast Cancer Clinical Trials Group Performance Status; IHC = immunohistochemistry; IRC = independent review committee; Weekly; R = randomization; s/p = post status; IV = intravenous. FIG. 22 is a flow chart of the Phase Ib trial schema. TNBC = triple-negative breast cancer; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; Rand. = randomized, pCR = pathologic complete response, QW = weekly, Q2W = every 2 weeks, Q3W = every 3 weeks. FIG. 23 is a flow chart of the Phase II trial schema. HPV = human papillomavirus; IHC = immunohistochemistry; IV = intravenous; Q3W = every 3 weeks; PD-L1 low = TIC 10%-49%; PD-L1 high = TIC ≥ 50%; RECIST=response evaluation criteria in solid tumors. Figure 24 is a schematic showing the design of the muscle-invasive bladder cancer (MIBC) cohort of the WO39613 Phase Ib/II clinical trial. At the screening stage, patients with MIBC who are cisplatin ineligible and are either PD-L1 positive (+) (top) or PD-L1 negative (−) (bottom) are identified. After randomization (R), patients are treated with atezolizumab (atezo; control) or atezolizumab and tiragolumab (Tira). Figure 25 is a schematic showing the design of the metastatic urothelial carcinoma (mUC) cohort of the WO39613 Phase Ib/II clinical trial. In the screening phase, patients with second-line locally advanced or metastatic UC who have progressed on or after platinum-containing therapy and who are cancer immunotherapy (CIT) naive are identified. After randomization (R), patients will receive atezolizumab (Atezo; control) atezolizumab and enfortumab vedotin (EV); atezolizumab and niraparib (Nira); atezolizumab and Hu5F9-G4; atezolizumab and suctuzumab govitecan (SG); atezolizumab and tocilizumab (TCZ); atezolizumab and RO 7122290 (FAP-4-1 BBL); or RO7121661 (PD 1/TIM-3). ^aPatients who have experienced loss of clinical benefit or unacceptable toxicity as determined by the investigator during Stage 1 are eligible to receive different treatment combinations during Stage 2 if they meet the eligibility criteria. can be. ^b The Atezo+Nira group has 40 patients. ^c Patients who received enfortumab vedotin in stage 1 did not receive enfortumab vedotin in stage 2, and patients who received suctuzumab govitecan in stage 1 received suctuzumab in stage 2 Other patients who do not receive govitecan; who are eligible for more than one treatment arm will be assigned to treatment arms by the investigator. When the Atezo+SG arm opens, registration to the Atezo+EV arm is closed. ^d The Atezo+RO7122290 (FAP-4-1 BBL) arm has been established only in countries outside the US. FIG. 26 shows low or high PD-L1 TPS as assessed by the pharmDx 22C3 assay (high TPS≧50%; low TPS 1-49%) or CE-IVD VENTANA SP263 IHC assay (high TC≧50%; low Objective response rate (ORR) (complete response/partial response (CR/PR)) in patients from the CITYSCAPE trial with low or high PD-L1 tumor content (TC) as assessed by TC 1-49%) stable disease/progressive disease (SD/PD); not evaluable (NE)). FIG. 27A is a bar graph showing the response rate (95% confidence interval (CI)) for patients from the CITYSCAPE trial with TPS≧1% as measured using the 22C3 IHC assay. Figure 27B shows the response rate (95 Bar graph showing % CI). Figure 28A shows progression-free survival (percentage) of patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira + atezo) or placebo + atezo and had TPS > 1% as measured using the 22C3 IHC assay. graph. The inset table shows median PFS in months (mo) and hazard ratio (HR). Figure 28B shows treatment with tiragolumab and atezolizumab (tira + atezo) or placebo + atezo, TC > 1% as measured using the SP263 IHC assay (and TPS > 1% as measured using the 22C3 IHC assay). Figure 10 is a graph showing progression-free survival (percentage) of patients from the CITYSCAPE trial with Inset shows median PFS in months and HR. FIG. 29A is a bar graph showing the response rate (95% confidence interval (CI)) for patients from the CITYSCAPE trial with TPS≧50% as measured using the 22C3 IHC assay. FIG. 29B is a bar graph showing the response rate (95% CI) for patients from the CITYSCAPE trial with TC≧50% as measured using the SP263 IHC assay. FIG. 30A shows progression-free survival (percentage) of patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira+atezo) or placebo+atezo and had TPS≧50% as measured using the 22C3 IHC assay. graph. Inset shows median PFS in months and HR. FIG. 30B shows progression-free survival (percentage) of patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira+atezo) or placebo+atezo and had a TC≧50% as measured using the SP263 IHC assay. graph. Inset shows median PFS in months and HR.

Detailed Description of the Invention The present invention is directed to 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 unresectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., , subject has not been previously treated for stage IV NSCLC))): cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent 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); renal cancer or renal cancer (e.g. RCC); melanoma; ovarian cancer; gastric cancer (e.g. gastroesophageal junction cancer); For example, therapeutic methods and compositions for the treatment of MSS or MSI-Low CRC) are provided. The present invention provides that immunotherapy comprising anti-TIGIT antibodies (e.g. anti-TIGIT antagonist antibodies such as tiragolumab) in combination with PD-1 axis binding antagonists, VEGF antagonists and/or chemotherapeutic agents are useful for treating cancer. Based at least in part on the discovery of obtaining Compositions, uses and kits comprising such combinations and/or dosing regimens are also provided herein.

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

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

As used herein, the term "about" refers to the normal error range for the respective value, readily understood by those skilled in the art. As used herein, reference to "about" a value or parameter includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X."

The terms "level of expression" or "expression level" are generally used interchangeably and generally refer to the amount of a biomarker in a biological sample. "Expression" generally refers to the process by which information (eg, genetic code and/or epigenetic information) is converted into structures present and functional in a cell. Thus, as used herein, "expression" refers to transcription into a polynucleotide, translation into a polypeptide, or further polynucleotide and/or polypeptide modification (e.g., post-translational modification of a polypeptide). may point. Transcribed polynucleotides, translated polypeptides, or fragments of polynucleotide and/or polypeptide modifications (e.g., post-translational modifications of polypeptides) may also be transcripts they are produced by alternative splicing or degraded Expressed is to be considered whether derived from transcript or from post-translational processing of the polypeptide, eg, by proteolysis. "Expressed genes" include those that are transcribed as mRNA into polynucleotides that are subsequently translated into polypeptides, and those that are also transcribed into RNA but not translated into polypeptides (e.g., transposed and ribosomal RNA). include. The "amount" or "level" (eg, expression level) of a biomarker can be measured by methods known to those of skill in the art and are also disclosed herein. An "amount" or "level" of a biomarker associated with increased clinical benefit to an individual can be, for example, a detectable level in a biological sample. In some aspects, the biomarker expression level or amount is used to determine a particular treatment (e.g., a treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody, or an anti-TIGIT antagonist Subjects with cancer who are likely to respond to or benefit from a treatment comprising one or more dosing cycles of an antibody) can be identified/characterized.

"Increased expression", "increased expression level", "increased level", "elevated expression", "elevated expression level" or "elevated level" refers to a disease or disorder (e.g., cancer) Refers to an increase in the expression of a biomarker or an increase in its level in an individual compared to one or more individuals who are not afflicted with HIV or a control, such as an internal control (eg, a housekeeping biomarker).

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

The presence and/or expression level/amount of various biomarkers described herein in a sample can be analyzed by several methodologies, many of which are known in the art and understood by those of ordinary skill in the art. Cages, Immunohistochemistry (“IHC”), Western Blot Analysis, Immunoprecipitation, Molecular Binding Assays, ELISA, ELISA, Flow Cytometry, Fluorescence Activated Cell Sorting (“FACS”), MassARRAY, Proteomics, Quantitative Blood-Based Assays (e.g. serum ELISA), biochemical enzymatic activity assays, in situ hybridization (ISH), fluorescence in situ hybridization (FISH), Southern analysis, Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g. generational sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real-time PCR (qRT-PCR) and other amplification-type detection methods such as branched-DNA, SISBA, TMA, RNA- Seq, microarray analysis, gene expression profiling, and/or serial gene expression analysis (“SAGE”), and any one of a wide variety of assays that can be performed by protein, gene, and/or tissue array analysis. but not limited to these. Exemplary protocols for assessing gene and gene product status are described, for example, in Ausubel et al. , eds. , 1995, Current Protocols In Molecular Biology, Part 2 (Northern blotting), Part 4 (Southern blotting), Part 15 (Immunoblotting), and Part 18 (PCR analysis). Multiplexed immunoassays, such as those available from Rules Based Medicine or Meso Scale Discovery (“MSD”), may also be used.

"Correlate" or "correlating" means comparing the performance and/or results of a first analysis or protocol to the performance and/or results of a second analysis 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 the first analysis or protocol are used to perform the second analysis or protocol. may decide whether to With respect to aspects of the polypeptide analysis or protocol, the results of the polypeptide expression analysis or protocol can be used to determine whether a particular therapeutic regimen should be administered. With respect to the polynucleotide analysis or protocol aspect, the results of the polynucleotide expression analysis or protocol can be used to determine whether a particular therapeutic regimen should be administered.

The terms "substantially reduced" or "substantially different" as used herein refer to two numerical values (generally one associated with a molecule and the other a reference/comparison molecule). ), such that the difference between these two values is measured by such values (e.g., K _D values) to those skilled in the art. With respect to biological characteristics, it will be considered statistically significant. The difference between two such values is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or about 50% as a function of the value of the reference/comparison molecule. Super.

The terms "substantially similar" or "substantially the same" as used herein refer to two numerical values, generally one associated with the molecule and the other with the reference/comparison molecule. ), such that the difference between these two values is determined by such values (e.g., K _D values). With respect to scientific characteristics, one would assume little or no biological and/or statistical significance. The difference between two such values is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and/or about 10% as a function of the reference/comparison value. is.

The phrase "based on," as used herein, means that information about one or more biomarkers is used to inform treatment decisions, information provided in package inserts, marketing/promotional guidance, or the like. meant to be used.

As used herein, "TIGIT" or "T-cell immunoreceptor with Ig and ITIM domains" refers to primates (e.g., humans) and Refers to any naturally occurring TIGIT from any vertebrate source, including mammals such as rodents (eg, 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 includes "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 results from processing in a cell (e.g., SEQ ID NO:31). processed human TIGIT with the amino acid sequence but without the signal sequence). The term also includes naturally occurring variants of TIGIT, eg, splice variants, or allelic variants. An exemplary human TIGIT amino acid sequence can be found, for example, at UniProt Accession No. Q495A1.

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

The terms "PD-1" or "programmed cell death protein 1" are used herein, unless otherwise indicated, for mammals, such as primates (eg humans) and rodents (eg mice and rats). ), any native PD-1 from any vertebrate source. PD-1 is also known in the art as CD279, PDCD1, and programmed cell death-1. The term also includes naturally occurring variants of PD-1, such as splice or allelic variants. An exemplary human PD-1 acid sequence can be found, for example, at UniProt Accession No. Q15116.

The terms "PD-L2" or "programmed cell death 1 ligand 2" are used herein, unless otherwise indicated, in mammals such as primates (eg humans) and rodents (eg mice and It refers to any native PD-L2 from any vertebrate source, including rat). PD-L2 is also known in the art as the CD273 molecule, B7DC, and PDCD1L2. The term also includes naturally occurring variants of PD-L2, such as splice or allelic variants. An exemplary human PD-L2 acid sequence can be found, for example, at UniProt Accession No. Q9BQ51.

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

The term "PD-1 axis binding antagonist" refers to a PD-1 axis binding partner and any one of its binding partners so as to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis. Refers to a molecule that inhibits interaction with one or more and, as a result, restores or enhances T cell function (eg, 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 examples, the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist or PD-1 binding antagonist In some embodiments, 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 blockade that reduces signaling due to interaction of PD-1 with one or more of its binding partners, e.g. Refers to a molecule that acts, inhibits, abrogates, or interferes. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some examples, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain aspects, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and interactions between PD-1 and PD-L1 and/or PD-L2. Including other molecules that reduce, block, inhibit, abrogate, or interfere with signaling to. In one example, a PD-1 binding antagonist can bind T lymphocytes through PD-1-mediated signaling so as to render dysfunctional T cells non-dysfunctional (eg, enhance effector responses to antigen recognition). Reduce negative co-stimulatory signals mediated by or through cell surface proteins expressed on spheres. In some examples, the PD-1 binding antagonist binds to PD-1. In some examples, the PD-1 binding antagonist is an anti-PD-1 antibody (eg, an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680 (AMP 514), PDR001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalizumab, dostarimab, retifanlimab, sasanlimab, penplimab, CS1003, HLX10, SCT-I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG 404, CX-188, J4SyTX-401, J4TX-401 , LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 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 (pembrolizumab, formerly known as lambrolizumab). In another specific aspect, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as 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 (spartalizumab). In another specific aspect, the PD-1 binding antagonist is REGN2810 (semiplimab). In another specific aspect, the PD-1 binding antagonist is BGB-108. In another specific aspect, the PD-1 binding antagonist is progolimab. In another specific aspect, the PD-1 binding antagonist is canrelizumab. In another specific aspect, the PD-1 binding antagonist is Scintilimab. In another specific aspect, the PD-1 binding antagonist is ciserelizumab. In another specific aspect, the PD-1 binding antagonist is tripalimab. 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 antibody capable of binding PD-1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-1. Refers to a fragment or variant. For example, an anti-PD-1 antagonist antibody may reduce, block, inhibit, can deter or interfere; It will be appreciated by those skilled in the art that, in some instances, an anti-PD-1 antagonist antibody may antagonize one PD-1 activity without affecting another PD-1 activity. For example, an anti-PD-1 antagonist antibody for use in certain methods or uses described herein may have no effect or minimal effect on any other PD-1 interactions. Without limitation, anti-PD-1 antagonist antibodies that antagonize PD-1 activity in response to one of its binding partners (eg, PD-L1 or PD-L2). In one aspect, the extent of binding of the anti-PD-1 antagonist antibody to unrelated non-PD-1 protein is less than about 10% of the binding of the antibody to PD-1, eg, as measured by radioimmunoassay (RIA). is. In certain aspects, the PD-1 binding to the anti-PD-1 antagonist antibody is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM or ≤0.001 nM (e.g., ^10- It has a dissociation constant (K _D ) of ⁸ M or less, such as from 10 ⁻⁸ M to 10 ⁻¹³ M, such as from 10 ⁻⁹ M to 10− ⁻¹³ M). In certain aspects, the anti-PD-1 antagonist antibody binds to an epitope on PD-1 that is conserved among PD-1 from different species or to an epitope on PD-1 that allows for cross-species reactivity. do. In one aspect, the anti-PD-1 antagonist antibody is pembrolizumab (previously known as lambrolizumab). In one aspect, the anti-PD-1 antagonist antibody is nivolumab.

The term "PD-L1 binding antagonist" reduces signaling due to the interaction of PD-L1 with any one or more of its binding partners, e.g. PD-1 and/or B7-1 , refers to a molecule that blocks, inhibits, abolishes, or interferes. In some examples, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In some examples, the PD-L1 binding antagonist is one or more of an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and PD-L1 and its binding partner, such as , PD-1 and/or other molecules that reduce, block, inhibit, abrogate or interfere with signaling due to interaction with B7-1. In one example, a PD-L1 binding antagonist can bind T lymphocytes through PD-L1-mediated signaling so as to render dysfunctional T cells non-dysfunctional (eg, enhance effector responses to antigen recognition). Reduce negative co-stimulatory signals mediated by or through cell surface proteins expressed on the sphere. In some examples, the PD-L1 binding antagonist binds to PD-L1. In some examples, the PD-L1 binding antagonist is an anti-PD-L1 antibody (eg, an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC- 001, KL-A167, APL-502, cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 and HS-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one particular aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (semiplimab). In other aspects, the PD-L1 binding antagonist can be a small molecule such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, and in some instances can be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab, marketed as TECENTRIQ™. Atezolizumab is listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4 (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 antibody capable of binding PD-L1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-1L. Refers to a fragment or variant. For example, an anti-PD-L1 antagonist antibody may reduce, block, inhibit, can deter or interfere; It will be appreciated by those skilled in the art that, in some instances, an anti-PD-L1 antagonist antibody may antagonize one PD-L1 activity without affecting another PD-L1 activity. For example, anti-PD-L1 antagonist antibodies for use in certain methods or uses described herein do not affect, or minimally affect, any other PD-L1 interactions. Without limitation, anti-PD-L1 antagonist antibodies that antagonize PD-L1 activity in response to one of its binding partners (eg, PD-1 or B7-1). In one aspect, the extent of binding of the anti-PD-L1 antagonist antibody to unrelated non-PD-L1 protein is less than about 10% of the binding of the antibody to PD-L1, eg, as measured by radioimmunoassay (RIA). is. In certain aspects, the PD-L1 that binds to the anti-PD-L1 antagonist antibody is ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (eg, 10 ⁻ It has a dissociation constant (K _D ) of ⁸ M or less, such as from 10 ⁻⁸ M to 10 ⁻¹³ M, such as from 10 ⁻⁹ M to 10− ⁻¹³ M). In certain aspects, the anti-PD-L1 antagonist antibody binds to an epitope on PD-L1 that is conserved among PD-L1 from different species or to an epitope on PD-L1 that allows for cross-species reactivity. do. In one aspect, the anti-PD-L1 antagonist antibody is atezolizumab.

The term "PD-L2 binding antagonist" reduces, blocks or inhibits signaling resulting from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. It refers to molecules that interact with or interfere with PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2," "PDCD1LG2," "CD273," "B7-DC," "Btdc," and "PDL2." be done. Exemplary human PD-L2 is available at UniProtKB/Swiss-Prot Accession No. It is shown in Q9BQ51. In some examples, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In one specific aspect, the PD-L2 binding antagonist inhibits 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 any one or more of PD-L2 and its binding partners such as PD-1. Other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction due to interaction with are included. In one embodiment, the PD-L2 binding antagonists signal through PD-L2 to render dysfunctional T cells less dysfunctional (e.g., to enhance effector responses to antigen recognition). reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that mediate In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, the PD-L2 binding antagonist is an immunoadhesin.

Further examples of PD-1 axis binding antagonists include semiplimab, prorgolimab, camrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, spartalizumab, southernlimab, penplimab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001 , embafolimab, TQB2450, ZKAB001, LP-002, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, CX-072, IMC-001, KL-A167, budicarimab, AMG 404, CX-18 JTX-4014, 609A, Sym021, LZM009, F520, SG001, APL-502, cosibelimab, rhodapolimab, GS-4224, INCB086550, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004, AM0001, CB201, ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21, AVA-004, PDL- GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL-007, ABSK041, GB7003, JS-003, and HS-636.

For purposes herein, "atezolizumab" is an Fc engineered humanized non-glycosylated IgG1 kappa immunoglobulin that binds PD-L1 and comprises the heavy chain sequence of SEQ ID NO:28 and the light chain sequence of SEQ ID NO:29. Atezolizumab contains a single amino acid substitution (asparagine to alanine) at position 297 of the heavy chain (N297A) using EU numbering of Fc region amino acid residues and is non-glycosylated with minimal binding to Fc receptors. produce antibodies. Atezolizumab is listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4 (see page 485).

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

As used herein, "tiragolumab" is a fully human IgG1 derived from Open Monoclonal Technology (OMT) rats that binds to TIGIT and comprises the heavy chain sequence of SEQ ID NO:33 and the light chain sequence of SEQ ID NO:34. /kappa MAb. Tiragolumab contains two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31, No. 2 (see page 343).

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

The term "anti-TIGIT antagonist antibody" refers to an antibody, or antigen-binding fragment or variant thereof, capable of binding TIGIT with sufficient affinity to substantially or completely inhibit the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody may mediate PVR, PVRL2, and/or PVRL3 to restore functional responses to antigen stimulation from dysfunctional states (e.g., proliferation, cytokine production, target cell killing) by T cells. can block signal transduction. For example, an anti-TIGIT antagonist antibody can block signaling through PVR without affecting the PVR-CD226 interaction. It will be appreciated by those skilled in the art that in some instances, an anti-TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain methods or uses described herein will, for example, not affect, or minimally affect, any other TIGIT interactions, An anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of a PVR interaction, a PVRL3 interaction or a PVRL2 interaction. In one aspect, the extent of binding of the anti-TIGIT antagonist antibody to an unrelated non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT, eg, as measured by radioimmunoassay (RIA). In certain aspects, the TIGIT that binds to the anti-TIGIT antagonist antibody is ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 ⁻⁸ M or less, It has a dissociation constant (K _D ) of eg 10 ⁻⁸ M to 10 ⁻¹³ M, eg 10 ⁻⁹ M to 10− ⁻¹³ M). In certain aspects, the anti-TIGIT antagonist antibody binds to an epitope on TIGIT that is conserved among TIGIT from different species or to an epitope on TIGIT that allows for cross-species reactivity. In some aspects, the anti-TIGIT binding antibody has intact Fc-mediated effector functions (eg, tiragolumab, vivostolimab, etiglimab, EOS084448 or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc-mediated effector function (eg, SGN-TGT). In other aspects, the anti-TIGIT binding antibody lacks Fc-mediated effector functions (eg, domvanalimab, BMS-986207, ASP 8374, or COM902). In some aspects, the anti-TIGIT binding antibody is an IgG 1 class antibody (e.g., tiragolumab, vivostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308). In some aspects, the anti-TIGIT antagonist antibody is an IgG4 class antibody (eg, ASP8374 or COM902). In one aspect, the anti-TIGIT antagonist antibody is tiragolumab.

As used herein, "administering" refers to a compound (e.g., anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody), VEGF antagonist or chemotherapeutic agent (e.g., platinum chemotherapeutic agents (e.g. carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g. alkylating agents (e.g. cyclophosphamide), taxanes (e.g. paclitaxel, e.g. nab-paclitaxel) and /or a topoisomerase II inhibitor (e.g., doxorubicin))), or a pharmaceutical composition comprising a composition (e.g., a pharmaceutical composition, e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody) chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclophosphamide), taxanes ( paclitaxel, eg nab-paclitaxel) and/or topoisomerase II inhibitors (eg doxorubicin)), antibody-drug conjugates (ADC) (eg enfortumab vedotin or sacituzumab govitecan) and/or colonies A method of providing a dose of a stimulating factor (CSF) (e.g., pegfilgrastim, filgrastim, or sargramostim) to a subject Compounds and/or compositions used in the methods described herein is, for example, intravenous (e.g. by intravenous infusion), subcutaneous, intramuscular, intradermal, percutaneous, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, intraprostatic, intrapleural, intratracheal , intranasal, intravitreal, intravaginal, intrarectal, topically, intratumoral, intraperitoneal, subconjunctival, intravesicular, transmucosal, intrapericardial, intraumbilical, intraocular, oral, topical ( Administration can be topically, locally, inhalation, injection, infusion, continuous infusion, local perfusion that flows directly into the target cells, catheters, lavages, creams, or lipid compositions. may vary depending on various factors such as the compound or composition administered and the severity of the condition, disease or disorder being treated.

therapeutic agent (e.g., anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody), VEGF antagonist, chemotherapeutic agent (e.g., platinum-based or non-platinum-based chemotherapeutic agent), ADC (e.g., enfortuzumab vedotin or sacituzumab govitecan) or CSF (e.g., pegfilgrastim, filgrastim, or sargramostim). It refers to the dose administered to a patient regardless of surface area (BSA). Thus, a fixed or flat dose is provided as an absolute amount of therapeutic agent (eg, absolute amount (mg) of therapeutic agent) rather than as a mg/kg or mg/m ² dose.

As used herein, the term "treatment" or "treating" is designed to alter the natural course of the individual or cells being treated during the course of a clinical pathology. Refers to clinical interventions that have been Desirable effects of treatment include slowing or reducing the rate of disease progression, ameliorating or alleviating the disease state, and ameliorating or improving prognosis. For example, an individual may reduce the growth of (or destroy) cancerous cells, reduce the symptoms resulting from the disease, improve the quality of life of those with the disease, reduce the dose of other pharmaceutical agents needed to treat the disease. "Treatment" is successful if one or more symptoms associated with cancer are reduced or eliminated, including, but not limited to, reduction, slowing disease progression, and/or prolonging survival of the individual. It will be. For example, treatment may include 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., enfortuzumab vedotin or sacituzumab govitecan) and/or CSF (e.g., pegfilgrastim, filgrastim, or sargramostim)) or effective cancer treatment with a combination of therapeutic agents. Treatment herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (eg, locally advanced cancer therapy) and metastatic cancer therapy. Treatment may be first-line treatment (eg, the patient may have been previously untreated or has not received prior systemic therapy) or second-line treatment or subsequent treatment.

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

Drugs that are administered "concurrently" with one or more other drugs are administered during the same treatment cycle, on the same treatment days as the one or more other drugs, and optionally at the same time as the one or more other drugs. administered to For example, for cancer therapy given every 3 weeks, each co-administered drug is administered on day 1 of the 3-week cycle.

As used herein, the term "perioperative treatment" refers to treatment administered before or after surgery. Perioperative treatment may include the administration of pre-operative neoadjuvant therapy (eg, cystectomy) and post-operative therapy (eg, adjuvant therapy). For example, for perioperative treatment, post-diagnosis and prior to surgery (e.g., cystectomy) (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15) a week or more before) and after surgery (e.g., about 1, 2, 3, 4, 1, 2, 3, 4, 4, 5, 6, 7, 9, 10 or 12 after surgery). 5, 6, 7, 8, 9, 12, 13, 14, 15 weeks or more) treatment (eg, adjuvant therapy, such as anti-TIGIT antagonist antibody and PD-1 axis binding antagonist adjuvant therapy).

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

The term "dysfunction" with respect to immune dysfunction refers to a state of reduced immune responsiveness to antigenic stimulation.

As used herein, the term "dysfunctional" also includes refractory or unresponsiveness to antigen recognition, in particular antigen recognition to downstream T cell effector functions such as proliferation, cytokine production (e.g. gamma interferon) ), and/or impaired ability to convert to target cell killing.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. Cancer includes solid and non-solid tumor cancers and locally advanced or metastatic cancers (eg, locally advanced or metastatic tumors). Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, locally advanced and metastatic UC (mUC), bladder cancer (e.g., muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer). urothelial carcinoma (UC), including carcinoma (NMIBC), e.g. BCG refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney cancer or kidney cancer (e.g. renal cell carcinoma (RCC) ); urinary tract cancer; lung cancer such as small cell lung cancer (SCLC) (including extensive-stage SCLC (ES-SCLC)); non-small cell lung cancer (NSCLC) (locally advanced unresectable NSCLC (eg, IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (e.g., squamous cell carcinoma (e.g., squamous cell carcinoma of the lung)); pancreatic cancer ( e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC); head and neck cancers (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN, head and neck squamous cell carcinoma (HNSCC); cancer (OC); esophageal cancer; peritoneal cancer; hepatocellular carcinoma; Glioblastoma; urinary tract cancer; hepatoma; and HER2 (HER2-) negative); prostate cancer such as castration-resistant prostate cancer (CRPC), peritoneal cancer, hepatocellular carcinoma, gastric cancer or gastric cancer (including gastrointestinal cancer and gastrointestinal stromal cancer) pancreatic cancer (e.g. pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer (e.g. stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 positive cervical cancer); ovarian cancer; liver cancer (e.g. hepatocellular carcinoma (HCC), e.g. locally advanced or metastatic HCC and/or unresectable HCC); hepatoma; colon Cancer; rectal cancer; colorectal cancer (CRC; e.g., CRC with microsatellite stable (MSS) and microsatellite instability (MSI) low (MSI-Low); intrauterine or uterine carcinoma; salivary gland carcinoma) ;prostate cancer; vulvar cancer; thyroid cancer; liver carcinoma; anal carcinoma; penile carcinoma; multiple myeloma and B-cell lymphoma; Small lymphocytic (SL) NHL; Intermediate-grade/follicular NHL; Intermediate-grade diffuse NHL; High-grade immunoblastic NHL high-grade lymphoblastic NHL; high-grade non-cutting cell NHL; bulky mass disease NHL; mantle cell lymphoma; AIDS-related lymphoma; acute lymphoblastic leukemia (ALL); acute myogenic leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); MDS), as well as nevus, edema (such as those associated with brain tumors), Megs syndrome, brain cancer, head and neck cancer, and associated metastasis-related abnormal vascular proliferation.

As used herein, the term "persistent cervical cancer" refers to cervical cancer that has not become undetectable or benign after previous treatment.

As used herein, “Stage IVB cervical cancer” is defined as such using the cervical cancer staging system (e.g., the International Federation of Gynecology and Obstetrics (FIGO) staging system). Refers to cervical cancer classified as 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 inguinal and extra-abdominal lymph nodes.

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

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

Head and neck cancers include cancers that begin in the mucosal surfaces of the upper aerodigestive tract and affect the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx.

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

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

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

"Tumor immunity" refers to the process by which tumors evade immune recognition and elimination. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion 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" means the spread of cancer from its primary site to other locations in the body. Cancer cells may break away from a primary tumor, penetrate lymphatics and blood vessels, circulate through the bloodstream, and grow (metastasize) in distant foci in normal tissue elsewhere in the body. Metastases can be local or distant. Metastasis is a sequential process that requires tumor cells to break away from the primary tumor, migrate through the bloodstream, and arrest at distant sites. At the new site, the cells establish a blood supply and can grow to form life-threatening masses. Both stimulatory and inhibitory molecular pathways within tumor cells control this behavior, and interactions between tumor cells and host cells at distant sites are also important.

As used herein, the term "cytotoxic agent" refers to any agent that is detrimental to cells (e.g., causes cell death or destruction, inhibits proliferation, or otherwise inhibits cell function). or prevent). Cytotoxic agents include radioactive isotopes (e.g., radioactive isotopes of ^At211 , ^I131 , ^I125 , ^Y90 , ^Re186 , ^Re188 , ^Sm153 , ^Bi212 , ^P32 , ^Pb212 , and Lu); Chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; 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 antitumor agents disclosed below. or anticancer agents, but are not limited to these. Exemplary cytotoxic agents include antimicrotubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogues, signal transduction pathway inhibitors, non-receptive selected from somatic tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and metabolic inhibitors. obtain. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin). In one example, the cytotoxic agent is an EGFR antagonist, such as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (eg, erlotinib). In one example, the cytotoxic agent is a RAF inhibitor, such as a BRAF and/or CRAF inhibitor. In one example, the RAF inhibitor is vemurafenib. In one example, the cytotoxic agent is a PI3K inhibitor.

A "chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents and their derivatives include: Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Disulfiram, Epigaro Catechin Gallate, Salinosporamide A, Carfilzomib, 17-AAG (Geldanamycin), Radicol, Lactate Dehydrogenase A (LDH-A), Fulvestrant (FASLODEX®, AstraZeneca), Sunitinib (SUTENT®) , Pfizer/Sugen), Letrozole (FEMARA®, Novartis), Imatinib Mesylate (GLEEVEC®, Novartis), Finasanate (VATALANIB®, Novartis), Oxaliplatin (® ), Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafamib (SCH66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®), AstraZeneca), AG1478, thiotepa, CYTOXAN® cyclophosphamide; aziridines such as benzodopa, carboquone, metuledopa, uredopa; ethyleneimine and methylamelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamin; camptothecins (including topotecan and irinotecan); bryostatin; callistatin; CC-1065 (including adzelesin, calzelesin, vizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); Steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase, including finasteride and dutasteride); vorinostat, romidepsin, panovy nostat, valproic acid, mosetinostat dolastatin; aldesleukin, talc duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eletharobin; pancratistatin; sarcodictin; spongistatin; , chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, novenvitine, phenesterin, prednimustine, trophosphamide, nitrogen mustards such as uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine , and nitrosoureas such as ranimustine; antibiotics such as enidine antibiotics (eg calichemycins, particularly calichemycin γ1I and calichemycin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemycins, including dynemycin A; bisphosphonates such as clodronate; neocardinostatin chromophore and related chromophores, endiyne antibiotic chromophores, as well as esperamycin), aclacinomycin, actinomycin. , autoramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophylline, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinotoxorubicin, deoxydoxorubicin), epirubicin, ethorubicin, idarubicin, marceromycin, mitomycins such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, pepromycin, porphyromycin , puromycin, keramycin, rhodorubicin, streptozocin, tuberculidine, ubenimex, dinostatin, zorubicin methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; Purine analogues such as 6-mercaptopurine, thiamipurine, thioguanine. pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepithiosteine, testolactone; , anti-adrenals such as trilosteine; folic acid supplements such as floric acid; ace gratone; aldophosphamide glycoside; aminolevulinic acid; eriptine acetate; anepothilone; etogluside; gallium nitrate; hydroxyurea; lentinan; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); lazoxane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobroman; gacytosine; thiotepa; taxanes (taxoids) such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremopho-free), albumin-engineered nanoparticulate formulations of paclitaxel ( For example, nanoparticulate albumin-engineered paclitaxel (nab-paclitaxel) (American Pharmaceutical Partners, Schaumburg, Ill.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine) , 6-thioguanine, mercaptopurine, methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); a retinoid such as retinoic acid; salts, acids, and derivatives that can be

Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen; (including NOLVADEX®; tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxy tamoxifen, trioxyfen, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® ( exemestane; Pfizer), formestani, fadrozole, RIVISOR® (borzole), FEMARA® (letrozole; Novartis), ARIMIDEX® (anastrozole; AstraZeneca), antiandrogens such as (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and gosererelin; buserelin, triprelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-rethioic acid, fenretinide (iv) protein kinase inhibitors (e.g. anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (CH-5424802, also known as alectinib), along with troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Ralf and H-Ras; vii) ribozymes such as VEGF expression inhibitors (e.g. ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines such as ALLOVECTIN®, LEUVECTIN® and VAXID® vaccines such as PROLEUKIN®, rIL-2; topoisomerases such as LURTOTECAN® ABARELIX® 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 contain organic compounds containing platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes referred to as "platin" in the art. Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, tripplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin. A platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) may be combined with one or more additional chemotherapeutic agents, such as a nucleoside analogue (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" means that a subject is eligible for platinum-based chemotherapy, either at the discretion of the attending physician or according to standardized criteria for platinum-based chemotherapy eligibility known in the art. means eligible for treatment by

Chemotherapeutic agents, as used herein, also include "non-platinum-based chemotherapeutic agents," which refer to chemotherapeutic agents that are "non-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, orintricarboxylic acid, or HU-331), taxanes (eg, paclitaxel (eg, albumin-engineered paclitaxel, also called nanoparticle albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, mirataxel, tesetaxel, and/or orataxel). Exemplary non-platinum chemotherapeutic agents also include alkylating agents (eg, cyclophosphamide).

As used herein, "nucleoside analogue" refers to a nucleoside containing a nucleic acid analogue and a sugar. Nucleoside analogues can function as antimetabolites. Exemplary nucleoside analogues include, but are not limited to gemcitabine, cytarabine, fludarabine and cladribine.

As used herein, a "taxane" is a diterpene that can bind to tubulin to promote microtubule assembly and stabilization and/or prevent microtubule depolymerization. Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes include paclitaxel (ie, TAXOL®, CAS#33069-62-4), docetaxel (ie, TAXOTERE®, CAS#114977-28-5), larotaxel, cabazitaxel, mirataxel. , tesetaxel, and/or orataxel. In some aspects, the taxane is an albumin-coated nanoparticle (eg, nab-paclitaxel, ie ABRAXANE®, and/or nab-docetaxel, ABI-008). In some aspects, the taxane is nab-paclitaxel (ABRAXANE®). In some aspects, the taxane is formulated in a CREMAPHOR® (eg, TAXOL®) and/or a Tween, such as polysorbate 80 (eg, TAXOTERE®). In some aspects, the taxane is a liposome-encapsulated taxane. In some aspects, the taxane is in the form of a prodrug and/or a conjugate form of the taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel polygourmex, and/or linoleyl carbonate-paclitaxel). . In some aspects, paclitaxel is formulated substantially without surfactants (eg, in the absence of CREMAPHOR and/or Tween—TOCOSOL® paclitaxel, etc.).

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

Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, Denileukin, dexrazoxane, epoetin alfa, erotinib, filgrastim, histrelin acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nerarabine, nofetumomab, oprelvekin, palyfermin, pamidronate, pegademase , pegasparagase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid , as well as pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include: hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, acrometasone dipropionate, betamethasone valerate, betamethasone dipropionate, pred Nicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortone caproate, fluocortone pivalate and fluprednidene acetate, phenylalanine-glutamine-glycine (FEG) and its D isomeric forms ( feG) and other immunoselective anti-inflammatory peptides (ImSAIDs) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, etc. interleukin-1 (IL-1) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Timzia), golimumab (Simponi), anakinra (Kinele), abatacept (Orencia) ), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®), interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) such as lontarizumab Beta7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime, secreted homotrimeric LTa3 and membrane bound heterotrimeric LTa1/β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (such as radioisotopes of At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and Lu); thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or fal Other investigational drugs such as Nesyltransferase inhibitors (L-739749, L-744832); quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and their derivatives, etc. autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid and its derivatives; ); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g. BONEFOS® or OSTAC®), etidronate (DIDROCAL®) , NE-58095, bisphosphonates such as zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®)), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitors (eg celecoxib or etoricoxib), proteosome inhibitors tipifarnib (R11577); olafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®): pixantrone; and a pharmaceutically acceptable salt, acid or derivative of any of the above; and CHOP, which stands for combination therapy of cyclophosphamide, doxorubicin, vincristine, prednisolone, and 5-FU and leucovorin. A combination of two or more of the above, such as FOLFOX, which stands for oxaliplatin (ELOXATIN™) treatment regimen combined with

Chemotherapeutic agents can also include non-steroidal anti-inflammatory drugs that have analgesic, antipyretic, and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of non-steroidal anti-inflammatory drugs include propionic acid derivatives such as aspirin, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sullindac, etodolac and diclofenac, piroxicam, Enolic acid derivatives such as meloxicam. Fenamic acid derivatives such as tenoxicam, droxicam, ronoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib and valdecoxib. NSAIDs are used to treat rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylosis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, It may be indicated for symptomatic relief of conditions such as mild to moderate pain, fever, intestinal obstruction, and renal colic resulting from inflammation and tissue injury.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise interact directly with EGFR and block or reduce its signaling activity, alternatively referred to as "EGFR antagonists." be done. Examples of such agents include small molecules that bind to EGFR. EGFR antagonists are disclosed in U.S. Pat. Nos. 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, and the following PCT publications: WO 98/14451, WO 98/50038, WO 99/09016, and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech/OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro -4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3 '-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca ), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R) -6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl ) amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]- 4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine); be done.

Chemotherapeutic agents include "tyrosine kinase inhibitors", such as the EGFR-targeted drugs described in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, such as anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802. (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI®) and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitors such as Takeda CP-724,714 (Pfizer and OSI), an oral selective inhibitor of the ErbB2 receptor tyrosine kinase; a dual HER inhibitor, such as binding preferentially to EGFR, but HER2 and EGFR EKB-569, which inhibits both overexpressing cells (available from Wyeth); lapatinib (GSK572016, available from Glaxo-SmithKline); oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); - HER inhibitors such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors such as the antisense drug ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling; non-HER targeted TK inhibition agents such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multitargeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors agents such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular-regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706; (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); nitro tyrphostins containing a thiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (eg, those that bind to HER-encoding nucleic acids); quinoxalines (US Pat. No. 5,804,396); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly). PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); 787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or the following patent publications: US Patent No. 5,804,396; 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 thing of description in either is also mentioned.

The term "anthracycline" relates to chemotherapeutic agents, preferably anticancer agents for inducing apoptosis by inhibiting DNA recombination in topoisomerase II. Examples include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pirarubicin, valrubicin, N-trifluoro-acetyldoxorubicin-14-valerate, aclacinomycin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino -doxorubicin (cyanomorpholino-DOX), 2-pyrrolinodoxorubicin (2-PDOX), 5-iminodaunomycin, mitoxantrone and aclacinomycin A (acrubicin). In some aspects, an anthracycline is administered in combination with an alkylating agent, such as doxorubicin in combination with cyclophosphamide (treatment with AC).

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

Compounds such as anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antibodies), VEGF antagonists, chemotherapeutic agents (e.g., platinum-based or non-platinum-based chemotherapeutic agents), ADCs ( e.g., enfortuzumab vedotin or sacituzumab govitecan) or CSF (e.g., pegfilgrastim, filgrastim, or sargramostim) is at least the desired therapeutic result, e.g. is the minimum amount required to achieve a measurable increase in overall survival or progression-free survival for a disease or disorder (eg, cancer) of Effective amounts 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 the desired response in the subject. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the beneficial effects of the treatment. Beneficial or desired results for prophylactic use include biochemical, histological and/or behavioral manifestations of the disease, its complications, and intermediate pathological manifestations during the development of the disease. Outcomes such as elimination or reduction of risk, reduction in severity, or delay in onset of disease, including type. For therapeutic use, beneficial or desired results include reduction of one or more symptoms attributable to the disease (e.g., cancer-related pain, reduction or delay of symptomatic skeletal-related events (SSE), European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30, including fatigue, nausea, vomiting, pain, dyspnea, insomnia, anorexia, constipation, diarrhea, or physical, cognitive, or reduction in symptoms according to the general level of social functioning), e.g., reduction in pain as measured by a Numerical Rating Scale (NRS) of 10-point pain severity (measured at worst), those with the disease decrease the dose of other drugs needed to treat the disease; enhance the effect of another drug, such as by targeting; delay disease progression (e.g., progression-free survival or radiation-free progression survival (rPFS); definite clinical progression (e.g. cancer-related pain progression, symptomatic skeletal-related events, US East Coast Cancer Clinical Trials Group (ECOG) performance (PS) decline impact on the patient's ability to perform daily activities), and/or delaying initiation of subsequent systemic anticancer therapy), and/or prolonging survival. Effective amounts of the drug reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow or desirably stop to some extent) invasion of cancer cells into peripheral organs, and inhibit tumor metastasis. may have the effect of slowing (i.e., slowing or desirably halting to some extent), inhibiting to some degree tumor growth, and/or alleviating one or more of the symptoms associated with the disorder. Administration may be in single or multiple doses.For the purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve, directly or indirectly, prophylactic or therapeutic treatment. As understood in the clinical arts, an effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition. An "effective amount" can be considered in the context of administration of one or more therapeutic agents, which alone can or are capable of achieving a desired result in combination with one or more other agents. In some embodiments, beneficial or local Desirable outcomes are assessed by symptoms of the lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspnea and chest pain) and/or delay in time to lung-specific antigen progression in health-related living. Reduction in lung cancer-related symptoms by quality (HRQoL) questionnaire.

"Immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic, and enhancing tumor immunogenicity helps the immune response eliminate tumor cells. Examples of enhancing tumor immunogenicity include, but are not limited to, treatment with TIGIT and/or PD-L1 antagonists (eg, anti-TIGIT antagonist antibodies and/or anti-PD-L1 antibodies).

"Individual response" or "response" includes, but is not limited to: (1) disease progression (cancer progression, e.g., lung cancer (e.g., small cell lung cancer, including small cell lung cancer [e.g., extensive-stage SCLC (ES-SCLC)); Cell lung cancer (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 recurrence or metastasis UC, such as bladder cancer (eg, MIBC), urothelial bladder cancer (UBC), pancreatic cancer (eg, pancreatic ductal adenocarcinoma ( PDAC), e.g. metastatic PDAC)), renal cancer or kidney 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. microsatellite stable (MSS) and microsatellite instability (MSI) low (MSI-low) CRC), or breast cancer (e.g., HER2+ breast cancer and triple negative breast cancer (TNBC) (estrogen receptor (ER-), progesterone receptor (PgR-), and HER2 (HER2 (2) reduction in tumor size; (3) suppression of cancer cell invasion into adjacent peripheral organs and/or tissues (i.e., reduction, (4) inhibition of metastasis (i.e., reduction, slowing or complete arrest); (5) some relief of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) and/or (9) reduced mortality at a given time point after treatment using any endpoint that indicates benefit to the subject. can be graded.

As used herein, "pathologic complete response" (pCR) is defined as the percentage of patients with completely resected specimens with no residual invasive cancer. In the context of breast cancer, "pathologic complete response" or "pCR" refers to eradication of tumor from both breast cancer and lymph nodes (ypT0/ is ypN0).

As used herein with respect to urothelial carcinoma (UC), "rate of reduction in pathologic extent" is defined as the proportion of patients reaching ≤pT1pN0 at cystectomy.

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

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

As used herein, "objective response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

As used herein, "period of objective response" (DOR) is the time from the first onset of a documented objective response to disease progression or any It is defined as the time of death from any cause, whichever occurs first.

"Durable response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, tumor size may remain the same or become smaller compared to the size at the start of the dosing phase. In some aspects, the sustained response has a duration that is at least as long as the treatment period, at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

A subject's "effective response" or a subject's "responsiveness" to treatment with a pharmaceutical agent and similar terms refer to a clinical term given to a subject at risk for or suffering from a disease or disorder, such as cancer. or refers to therapeutic benefit. In one aspect, such benefit is prolonged survival (including overall survival and progression-free survival); results in an objective response (including CR or PR); or ameliorates cancer signs or symptoms , any one or more of

A subject "no effective response" to treatment results in prolonged survival (including overall survival and progression-free survival); results in an objective response (including CR or PR); Refers to a subject who has neither improved signs nor symptoms.

As used herein, the term "survival" refers to patient survival and includes overall survival and progression-free survival.

As used herein, “overall survival” and “OS” refer to the length of time from either the date of diagnosis of the disease (e.g., cancer) or the date of initiation of treatment that the patient is still alive. Point. For example, OS can be defined as the time from randomization to death from any cause.

As used herein, "overall survival" refers to the proportion of subjects in a group who are alive after a specified period of time, eg, 6 months, 1 year or 5 years from the time of diagnosis or treatment.

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

As used herein, "symptom-free survival" (EFS) is defined as from randomization to disease progression (e.g., progression precluding surgery as assessed by the investigator); local or distant disease recurrence; Defined as the time to either (whichever occurs first) event of death from any cause.

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

As used herein, "stable disease" or "SD" is based on minimal SLD since treatment initiation, with target lesion shrinkage sufficient to qualify as CR or PR, or sufficient to qualify as PD. It means that there is no significant increase.

As used herein, “progressive disease” or “PD” refers to the longest disease of a target lesion relative to the smallest SLD recorded since treatment initiation or since the presence of one or more new lesions. Refers to an increase in diameter (SLD) of at least 20%.

As used herein, "pathologic response" (MPR) is defined as 10% or less residual viable tumor upon surgical resection of the primary tumor.

As used herein, "slowing progression" of a disease or disorder means postponing, preventing, delaying, delaying, stabilizing, and/or postponing the onset of a disease or disorder (e.g., cancer). refers to doing This delay can be of varying duration depending on the medical history and/or subject being treated. As will be apparent to one skilled in the art, a sufficient or significant delay can in effect encompass prophylaxis, in that the subject will not develop the disease. For example, in late-stage cancer, the development of central nervous system (CNS) metastases may be delayed.

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

"Reduce or inhibit" means an overall reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more means the ability to bring about Reduction or inhibition may refer to the symptoms of the disorder (eg, cancer) being treated, the presence or size of metastases, or the size of the primary tumor.

By "prolonged survival" is meant relative to untreated patients (e.g., untreated patients) or to patients who do not express the biomarker at a specified level, and/or An increase in overall survival or progression-free survival in treated patients relative to patients treated with approved anti-tumor agents. Objective response refers to a measurable response, including CR or PR.

The terms "detect" and "detection" are used most broadly herein to include both qualitative and quantitative measurement of target molecules. Detection involves simply identifying the presence of the target molecule in the sample as well as determining whether the target molecule is present in the sample at detectable levels. Detection may be direct or indirect.

As used herein, a “PD-L1 positive tumor cell fraction” is an immunohistochemistry (IHC) assay, such as those staining for PD-L1 using antibodies SP263, SP142, 22C3, or 28-8. Percentage of viable tumor cells showing partial or complete membrane staining (excluding cytoplasmic staining) of any intensity relative to all viable tumor cells present in the sample after staining of the sample for an IHC assay for . Therefore, the PD-L1 positive tumor cell fraction can be determined using the PD-L1 IHC SP263 (Ventana) assay, eg, with the formula: PD-L1 positive tumor cell fraction = (number of PD-L1 positive tumor cells)/ (total number of PD-L1-positive and PD-L1-negative tumor cells), the PD- L1 cytoplasmic staining is excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond to a particular IHC assay protocol and/or scoring term that can be used to obtain a PD-L1 positive tumor cell fraction. be. For example, the PD-L1 positive tumor cell fraction can be determined by OPTVIEW® detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTVIEW® detection and amplification on Benchmark ULTRA, or EnVision on AutostainerLink 48, respectively. Flex can be used from tumor cell samples stained with SP263, 22C3, SP142, or 28-8. In another example, the PD-L1 IHC 22C3 pharmDx assay (Dako) can be used according to the formula above to calculate the PD-L1 positive tumor cell fraction. One skilled in the art will appreciate that sensitivity may vary between different PD-L1 antibodies used in IHC assays. For example, only about 64% of the samples meeting the 1% TC or 25% TC threshold defined by staining with 28-8 or 22C3 and SP263, respectively, meet the threshold when stained using SP142. Hirsch et al. , Journal of Thoracic Oncology 2016, 12(2): 208-222. As used herein, the terms PD-L1 positive tumor cell fraction and "tumor percentage score" (TPS) are used interchangeably.

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

As used herein, the "Ventana SP263 IHC assay" is described in the Ventana PD-L1 (SP263) assay package insert (Tucson, Ariz.: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety. incorporated into the book.

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

As used herein, "pharmDx 28-8 IHC assay" refers to the PD-L1 IHC 28-8 pharmDx package insert (Carpinteria, CA: Dako, Agilent), which is incorporated herein by reference in its entirety. Pathology Solutions).

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

As used herein, the term "biomarker" is detected in a sample, such as PD-L1, ctDNA, or cytokines (eg, cytokines associated with T cell activation and/or lymphocyte subpopulations) It refers to a predictable, diagnostic, and/or prognostic indicator. A biomarker can serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer) characterized by certain molecular, pathological, histological, and/or clinical features. . In some embodiments, biomarkers are genes. Biomarkers include polypeptides, polynucleotides (e.g., DNA (e.g., ctDNA), and/or RNA), polynucleotide copy number changes (e.g., DNA copy number), polypeptide and polynucleotide modifications (e.g., translational post-modification), 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 biomarkers are one or more cytokines (eg, one or more cytokines associated with T cell activation and/or lymphocyte subpopulations). In some aspects, the biomarkers are cells (eg, immune cells, eg, T cells, eg, T cell subsets, eg, activated T cells). In some aspects, a biomarker is a direct or indirect indicator of human papillomavirus (HPV) status. In some aspects, the biomarker is p16. In some aspects, the biomarkers are HPV proteins or nucleic acids.

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

As used herein, "circulating tumor DNA" and "ctDNA" refer to tumor-derived DNA in the circulating system that is not associated with cells. ctDNA is a type of cell-free DNA (cfDNA) that can be derived from tumor cells or circulating tumor cells (CTCs). ctDNA can be found, for example, in a patient's bloodstream or in a biological sample obtained from a patient (eg, blood, serum, plasma, or urine). In some aspects, the ctDNA may contain aberrant mutations (eg, 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 with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), Included are diabodies and single chain molecules, as well as antibody fragments, including antigen binding fragments such as Fab, F(ab') ₂ and Fv, so long as they exhibit the desired biological activity. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. In one example, the antibody is a full-length monoclonal antibody.

The terms IgG "isotype" or "subclass" as used herein refer to any of the immunoglobulin subclasses defined by the chemical and antigenic properties of their constant regions.

Depending on the amino acid sequences of the constant domain of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which are further subclassed (isotypes), e.g. can be classified. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional organization of different classes of immunoglobulins are well known, see, for example, Abbas et al. Cellular and Mol. Immunology, ^4th ed. (WB Saunders, Co., 2000). An antibody can 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 four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies consist of five basic heterotetrameric units, plus an additional polypeptide called the J chain, which contains ten antigen-binding sites, whereas IgA antibodies consist of two to It is composed of five basic four-stranded units, which can polymerize to form multivalent assemblies that combine with J chains. For IgG, a four-stranded unit is generally 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 bridges. Each H chain has at its N-terminus a variable domain (V _H ) followed by three constant domains (C _H ) for each of the α and γ chains and four C _H domains for the μ and ε isotypes. have Each L chain has at its N-terminus a variable domain (V _L ) followed by a constant domain at its opposite end. The V _L is aligned with the V _H and the C _L is aligned with the first constant domain (C _H 1) of the heavy chain. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains. The _VH and _VL pair together to form a single antigen-binding site. For the structure and properties of various classes of antibodies, see, eg, Basic and Clinical Immunology, ^8th Edition, Daniel P.; Sties, Abba I.; Terr and TristramG. See page 71 and chapter 6 of Parsolw (eds), Appleton & Lange, Norwalk, Conn., 1994. Light chains from any vertebrate species can be assigned to one of two distinct classes, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequences of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins, IgA, IgD, IgE, IgG, and IgM, with heavy chains denoted α, δ, ε, γ, and μ, respectively. The γ and α classes are further subdivided into subclasses based on relatively minor differences in CH sequence and function, for example humans are subclassed into the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1, and IgA2. express.

As used herein, the term "hypervariable region" or "HVR" refers to regions of antibody variable domains that are hypervariable in sequence and determine antigen-binding specificity, e.g., "complementarity determining regions" (CDR).
In general, antibodies contain 6 CDRs, 3 in VH (CDR-H1, CDR-H2, CDR-H3) and 3 in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:
(a) excesses occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 (H3); variable loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

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

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

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

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

The terms "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat" and variations thereof are described in Kabat et al. refers to the numbering system used for the heavy or light chain variable domains of antibody compilations in . Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to truncations or insertions into the FRs or HVRs of the variable domain. For example, the heavy chain variable domain contains a single amino acid insertion after residue 52 of H2 (e.g. residue 52a according to Kabat) and the inserted residue after heavy chain FR residue 82 (e.g. residues 82a, 82b, and 82c, etc.) according to Kabat). The Kabat numbering of residues can be determined for a given antibody by aligning the regions of homology between the antibody's sequence and the "standard" Kabat numbered sequences.

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

The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among 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 throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light and heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of the naturally occurring heavy and light chains each connect a beta-sheet structure and, in some cases, a beta connected by three HVRs forming a loop forming part of the beta-sheet structure. It contains four FR regions that heavily adopt the seat configuration. The HVRs within each chain are closely linked to each other by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antibody's antigen-binding site (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 an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity.

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

"Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3 and FR4. Thus, HVR and FR sequences generally appear in VH (or VL) in the following sequence: 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, as opposed to antibody fragments. Specifically, whole antibodies include those having heavy and light chains, including an Fc region. The constant domains may be native sequence constant domains (eg, human native sequence constant domains) or amino acid sequence variant thereof. In some cases, an intact antibody may possess one or more effector functions.

A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or radiolabel. A naked antibody may be present in a pharmaceutical composition.
An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding region and/or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab') ₂ ; diabodies; linear antibodies (Example 2 of US Pat. No. 5,641,870; Zapata et al., Protein Eng. 8 (10 ): 1057-1062 [1995]

single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies yields two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, designated to reflect its ability to crystallize readily. A Fab fragment consists of the variable region domain of the H chain (V _H ) along with the entire L chain, as well as the first constant domain of one heavy chain (C _H 1). Each Fab fragment is monovalent with respect to antigen binding, ie, has a single antigen binding site. Pepsin treatment of the antibody yields a single large F(ab') ₂ fragment that roughly corresponds to a disulfide-linked disulfide-bonded Fab fragment with different antigen-binding activities, yet capable of cross-linking antigen. is possible. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the C _H 1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the constant domain cysteine residue(s) bear a free thiol group. F(ab') ₂ antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

The Fc fragment contains the carboxy termini of both heavy chains held together by a disulfide. The effector functions of antibodies are determined by sequences in the Fc region, which region is also recognized by Fc receptors (FcR) found on certain cell types.

A "functional fragment" of an antibody of the invention comprises a portion of an intact antibody, generally including the antigen-binding or variable region of an intact antibody, or an FcR that retains FcR-binding ability or has been modified. Included are Fc regions of antibodies capable of binding. Examples of antibody fragments include linear antibodies, single chain antibody molecules, and multispecific antibodies formed from antibody fragments.

"Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy and one light chain variable region domain in tight, non-covalent association. Folding of these two domains creates six hypervariable loops (three loops each from the H and L chains) that provide the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) recognizes and binds antigen, albeit with lower affinity than the entire binding site. have the ability.

"Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the _VH and _VL antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the _VH and _VL domains, which linker enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. , Springer-Verlag, New York, pp. 269-315 (1994).

The term "Fc region" is used herein to define a C-terminal region of an immunoglobulin heavy chain containing 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 carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, by expression of a particular nucleic acid molecule encoding a full-length heavy chain, the antibody produced by the host cell may contain the full-length heavy chain or may contain cleaved variants of the full-length heavy chain. good. This can be the case when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Thus, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. Amino acid sequences of heavy chains, including the Fc region, are shown herein without the C-terminal lysine (Lys 447) unless otherwise indicated. In one aspect, the heavy chains comprising the Fc regions specified herein included in the antibodies disclosed herein comprise additional C-terminal glycine-lysine dipeptides (G446 and K447). In one aspect, the heavy chains comprising the Fc regions specified herein included in the antibodies disclosed herein comprise an additional C-terminal glycine residue (G446). In one aspect, the heavy chains comprising the Fc regions specified herein included in the antibodies disclosed herein comprise an additional C-terminal lysine residue (K447). In one aspect, the Fc region comprises the heavy chain single amino acid substitution N297A. Unless otherwise indicated herein, amino acid residue numbering in the Fc region or constant region is that of Kabat et al. , Sequences of Proteins of Immunological Interest, 5th Ed. It follows the EU numbering system, also called the EU index, as described in 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. Further preferred FcRs are those that bind IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses (allelic variants and alternatively splice forms of these receptors). ), and FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. have Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) within its cytoplasmic domain. Inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain (see M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al. , Immunomethods 4:25-34 (1994); and de Haas et al. , J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those hereafter identified, are encompassed by the term "FcR" herein.

The term "diabody" refers to the combination of a VH domain and a V domain to achieve interchain, but not intrachain V domain pairing, thereby resulting _in a bivalent fragment, i.e., a fragment with two antigen-binding sites. Refers to a small antibody fragment prepared by constructing an sFv fragment (see previous paragraph) with a short linker (about 5-10 residues) between it and the _L domain. Bispecific diabodies are heterodimers of two "crossed" sFv fragments in which the _VH and _VL domains of the two antibodies are present in different polypeptide chains. Diabodies are described, for example, in EP 404,097, WO 93/11161; Hollinger et al. , Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993).

Monoclonal antibodies herein specifically include a portion of the heavy and/or light chain identical to or corresponding sequences in an antibody from a particular species or belonging to a particular antibody class or subclass. "Chimeric" antibodies that are homologous, while the remainder of the chain(s) are identical or homologous to corresponding sequences in an antibody from another species or belonging to another antibody class or subclass ( immunoglobulins), and fragments of such antibodies are included so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies, wherein the antigen-binding region of the antibody is, for example, an antibody produced by immunizing macaque monkeys with an antigen of interest derived from As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

The "class" of an antibody refers to the type of constant domain or region carried by its heavy chains. There are five major classes of antibodies, namely IgA, IgD, IgE, IgG, and IgM, some of which have further subclasses (isotypes), e.g., _IgG1 , _IgG2 , _IgG3 , IgG4 _. , IgA ₁ , and IgA ₂ . The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

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

A "human antibody" is an antibody that has an amino acid sequence corresponding to that of an antibody produced by a human and/or produced using any of the techniques for producing human antibodies disclosed herein. It is an antibody that has been This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, such as phage display libraries. Hoogenboom and Winter, J.; Mol. Biol. , 227:381 (1991); Marks et al. , J. Mol. Biol. , 222:581 (1991). Cole et al. , Monoclonal antibodies and Cancer Therapy, Alan R.; Liss, p. 77 (1985); Boerner et al. , J. Immunol. , 147(1):86-95 (1991) are also available for the preparation of human monoclonal antibodies. van Dijk and van de Winkel, Curr. Opin. Pharmacol. , 5:368-74 (2001). See also Human antibodies are modified to produce such antibodies in response to antigenic challenge, but by administering the antigen to a transgenic animal in which its endogenous locus has been disabled, e.g., an immunized xeno-mouse. (See, eg, US Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). Also, for human antibodies produced by human B-cell hybridoma technology, see, for example, Li et al. , Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006).

“Humanized” forms of non-human (eg, murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one aspect, a humanized antibody is a murine, rat, rabbit, or non-human antibody in which residues from the recipient's HVR (defined below) have the desired specificity, affinity, and/or ability. A human immunoglobulin (recipient antibody) that has been replaced with residues from the HVR of a non-human species such as a primate (donor antibody). In some instances, framework (“FR”) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are found neither in the recipient antibody nor in the donor antibody. These modifications can be made to further refine antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, typically two, variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences. , all or substantially all of the FR regions correspond to those of a human immunoglobulin sequence, but the FR regions contain one or more that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. individual FR residue substitutions may be included. The number of these amino acid substitutions in the FRs is typically 6 or less for H chains and 3 or less for L chains. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details see, for example, 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). For example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and US Pat. Nos. 6,982,321 and 7,087,409.

The term "isolated antibody" when used to describe the various antibodies disclosed herein has been identified, separated and/or recovered from a cell or cell culture in which the antibody was expressed. means an antibody that has been Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some aspects, antibodies are determined, for example, by electrophoresis (eg, SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (eg, ion-exchange or reverse-phase HPLC). , purified to greater than 95% or greater than 99% purity. For a review of methods for assessment of antibody purity, see, eg, Flatman et al. , J. Chromatogr. B 848:79-87 (2007). In a preferred embodiment, the antibody is (1) sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator, or (2) a Coomassie Purify to homogeneity by SDS-PAGE under non-reducing or reducing conditions using blue or preferably silver staining. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, 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. That is, the individual antibodies that make up the population are identical, except for possible variant antibodies that are generally present in minor amounts, including, for example, naturally-occurring mutations or mutations that arise during the manufacture of a monoclonal antibody preparation, and /or bind the same epitope. In contrast to polyclonal antibody preparations, which usually include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates the characteristics of antibodies obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention include, but are not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci. may be made by a variety of techniques that are not

As used herein, the terms “binds,” “binds specifically to,” or “is specific to” refer to a measurable and Refers to reproducible interactions, which dictate the presence of a target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds a target, which may be an epitope, binds to this target with higher affinity, avidity, more readily, and/or for a longer duration than it binds to other targets. It is an antibody that binds to In one aspect, the extent to which the antibody binds to an irrelevant target is less than about 10% of the antibody's binding to the target as measured by radioimmunoassay (RIA). In certain aspects, an antibody that specifically binds to a target has a dissociation constant (K _D ) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain aspects, the antibody specifically binds to an epitope on the protein that is conserved among proteins from different species. In another aspect, specific binding may, but does not require, exclusive binding. The term as used herein means, for example, 10 ⁻⁴ M or less, alternatively 10 ⁻⁵ M or less, alternatively 10 ⁻⁶ M or less, alternatively 10 ⁻⁷ M or less, alternatively 10 ⁻⁸ M or less, to the target, alternatively a K _D of 10 ⁻⁹ M or less, alternatively 10 ⁻¹⁰ M or less, alternatively 10 ⁻¹¹ M or less, alternatively 10 ⁻¹² M or less, or 10 ⁻⁴ M to 10 ⁻⁶ M, or 10 ⁻⁶ M to 10 ⁻ It can be demonstrated by molecules with a K _D of ¹⁰ M, or in the range of 10 ⁻⁷ M to 10 ⁻⁹ M. As will be appreciated by those skilled in the art, affinity and _KD values are inversely correlated. A high affinity for an antigen is measured by a low _KD value. In one aspect, the term "specific binding" refers to the molecule binding to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. Refers to the combination when

A "percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is obtained after aligning the sequences and introducing gaps, if necessary, to obtain the maximum percent sequence identity, after which any conservative substitutions are considered It is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a reference polypeptide, if not considered a fraction. Alignment for purposes of determining percent amino acid sequence identity may be performed in a variety of ways within the skill in the art, for example, by BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. can be accomplished using computer software available at Those skilled in the art can determine appropriate parameters for alignment of sequences, including any algorithms needed to achieve maximal alignment over the entire length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program is available from Genentech, Inc.; and the source code, together with user documentation, is available from the United States Copyright Office, Washington, D.C. C. , 20559, where it is registered under US Copyright Registration Number TXU510087. The ALIGN-2 program is available from Genentech, Inc. (South San Francisco, California) or may be compiled from its source code. ALIGN-2 programs should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and remain unchanged.

In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (or A given amino acid sequence A having or including a certain % amino acid sequence identity to, with, or to a given amino acid sequence B) can be described as: Computed:
100 x Fractional X/Y
where X is the number of amino acid residues scored as identical matches in the alignment of A and B by the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B is. It will be understood that the % amino acid sequence identity of A to B is not equal to the % amino acid sequence identity of B to A if the length of amino acid sequence A is not equal to the length of amino acid sequence B. Unless otherwise stated, all % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

As used herein, "subject" or "individual" means a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. do. In some embodiments, the subject is human. Patients are also a subject herein.

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

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

As used herein, the term "sample" refers to cellular entities and/or Refers to a composition obtained or derived from a subject and/or individual of interest that contains other molecular entities. For example, the phrases “tumor sample,” “disease sample,” and variations thereof are used from a subject of interest that is expected or known to contain the cellular and/or molecular entity to be characterized. Refers to any sample obtained. Samples include tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph, 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 include, but are not limited to.

A "tissue sample" or "cell sample" refers to a similar collection of cells obtained from tissue of a subject or individual. Sources of tissue or cell samples may be solid tissues such as from fresh, frozen and/or preserved organs, tissue samples, biopsies, and/or aspirates; blood such as plasma or any blood constituent. body fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; cells at any stage in the subject's pregnancy or development. A tissue sample may be a primary or cultured cell or cell line. Optionally, tissue or cell samples are obtained from diseased tissues/organs. For example, a "tumor sample" is a tissue sample obtained from a tumor or other cancerous tissue. A tissue sample may contain a mixed population of cell types (eg, tumor and non-tumor cells, cancerous and non-cancerous cells). Tissue samples may contain compounds that are not naturally mixed with native tissue, such as preservatives, anticoagulants, buffers, fixatives, waxes, nutrients, or antibiotics. In some aspects, the tissue sample is a tumor tissue sample. In some aspects, the tumor tissue sample is a UC tumor tissue sample (eg, a bladder cancer tumor tissue sample (eg, an MIBC tumor tissue sample)). In some embodiments, the sample is a bladder tumor transurethral resection (TURBT) 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., early stage lung cancer tissue sample (e.g., NSCLC tumor tissue sample (e.g., stage II, IIIA or IIIB NSCLC tumor tissue sample)), e.g., squamous or non-squamous NSCLC tumor tissue sample, eg resectable NSCLC tumor tissue sample)). In some embodiments, the sample is a locally advanced unresectable NSCLC tumor tissue sample (eg, stage IIIB NSCLC tumor tissue sample), or a recurrent or metastatic NSCLC tumor tissue sample (eg, stage IV NSCLC tumor tissue sample)). , pancreatic cancer tumor tissue sample (eg, PDAC tumor tissue sample), eg metastatic PDAC tumor tissue sample), or breast cancer tumor tissue sample (eg, HER2+ breast cancer tumor tissue sample or TNBC tumor tissue sample).

For purposes herein, a "section" of a tissue sample means a single portion or piece of tissue sample, eg, a thin section of tissue or cells cut from a tissue sample (eg, a tumor sample). It is understood that multiple sections of the tissue sample can be taken and subjected to analysis, provided that the same section of the tissue sample can be analyzed at both the morphological and molecular level, or the polypeptide ( for example, by immunohistochemistry) and/or for polynucleotides (eg, by in situ hybridization).

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

As used herein, the term "protein" refers to any vertebral protein, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. It refers to any naturally occurring protein from an animal source. The term also includes "full-length," unprocessed protein and any form of protein resulting from processing within a cell. The term also includes naturally occurring variants of proteins, eg, splice or allelic variants.

"Polynucleotide," or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or analogs 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 single- and double-stranded DNA, DNA containing single- and double-stranded regions, single- and double-stranded RNA, and single-stranded and RNA containing double-stranded regions, hybrid molecules comprising DNA and RNA which may contain single-stranded or more typically double-stranded or may contain single- and double-stranded regions, including but not limited to: Not limited. In addition, the term "polynucleotide" as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands within such regions may be from the same molecule or from different molecules. These regions may include all of one or more of these molecules, but more typically include only regions of some of these molecules. One of the molecules in the triple helix region is often an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically include mRNA and cDNA.

A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. Modifications to the nucleotide structure, if present, may be imparted before or after assembly of the polymer. A sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include substitutions of one or more analogs of naturally occurring nucleotides, internucleotide modifications, e.g., uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphoamidates, , carbamates, etc.), and by charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), pendent moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), etc. by intercalating agents (e.g., acridine, psoralen, etc.), chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), alkylating agents, modified linkages (e.g., alpha anomeric nucleic acids), as well as unmodified forms of the polynucleotide(s). Furthermore, any of the hydroxyl groups normally present in sugars may be replaced by, for example, a phosphonate group, a phosphate group, protected by standard protecting groups, or activated and added. may be provided with additional attachments to nucleotides of or may be conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1-20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides may include, for example, 2′-O-methyl-, 2′-O-allyl-, 2′-fluoro-, or 2′-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric Ribose sugars commonly known in the art, including sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acrylic acid analogues, and abasic nucleoside analogues such as methylriboside or analogous forms of deoxyribose sugars. One or more phosphodiester bonds may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, phosphates P(O)S (“thioates”), P(S)S (“dithioates”), “(O)NR ₂ (“amidates” ), P(O)R, P(O)OR′, CO or CH ₂ (“formacetal”), wherein each R or R′ is independently H or substituted or unsubstituted alkyl (1-20C) (optionally containing an ether (--O--) bond), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl; Not all bonds in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

A "carrier" as used herein is a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals to which it is exposed at the dosages and concentrations employed. included. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; serum albumin. hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other sugars, including glucose, mannose, or dextrins; carbohydrates; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; agents.

The phrase "pharmaceutically acceptable" means that a substance or composition is chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal being treated therewith. Indicates what must be done.

The term "pharmaceutical formulation" or "pharmaceutical composition" means a form in which the biological activity of the active ingredients contained therein is effective and to an extent unacceptable to the subject to whom the formulation is administered. It refers to preparations that do not contain any toxic ingredients.

The term "package insert" refers to indications, usage, dosage, administration, concomitant therapy, other medicines in combination with the packaged product, and/or contraindications and/or warnings regarding the use of such therapeutic products or medicines. Used to refer to instructions that are commonly included in the commercial packaging of therapeutic products or pharmaceuticals that contain information.

As used herein, the term “introduction phase” refers to the period of one or more therapeutic agents (e.g., anti-TIGIT antagonist antibody, PD-1 axis binding antagonist and/or chemotherapeutic agent) administered to the subject. Refers to a series of one or more dosing cycles (eg, about 4-6 cycles), optionally followed by a maintenance phase.

As used herein, the term "maintenance phase" refers to one or more therapeutic agents (e.g., anti-TIGIT antagonist antibody, PD-1 axis binding antagonist and/or A series of one or more dosing cycles of a chemotherapeutic agent). In some instances, the Maintenance Phase is initiated only if the subject did not experience disease progression or unacceptable toxicity during the Run-in Phase. The induction phase and maintenance phase may or may not involve the use of the same therapeutic agent. For example, in some instances, the induction phase includes the use of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents, and the maintenance phase includes anti-TIGIT antagonist antibodies and Including the use of PD-1 axis binding antagonists.

In the context of bladder cancer, the term "ineligible for treatment with platinum-based chemotherapy" or "ineligible for treatment with platinum-based chemotherapy" means that the subject, in the judgment of the attending physician or in the art Means ineligible or ineligible for treatment with platinum-based chemotherapy according to standardized criteria for platinum-based chemotherapy eligibility known in the art. See, for example, Galsky et al. Lancet Oncol. 12(3):211-4, 2011 can be used to determine whether a subject is eligible for cisplatin-based chemotherapy. Galsky et al. describes a consensus definition of patients with metastatic UC (mUC) who are considered ineligible for cisplatin-based chemotherapy if they meet at least one of the following: (i) World Health Association (WHO) or US East Coast Cancer Clinical Trials Group (ECOG) Performance Status 2 or Karnofsky Performance Status 60-70%; (ii) creatinine clearance (calculated or measured) less than 1 mL/s; (iii) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade ≥ 2 hearing loss; (iv) CTCAE v. 4.0 Grade ≧2 peripheral neuropathy; and/or New York Heart Association (NYHA) Class III heart failure. In one example, a patient is considered unsuitable for cisplatin-based chemotherapy if they have one or more of the following: renal dysfunction (e.g., glomerular filtration rate (GFR) >30 but <60 mL/min); GFR can be assessed by direct measurement (i.e., creatinine clearance or ethyldiamine tetraacetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula); hearing loss (e.g., NCI CTCAE v 4.0 grade ≥2, hearing loss of 25 decibels at two consecutive frequencies); and/or an ECOG performance status rating (Oken et al. Am. J. Clin. Oncol. 5:649-655, 1982, incorporated herein by reference in its entirety) (e.g., an ECOG performance status of 2) . In some aspects, subjects with one of the following may be eligible for carboplatin-based chemotherapy: renal dysfunction (e.g., GFR>30 but <60 mL/min); (i.e., creatinine clearance or ethyldiamine tetraacetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula); CTCAE v 4.0 grade ≧2 hearing loss); peripheral neuropathy (e.g., NCI CTCAE v 4.0 grade ≧2 peripheral neuropathy (i.e., sensory changes or paresthesias, including stinging)); and/or ECOG performance Status rating (eg, ECOG performance status of 2). For example, cisplatin ineligibility may be defined by any one of the following criteria: (i) renal dysfunction (GFR<60 mL/min); (ii) 25 dB hearing loss at two adjacent frequencies (measured by audiometry); (iii) Grade 2 or greater peripheral neuropathy (ie, sensory changes or parasthesis, including stinging); and (iv) ECOG performance status 2.

III. THERAPEUTIC AND DIAGNOSTIC METHODS AND USES A. Treatment Methods and Uses for Cancer Treatment Methods and Compositions As used herein, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab), or both an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or an anti-PD-1 antagonist antibody (e.g., pembrolizumab) in a combination of cancers (e.g., solid tumors, and/or locally advanced or metastatic cancer, such as lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), small cell lung cancer (SCLC) (eg, extensive stage (ES)-SCLC), non-small Cell lung cancer (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., non-stage IV squamous NSCLC)), or stage IV NSCLC (e.g., subject has not been previously 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 (HER2-) breast cancer, e.g. early TNBC (eTNBC) or HER2-positive breast cancer); head and neck cancers (e.g. head and neck squamous cell carcinoma) (SCCHN), e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer (e.g. muscle invasive bladder cancer (MIBC) or locally advanced or metastatic urothelial carcinoma (mUC)); esophageal cancer; pancreatic cancer (e.g. pancreatic ductal adenocarcinoma (PDAC), e.g. metastatic PDAC) ); renal cancer or kidney cancer (e.g., renal cell carcinoma (RCC)); melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer), or colorectal cancer (CRC; Methods and uses are provided for treating CRC with Microsatellite Stable (MSS) or Microsatellite Instable (MSI) Low (MSI-Low).

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). (e.g., an anti-PD-1 antagonist antibody, such as pembrolizumab) to a subject in need thereof every four weeks (e.g., on day 1 of each 28-day dosing cycle). include. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibodies) results in complete responses (CR) or partial responses (PR). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibodies) results in increased progression-free survival (PFS) or duration of objective response (DOR). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibodies) results in increased overall survival (OS). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in an increase in the subject's PFS. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. , extends the target OS.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof for four weeks (e.g., 28 days each dosing). on day 1 of the cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 4 weeks (e.g., on day 1 of each 28-day dosing cycle) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab) for 2 weeks (eg, 1 and 15 of each 28-day dosing cycle). day), every 3 weeks (eg, on day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on day 1 of each 28-day dosing cycle). In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in CR or PR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in increased PFS in a subject compared to a reference . In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in an increase in DOR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof for two weeks (e.g., 28 days each dosing). on days 1 and 15 of the cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered for two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). ) and administer a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab) every 2 weeks (e.g., each 28-day dosing cycle). every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). (e.g., an anti-PD-1 antagonist antibody, such as pembrolizumab) to a subject in need thereof every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). Including methods and uses. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in an increase in the subject's PFS. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. to extend the target OS.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every three weeks (e.g., each 21 doses). on day 1 of a daily dosing cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 3 weeks (e.g., on day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab) for 2 weeks (eg, 1 and 15 of each 28-day dosing cycle). day), every 3 weeks (eg, on day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on day 1 of each 28-day dosing cycle). In certain examples, the invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every three weeks. Includes methods and uses that include administering (eg, on day 1 of each 21-day dosing cycle). In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in CR or PR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in increased PFS in a subject compared to a reference . In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject. In some examples, the invention provides a method of treating a subject with cancer, wherein the subject is administered an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, about 900 mg to about 700 mg every 3 weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1500 mg, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks. , including methods. In some examples, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of 500 mg to 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of 900 mg to 1500 mg every 3 weeks, a platinum-based administering a dosing regimen comprising one or more dosing cycles of a chemotherapeutic agent and a non-platinum chemotherapeutic agent every three weeks.

In certain examples, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered without a chemotherapeutic agent (e.g., without a chemotherapeutic agent, e.g., if the overall dosing regimen requires administration of a chemotherapeutic agent to the subject). missing).

In some embodiments, the subject has not been previously treated with cancer therapies (eg, cancer immunotherapy and/or chemotherapeutic agents). In some embodiments, the subject has undergone prior treatment with cancer therapy (eg, cancer immunotherapy and/or chemotherapeutic agents). In some examples, the subject is within at least 1 month of administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (e.g., within 2 months prior to administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody, Prior systemic treatment (e.g., curative intent) within 3 months, 4 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years No previous systemic therapy (e.g., chemotherapy). In some examples, the subject is chemotherapy naive.

In some embodiments, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are administered in combination with chemotherapy. For example, one or more PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody once every two weeks (Q2W), once every three weeks (Q3W) or once every four weeks (Q4W) dosing regimens can be administered in combination with a chemotherapeutic agent. The one or more chemotherapeutic agents are administered at the same frequency (Q2W, Q3W, or Q4W) or at a different frequency (e.g., 3 weeks on/1 week off) than the dosing frequency of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody. schedule (eg, days 1, 8, and 15 of every 28-day cycle)). For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every 2 weeks and one or more chemotherapeutic agents are administered weekly for 3 weeks on/1 week off, 2 Administer weekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are administered every three weeks and one or more chemotherapeutic agents are administered every week, every two weeks, every three weeks, or every four weeks. Alternatively, a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody administered every 4 weeks and one or more chemotherapeutic agents weekly, on 3 weeks on/1 week off, every 2 weeks, every 3 weeks, Or every 4 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). ) is administered.

In some embodiments, the dose of the chemotherapeutic agent is decreased after one or more initial doses (eg, after 1, 2, 3, 4, or more initial doses). For example, chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclophosphamide), taxanes ( For example, subsequent doses of paclitaxel, eg nab-paclitaxel) and/or topoisomerase II inhibitors (eg, doxorubicin))) are about 95%, 90%, 85%, 80%, 75%, 70% of the initial dose, It can be dosed at 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. For example, an initial dose of 125 mg/m ² nab-paclitaxel can be reduced for subsequent doses, eg, to 100 mg/m ² or 75 mg/m ² ; an initial dose of 100 mg/m ² nab-paclitaxel. ^{can be} reduced for subsequent doses ^, e.g. ² , 100 mg/m ² , or 75 mg/m ² ; an initial dose of paclitaxel of about 200 mg/m ² for subsequent doses such as 175 mg/m ² , 150 mg/m ² , initial doses of gemcitabine of about 1000 mg/m ² may be reduced to 125 mg/m ² , 100 mg/m ² , or 75 mg ^/ m ² ; m ² , 750 mg/m ² , 700 mg/m ² , 600 mg/m ^{2 ,} or 500 mg/m ² ; ^, 70 mg/m ² , 65 mg/m ² , 60 mg/m ² , 55 mg/m ² , 50 mg/m ² , or 45 mg/m ² ; and ^/ or ^AUC for ^{subsequent doses , e.g.} An initial dose of carboplatin sufficient to achieve AUC = 5.5. The dose may be reduced enough to achieve mg/ml/min, 5.0 mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min. In some examples, an initial dose of 125 mg/m ² nab-paclitaxel can be reduced for subsequent doses, eg ^, 100 mg/m ² or 75 mg/m ² ; The initial dose ^of paclitaxel can be ^{reduced to, for example, 75 mg/m 2 for} subsequent doses; initial dose of paclitaxel of ²⁰⁰ mg/m ² may be reduced to 125 mg/m ² , 100 mg/m ² , or 75 mg/m ² ; ² , 125 mg/m ² , 100 mg/m ^{2 ,} or 75 mg/ ^{m 2} ; /m ² , 750 mg/m ² , 700 mg/m ² , ⁶⁰⁰ mg/m ² , or 500 mg/m ² ; , 70 mg/m ² , 65 mg/m ² , 60 mg/m ² , ⁵⁵ mg/m ² , 50 mg/m ² , or 45 mg/m ² ; ^{and / or AUC = _} An initial dose of carboplatin sufficient to achieve 6 mg/ml/min was followed by subsequent doses, eg, AUC=5.5. The dose may be reduced enough to achieve mg/ml/min, 5.0 mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). antibodies, or anti-PD-1 antagonist antibodies such as pembrolizumab) and chemotherapy in combination to a subject in need thereof. In some embodiments, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg, , atezolizumab) every 2 weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (e.g., on day 1 of each 21-day dosing cycle), or every 4 weeks (e.g., Day 1 of each 28-day dosing cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 4 weeks (e.g., on day 1 of each 28-day dosing cycle) and a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 2 weeks (e.g., on days 1 and 15 of each 28-day dosing cycle) for 3 weeks (e.g., each on day 1 of each 21-day dosing cycle) or every 4 weeks (eg, on day 1 of each 28-day dosing cycle). In some examples, the chemotherapy combination comprises an effective amount of a first non-platinum-based chemotherapeutic agent and an effective amount of a second non-platinum-based chemotherapeutic agent. In some examples, the first non-platinum chemotherapeutic agent is an antimetabolite and the second non-platinum chemotherapeutic agent is a taxane. In some embodiments, chemotherapy combinations (e.g., antimetabolites (e.g., gemcitabine, pemetrexed or capecitabine) and taxanes (e.g., nab-paclitaxel and paclitaxel)) are administered weekly, biweekly, or three times every four weeks ( for example, on days 1, 8 and 15 of each 28-day dosing cycle).

In certain embodiments, the method comprises administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), PD-1 axis administration of a binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), gemcitabine and paclitaxel; tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered biweekly (e.g., on days 1 and 15 of each 28-day dosing cycle) and chemotherapy Combinations (e.g., antimetabolites and taxanes (e.g., gemcitabine and paclitaxel)) are administered more frequently (e.g., three times every four weeks (e.g., on days 1, 8 and 15 of each 28-day dosing cycle)) be done.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), antimetabolites (eg gemcitabine) and taxanes (eg paclitaxel) result in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), antimetabolites (eg gemcitabine) and taxanes (eg paclitaxel) result in increased PFS in subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), antimetabolites (eg gemcitabine) and taxanes (eg paclitaxel) prolong OS in subjects.

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

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD - an anti-TIGIT antagonist, including administering an L1 antagonist antibody (e.g., atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) to a subject in need thereof Antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab) every 3 weeks (e.g. , on day 1 of each 21-day dosing cycle), and a chemotherapy combination (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed) at the same frequency (e.g., every 3 weeks, e.g., on day 1 of each 21-day dosing cycle.In some examples, dosing continues for 4-6 induction dosing cycles (e.g., 4 induction dosing cycles). cycle, 5 induction dosing cycles, or 6 induction dosing cycles) After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In , the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and antimetabolites (eg pemetrexed) result in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and antimetabolite agents (eg, pemetrexed) result in increased PFS in subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and antimetabolite agents (eg, pemetrexed) prolong OS in subjects.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab). ), platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin), and subjects receiving antimetabolite agents (e.g., pemetrexed) undergoing treatment for solid tumors or locally advanced or metastatic cancer . Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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); renal cancer or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer); MSI-Low CRC).

The present invention also provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD-L1, such as atezolizumab). antagonist antibodies, or anti-PD-1 antagonist antibodies such as pembrolizumab) and chemotherapy (e.g., taxanes (e.g., paclitaxel or nab-paclitaxel)) to a subject in need thereof. . In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 2 weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (e.g., on day 1 of each 21-day dosing cycle), or every 4 weeks (e.g., on days 1 and 15 of each 21-day dosing cycle) Day 1 of a 28-day dosing cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In some embodiments, the chemotherapy is administered weekly, every two weeks, every four weeks, or three times every four weeks (eg, on days 1, 8 and 15 of each 28-day dosing cycle). In some embodiments, chemotherapy is administered weekly.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies, or anti-PD-1 antagonist antibodies such as pembrolizumab) and chemotherapy (eg, taxanes (eg, paclitaxel or nab-paclitaxel)) results in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of an L1 antagonist antibody, or an anti-PD-1 antagonist antibody such as pembrolizumab) and chemotherapy (eg, a taxane (eg, paclitaxel or nab-paclitaxel)) results in an increase in the subject's PFS compared to the reference. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies, or anti-PD-1 antagonist antibodies such as pembrolizumab) and chemotherapy (eg, taxanes (eg, paclitaxel or nab-paclitaxel)) results in an increase in DOR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of an L1 antagonist antibody, or an anti-PD-1 antagonist antibody such as pembrolizumab) and chemotherapy (eg, taxanes (eg, paclitaxel or nab-paclitaxel)) prolongs OS in subjects.

The present invention also provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD-L1, such as atezolizumab). antagonist antibody, or an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapeutic combination comprising administering to a subject in need thereof, the chemotherapeutic combination comprising an effective amount of platinum A chemotherapeutic agent and an effective amount of a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is a taxane (eg, paclitaxel or nab-paclitaxel). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 2 weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (e.g., on day 1 of each 21-day dosing cycle), or every 4 weeks (e.g., on days 1 and 15 of each 21-day dosing cycle) Day 1 of a 28-day dosing cycle). In some embodiments, chemotherapy combinations (e.g., platinum-based chemotherapeutic agents and taxanes (e.g., paclitaxel or nab-paclitaxel)) are given every week, every two weeks, every four weeks, or three times every four weeks ( for example, on days 1, 8 and 15 of each 28-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD- anti-TIGIT, including administering an L1 antagonist antibody (e.g., atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) to a subject in need thereof; Antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 3 weeks ( for example, on day 1 of each 21-day dosing cycle) and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and taxanes (e.g., paclitaxel or nab-paclitaxel) at the same frequency. (e.g., every 3 weeks, e.g., on day 1 of each 21-day dosing cycle.) In some examples, dosing continues for 4-6 induction dosing cycles (e.g., 4 , 5 induction dosing cycles, or 6 induction dosing cycles) After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In embodiments of , the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and taxanes (eg paclitaxel or nab-paclitaxel) result in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and taxanes (eg, paclitaxel or nab-paclitaxel) result in increased PFS in subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and taxanes (eg paclitaxel or nab-paclitaxel) prolong OS in subjects.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab). ), platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and taxanes (e.g., paclitaxel or nab-paclitaxel) undergoing treatment for solid tumors or locally advanced or metastatic cancer. ing. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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 renal or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI- Low CRC).

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

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD- an anti-TIGIT antagonist, including administering an L1 antagonist antibody (e.g., atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) to a subject in need thereof; Antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab) every 3 weeks (e.g. , on day 1 of each 21-day dosing cycle), and a chemotherapy combination (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a topoisomerase II inhibitor (e.g., etoposide) at the same frequency (e.g., , every 3 weeks, e.g., on day 1 of each 21-day dosing cycle.In some examples, dosing continues for 4-6 induction dosing cycles (e.g., 4 induction dosing cycles). 5 induction dosing cycles, or 6 induction dosing cycles) After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In a form, the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent or a topoisomerase II inhibitor (eg, etoposide).

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and topoisomerase II inhibitors (eg etoposide) lead to (a) CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and topoisomerase II inhibitors (eg etoposide) result in increased PFS in subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and topoisomerase II inhibitors (eg etoposide) prolong OS in subjects.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab). ), platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin), and subjects receiving topoisomerase II inhibitors (e.g., etoposide) undergoing treatment for solid tumors or locally advanced or metastatic cancer there is Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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 renal or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI- Low CRC).

an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or pembrolizumab) Also provided herein are methods and uses comprising administering an anti-PD-1 antagonist antibody (such as an anti-PD-1 antagonist antibody) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) to a subject in need thereof. In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) are administered every 3 weeks (eg, on day 1 of each 21-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD - an L1 antagonist antibody (e.g., atezolizumab) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) to a subject in need thereof, including an anti-TIGIT antagonist antibody (e.g., disclosed herein) anti-TIGIT antagonist antibodies, such as tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, such as atezolizumab) and VEGF antagonists (e.g., anti-VEGF antibodies (e.g., bevacizumab)) , administered every 3 weeks (eg, on day 1 of each 21-day dosing cycle). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibodies) and VEGF antagonists (eg, anti-VEGF antibodies (eg, bevacizumab)) result in increased OS in subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibodies) and VEGF antagonists (eg, anti-VEGF antibodies (eg, bevacizumab)) result in increased PFS in subjects.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab). ) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is being treated for solid tumors or locally advanced or metastatic cancer. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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 ( bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, renal cancer or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI-Low CRC) may be

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

an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) Also provided herein are methods and uses comprising administering to a subject in need thereof, the anti-PD-1 antagonist antibody is pembrolizumab. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered every 3 weeks (eg, on day 1 of each 21-day dosing cycle) and the anti-PD-1 antagonist antibody is pembrolizumab.

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), an anti-PD-1 antagonist antibody, and a VEGF antagonist ( anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof; , an anti-PD-1 antagonist antibody, and a 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) and anti-PD-1 An antagonist antibody is pembrolizumab. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (eg, bevacizumab)) results in increased OS in subjects, and the anti-PD-1 antagonist antibody is pembrolizumab. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (eg, bevacizumab)) resulted in increased PFS in subjects, and the anti-PD-1 antagonist antibody is pembrolizumab.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., Subjects receiving bevacizumab)) are being treated for solid tumors or locally advanced or metastatic cancer, and the anti-PD-1 antagonist antibody is pembrolizumab. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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 ( bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, renal or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI-Low CRC). may

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

In certain embodiments, the method comprises administering to a subject in need thereof an effective amount of tiragolumab and pembrolizumab, wherein tiragolumab is administered every three weeks (e.g., on day 1 of each 42-day dosing cycle). and Day 22), pembrolizumab is administered every 6 weeks (eg, on Day 1 of each 42-day dosing cycle). In some examples, the effective amount of tiragolumab and pembrolizumab results in increased OS in the subject and the anti-PD-1 antagonist antibody is pembrolizumab. In some examples, the effective amount of tiragolumab and pembrolizumab results in increased PFS in the subject and the anti-PD-1 antagonist antibody is pembrolizumab.

In some examples, the subject receiving tiragolumab and pembrolizumab is being treated for a solid tumor or locally advanced or metastatic cancer and the anti-PD-1 antagonist antibody is pembrolizumab. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced resection). Inoperable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., subject is at stage IV NSCLC never previously treated))): Cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 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 ( bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, renal or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI-Low CRC). may

Also, a method of treating a subject with cancer, wherein the subject is administered an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, PD-1 at a dose of about 900 mg to about 1500 mg every three weeks. Provided herein are methods comprising administering a dosing regimen comprising one or more dosing cycles of an axially bound antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. be done. In some examples, the method includes an induction phase and a maintenance phase. In some examples, the induction phase and the maintenance phase each include one or more dosing cycles. In some examples, the maintenance phase does not include administration of a platinum-based chemotherapeutic agent. In some examples, the maintenance phase does not include administration of non-platinum chemotherapeutic agents. In some examples, the maintenance phase comprises one or more administrations of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. Including dosing cycles.

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

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

Also provided herein is the use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or subject population with cancer in combination with a PD-1 axis binding antagonist, the treatment methods provided herein. It is due to 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, tiragolumab and atezolizumab are combined in an IV bag prior to administration.

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

Characterization and Selection of Cancer In any of the methods, uses or compositions for use described herein, the cancer can be a solid tumor or a locally advanced or metastatic cancer. In some examples, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC locally advanced unresectable NSCLC, stage IIIB NSCLC, 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., if the subject has stage IV never previously treated for NSCLC))): cervical cancer (e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-L1 positive child 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, such as metastatic PDAC); renal or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); ). In some instances the subject has breast cancer, the subject has no prior systemic treatment for metastatic breast cancer.

In some examples, in any of the methods, uses or compositions for use described herein, the subject has epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumors. No abnormalities. In some examples, the subject does not have a sensitizing EGFR gene mutation or ALK gene rearrangement in any of the methods, uses or compositions for use described herein. In some examples, the subject has a US East Coast Clinical Trials Group (ECOG) Performance (PS) of 0 or 1.

Methods for detecting mutational status EGFR and ALK are well known in the art and include, but are not limited to, Frampton et al. (Nature Biotechnology. 31(11): 1023-1033, 2013) using next-generation sequencing methods such as targeted gene pull-down and sequencing methods described in Clinical samples (e.g., tumor biopsies or blood samples). (eg, circulating tumor DNA in blood)). Such next-generation sequencing methods employ the use of small samples (e.g., from small core needle biopsies, fine needle aspirates, and/or cell blocks) or fixed samples (e.g., formalin-fixed paraffin-embedded (FFPE) samples). use 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 allowing be able to. Other methods for detecting EGFR and ALK mutational status include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods. An exemplary method for detecting the mutational status of ALK is disclosed in US Pat. No. 9,651,555, which is incorporated herein by reference in its entirety. In some examples, the VENTANA® Anti-ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.

In some examples 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 described in US Patent Application Publication No. 2018/0235968 and Juan et al. (Therapeutic Advances in Medical Oncology. 9(3):201-216, 2017), which are incorporated herein by reference in their entireties. In some examples, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (eg, mutations in exon 18, exon 19, exon 20 and/or exon 21). In some examples, the sensitizing EGFR mutation is a deletion of exon 19 (del19). In another example, the sensitizing EGFR mutation is the L858R point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the G719X point mutation in exon 18, where "X" is most commonly C, A or S. In some examples, the sensitizing EGFR mutation is the G719S point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the G719A point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the S720F point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the L861Q point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the L861R point mutation in exon 21. In another example, the sensitizing EGFR mutation is the T790M point mutation. In some examples, the sensitizing EGFR mutation is the E709X point mutation, where "X" is most commonly K, A, or H. In some examples, the sensitizing EGFR mutation is the S768I point mutation.

In some examples of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are well known in the art and are described in US Pat. No. 9,651,555 and Du et al. (Thoracic Cancer. 9:423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, ALK gene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways to increase cell proliferation and survival. In some instances, the ALK gene rearrangement results in the formation of a fusion oncogene, EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC , TMP4, and MSN. In some instances, the ALK gene rearrangement is an EML4 rearrangement with ALK, resulting in the formation of the fusion oncogene EML4-ALK.

In some examples, in any of the methods, uses or compositions for use described herein, the subject does not have pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. Methods for detecting subtypes of NSCLC are well known in the art and include, but are not limited to, histopathological criteria or molecular characteristics (e.g., biomarkers (e.g., specific genes or (subtype) characterized by expression of one or a combination of proteins). In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample.

In some examples, in any of the methods, uses, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection; or no known or suspected chronic active EBV infection. Indicators of active or chronically active EBV infection for use in the methods described herein include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and subject-derived samples ( Examples include Epstein-Barr virus particles detected in blood or serum samples). To detect the presence of one or more indicators of active or chronically active EBV infection, including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from a subject are well known in the art and include serological diagnostics (e.g. detection of EBV DNA (e.g. by PCR analysis of blood samples to detect EBV virions) or detection of EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV IgM or EBV IgG using heterophilic antibodies) In some examples, the sample is a whole blood sample, a serum sample and a plasma sample. is selected from the group consisting of: In some examples, the subject is EBV IgM negative and/or is negative by EBV PCR, In some examples, the subject is EBV IgM negative and /or negative for EBV PCR and positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA) In other examples, the subject is negative for EBV IgG and/or Negative for EBNA.

In some examples, in any of the methods, uses or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., as determined by IHC using the SP 263 or 22C3 antibody). tumor PD-L1 expression with a minimum PD-L1 positive tumor cell fraction or TPS ≥ 30% (e.g., ≥ 50%), or PD-L1 expression in tumor samples as determined by IHC using the SP 142 antibody 1% or more of the tumor area occupied by tumor-infiltrating immune cells (IC)). In some examples, a PD-L1-selected tumor is determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater) or PD-L1 TPS by immunohistochemistry (IHC) assay. tumor. In some examples, a PD-L1-selected tumor is a tumor that has 1% or more of the tumor area occupied by PD-L1-expressing immune cells (ICs) as determined by an immunohistochemistry (IHC) assay. . In some examples, the IHC assay uses anti-PD-L1 antibodies SP263, 22C3, SP142 or 28-8. In some examples, the IHC assay uses the anti-PD-L1 antibody SP263. In some examples, the IHC assay uses the anti-PD-L1 antibody SP142. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some instances, the tumor sample has been determined to have a TPS of 50% or greater. In some examples, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), anti-PD- as determined by positive staining with the L1 antibody 22C3 (eg using the pharmDx assay) or by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142. In some instances, the IC has been determined to be 1% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be 5% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC has been determined to be 10% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 50% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 30% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay).

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

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

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

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. In comparison, it results in an increase in the subject's PFS. For example, in embodiments in which no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tiragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), treatment may include, for example, anti-TIGIT Compared to treatment with a PD-1 axis binding antagonist without an antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist, it may result in an increase in PFS in a subject. an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more of 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)) In embodiments, the treatment is, for example, (i) compared to treatment with a PD-1 axis binding antagonist and one or more chemotherapeutic agents without an anti-TIGIT antagonist antibody; (ii) PD-1 axis binding compared to treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents without an antagonist; and/or (iii) a PD-1 axis binding antagonist and anti-TIGIT without one or more chemotherapeutic agents. It may result in an increase in PFS of the subject or population of subjects compared to treatment with the antagonist antibody.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Compare and extend the target OS. For example, in embodiments in which no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tiragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), treatment may include, for example, anti-TIGIT Compared to treatment with a PD-1 axis binding antagonist without an antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist, it may result in increased OS in the subject. an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more of non-platinum chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed, gemcitabine or capecitabine), taxanes (e.g., paclitaxel, such as nab-paclitaxel) and/or topoisomerase II inhibitors (e.g., etoposide))) In administered embodiments, the treatment is, for example, (i) compared to treatment with a PD-1 axis binding antagonist and one or more chemotherapeutic agents without an anti-TIGIT antagonist antibody; (ii) PD-1 compared to treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents without an axis binding antagonist; and/or (iii) a PD-1 axis binding antagonist and without one or more chemotherapeutic agents. It may result in an increase in OS of the subject or population of subjects compared to treatment with an anti-TIGIT antagonist antibody.

Subject progression-free survival was determined according to Eisenhauer et al. , Eur. J. Cancer. 2009, 45:228-47, according to the RECIST v1.1 standard. In some embodiments, PFS is measured as the time from initiation of treatment to the first occurrence of disease progression as determined by the criteria of RECIST version 1.1. In some embodiments, PFS is measured as the time from initiation of treatment to death.

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

In some embodiments, treatment described herein reduces the subject's DOR by at least about 2.4 months (eg, 2.4-120 months, 2.5-100 months, 3.0-80 months). , 4.0-60 months, 5.0-48 months, 6.0-36 months, 8.0-24 months or 10-12 months, such as at least about 2.4 months, 2.5 months,2. 6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3. 6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4. 6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 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) Extend. In some embodiments, treatment reduces the subject's DOR by at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9-36 months). , or 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months , 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months , 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months , 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, treatment reduces the subject's DOR by at least about 2 months (eg, 2-120 months, 3-100 months, 4-80 months, 6-60 months, 8-48 months, 9-36 months). , or 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months , 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months , 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months , 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months , 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months , 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 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 time from initiation of treatment to death. In some examples, the treatment reduces the subject's OS by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months,2. 7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.6 months; 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 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 examples, the treatment reduces the subject's OS by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-3 months). 36 months, or 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months 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 months. 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 examples, the treatment reduces the subject's OS by at least about 5.3 months (eg, 5.3-120, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months 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. Treatment Methods and Uses for Lung Cancer Lung cancer remains the leading cause of cancer death worldwide. In the United States, it is the most common cancer in both men and women, accounting for 12%-14% of all new cancer cases. There will be an estimated 228,820 new lung cancer cases and 135,720 deaths in the United States in 2020 (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 about 80%-85% of all cases (Osmani et al. Semin Cancer Biol. 52(Pt 1):103-9 (2018) ). NSCLC can be divided into two major histologic types: adenocarcinoma and squamous cell carcinoma (Travis et al. 2011). Adenocarcinoma histology accounts for approximately 40%-50% of all NSCLCs, and squamous histology accounts for approximately 20%-30% of NSCLCs (Osmani et al. Semin Cancer Biol. 52(Pt 1):103-9). (2018)). The remaining cases of NSCLC are represented by large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated histology.

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

For progressive disease, the overall 5-year survival rate is 2%-4%. Poor prognostic factors for survival of NSCLC patients include advanced stage of the disease at initial diagnosis, poor performance status, and a history of unintended weight loss. More than half of NSCLC patients are diagnosed with distant disease, which directly contributes to their poor survival prospects.

Despite improvements in first-line treatment of patients with advanced NSCLC that have resulted in longer survival and fewer disease-related symptoms, nearly all patients experience disease progression. Cancer immunotherapy, in particular, offers the potential for long-term disease control. In the setting of metastatic NSCLC, PD-L1/PD-1 blocking antibodies (eg, atezolizumab, nivolumab, and pembrolizumab) are clinically relevant in either unselected or PD-L1-selected advanced NSCLC patients. brought some benefit. However, a significant proportion of patients remain unresponsive or progressing to anti-PD-L1/PD-1 treatment, and the escape mechanisms for such treatment are poorly understood.

Therefore, lung cancers (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 a better benefit-risk profile. There is an unmet need in the art for the development of effective immunotherapies and methods of administering them for the treatment (eg, first-line therapy) of )).

Small Cell Lung Cancer Small cell lung cancer (SCLC) accounts for approximately 15% of all cases of lung cancer. The majority of SCLC patients (approximately 70%) are diagnosed with advanced-stage disease (ES-SCLC), which has a poor survival prospect (median OS approximately 10-12 months). Chemotherapy alone can relieve symptoms and prolong survival in ES-SCLC patients, but long-term survival is rare. The 5-year relative survival rate for people with stage I SCLC is about 31%. In Stage IV, the 5-year relative survival rate drops to approximately 2%.

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

i. Methods and Uses for Treating Lung Cancer United States Patent Application 20070010000 Kind Code: A1 A method of treating a subject population with lung cancer comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor. wherein the treatment is at least about 6 months (e.g., at least about 6 months (e.g., between 6 months and 24 months (e.g., about 6 months and about for 15 months (eg, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, or 15 months), such as between about 6 months and about 13 months (For example, 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months , 12 months, 12.5 months, 13 months)), for example, between about 8 months and about 10 months (eg, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.1 months, 8.2 months, 8.3 months, 8.4 months; 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. Provided herein are methods that yield a median PFS for a subject population of 5 months, 9.6 months, 9.7 months, 9.8 months, 9.9 months, 10.0 months)). In an example of, the treatment is for about 8.2 months to about 9.2 months (eg, about 8.2, 8.4, 8.6, 8.8, 9.0, or 9.2 months, such as 8.2-8.4, 8.4-8.6, 8.6-8.8, 8.8-9.0, or 9.0-9.2 months) median PFS of the target population Bring.

A method of treating a subject population having lung cancer, comprising 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. administering to a subject population, wherein the treatment is 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))) of the subject population Also provided herein is a method for generating the median value. In some examples, the treatment is for about 15.3 months to about 17.6 months (eg, about 15.5, 16, 16.5, 17, 17.5, or 17.6 months, eg, 15.6 months). 3-16 months, 16-17 months, or 17-17.6 months).

ii. Methods and uses for treating small cell lung cancer an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab), platinum Provided herein are methods and uses comprising administering to a subject or population of subjects one or more dosing cycles of a systemic chemotherapeutic agent (e.g., carboplatin or cisplatin) and a topoisomerase II inhibitor (e.g., etoposide). .

Dosing Regimens, Administration, and Response to Treatment The treatment methods and uses of the invention described herein, in one aspect, provide a subject or subject population with lung cancer (eg, SCLC, eg, ES-SCLC) with an effective amount of an antimicrobial agent. TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies as disclosed herein, eg, tiragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), platinum-based chemistries comprising administering a therapeutic agent and a topoisomerase II inhibitor, wherein the treatment 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 or prolong the progression-free survival (PFS) of a subject population, thereby treating the subject or subject population. In some examples, the treatment prolongs OS of a 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, an individual's PFS is determined according to RECIST v1.1 criteria, as described in Eisenhauer et al. , Eur. J. Cancer. 2009, 45:228-47. In some embodiments, PFS is measured as the time from initiation of treatment to the first occurrence of disease progression as determined by the criteria of RECIST version 1.1. In some embodiments, PFS is measured as the time from initiation of treatment to death.

In some embodiments, the treatment reduces the subject's or subject population's PFS by at least about 2.4 months (e.g., 2.4-120 months, 2.5-100 months, 3.0-80 months, 4.0-60 months, 5.0-48 months, 6.0-36 months, 8 .0-24 months, or 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10 months. 5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's or population of subjects' PFS to at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9-36 months, or 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10 months. 5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's or population of subjects' PFS to at least about 2 months (eg, 2-120 months, 3-100 months, 4-80 months, 6-60 months, 8-48 months, 9-36 months, or 10-24 months, such as at least about 2.0 months, 2 .1 month, 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 months .1 month, 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 months .1 month, 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 months .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 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 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 reduces the subject's or population of subjects' PFS by at least about Extend for 3 to 4 months.

In some examples, methods and uses of treating a subject or subject population with lung cancer (eg, SCLC, eg, ES-SCLC) include an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antibody disclosed herein). TIGIT antagonist antibodies (eg, tiragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies such as atezolizumab), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and topoisomerase II inhibitors (eg, etoposide). ) to a subject or population of subjects, wherein the treatment is 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 the subject or Extend OS in the subject population.

In some embodiments, OS is measured as the time from initiation of treatment to death. In some examples, treatment reduces the OS of a subject or population of subjects by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months 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 months. 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 examples, treatment reduces OS of a subject or population of subjects by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, eg, at least about 3.3 months; 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 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 examples, treatment reduces the OS of a subject or population of subjects by at least about 5.3 months (eg 5.3 to 120 months, 6 to 60 months 7 to 48 months 8 to 36 months or 10 to 24 months such as at least about 5.3 months 5.5 months 6.0 months 6.5 months 7. 0 months 7.5 months 8.0 months 8.5 months 9.0 months 9.5 months 10 months 10.5 months 11 months 11.5 months 12 months 13 months 14 months 15 months 16 months 17 months 18 months 19 months 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

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

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

In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 600 mg (eg, fixed dose) every three weeks. In some examples, combination therapy (e.g., combination treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, e.g., atezolizumab)), a topoisomerase II inhibitor (e.g., etoposide), and/or A dose (e.g., fixed dose) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) administered with a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) can be It may be reduced compared to standard doses of anti-TIGIT antagonist antibody administered as drug therapy.

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

In some examples, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., fixed dose) of about 1400 mg to 2000 mg every 4 weeks. . In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, fixed dose) of 1400 mg to 2000 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, fixed dose) of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg (eg, fixed dose) every 4 weeks. In some examples, combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), a topoisomerase II inhibitor (e.g., etoposide), and / or a dose (e.g., fixed dose) of a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered with a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) It may be reduced compared to standard doses of PD-1 axis binding antagonists administered as drug therapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg, e.g., between about 1 mg/kg and about 35 mg/kg) such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as about 12 mg/kg. between 5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0 .1 mg/kg, eg about 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.1 mg/kg and about 15 mg/kg, e.g., between about 0.5 mg/kg and about 15 mg/kg, e.g., between about 1 mg/kg and about 15 mg/kg) between about 2.5 mg/kg and about 15 mg/kg, such as between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as about between 10 mg/kg and about 15 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg; For example, about 15±0.5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 15 mg/kg administered every 3 weeks.

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

In some examples, combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), a topoisomerase II inhibitor (e.g., etoposide), and /or a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered with a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered as monotherapy It may be reduced compared to standard doses of PD-1 axis binding antagonists.

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

AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol. 1989, 7:1748-56):
Total Dose (mg) = (Target AUC) X (Glomerular Filtration Rate [GFR] + 25)

In some instances, for example, 1200 mg of atezolizumab corresponds to an average weight-based dose of 15 m/kg.

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

In some examples, the effective amount of topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg / ^m2 , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/ ^m2 , about 100 mg/m2, about 110 mg/ ^m2 , about 120 mg/ ^m2 , about 130 ^{mg/m2 ,} about 140 mg/m ² , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/m2, about 180 mg ^{/m2, about 190 mg/m2, about 200 mg/m2, about 250 mg/m2 , about 300 mg} / ^m2 , about 400 mg/ ^m2 , about 500 mg/ ^m2 , about 600 mg/ ^m2 , about 700 mg/ ^m2 , about 800 mg/ ^m2 , about 900 mg/ ^m2 , or about 1000 mg/ ^m2 ). In some examples, an effective amount of topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² .

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

In some examples, the effective amount of topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg / ^m2 , 80 mg/ ^m2 , 90 mg/ ^m2 , 100 mg/m2 ^, 110 mg/ ^m2 , 120 mg/ ^m2 , 130 mg/ ^m2 , 140 mg/ ^m2 , 150 mg/ ^m2 , 160 mg/ ^m2 , 170 mg / ^m2 , 180 mg/ ^m2 , 190 mg/ ^{m2 ,} 200 mg/m2, 250 mg/ ^m2 , 300 mg/ ^m2 , 400 mg/ ^m2 , 500 mg/ ^m2 , 600 mg/ ^m2 , 700 mg/ ^m2 , 800 mg /m ² , 900 mg/m ² , or 1000 mg/m ² ). In some examples, the effective amount of topoisomerase II inhibitor (eg, etoposide) is 100 mg/m ² .

In any of the methods and uses of the invention, anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies as disclosed herein, eg, tiragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 Antagonist antibodies (e.g., atezolizumab)), platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin), and topoisomerase II inhibitors (e.g., etoposide)) may be administered for 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) can be administered at In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) (with or without platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or topoisomerase II inhibitors (e.g., etoposide)) to clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 18 days to 24 days (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 examples, the dosing cycle length is about 21 days. In another example, the dosing cycle length is about 14 days. In another example, the dosing cycle length is about 28 days.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. be done. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 600 mg on day 1 of each dosing cycle, e.g., each 21-day cycle (e.g., fixed dose) (ie, at a dose of about 600 mg every 3 weeks) intravenously. In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg on day 1 of each dosing cycle, e.g., each 21-day cycle. (eg, fixed dose) (ie, at a dose of 600 mg every 3 weeks) intravenously. Similarly, in some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) on about day 1 (e.g., day 1±3) of each dosing cycle Administer. For example, in some instances, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., about 1200 mg ) every 3 weeks) intravenously. In other examples, for example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., about 1200 mg dose every 3 weeks) is administered intravenously. In some examples, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 1200 mg on day 1 of each 21-day cycle (ie, at a dose of 1200 mg for 3 days). weekly) is administered intravenously. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (eg, day 1±3) of each dosing cycle. In some examples, the platinum-based chemotherapeutic agent is administered on about day 1 (eg, day 1±3) of each dosing cycle. In some examples, the topoisomerase II inhibitor is present on about day 1 (eg, day 1±3) of each dosing cycle. For example, in some instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on day 1 of each 21-day cycle (i.e., every 3 weeks). A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose of about 600 mg on day 1 of each 21-day cycle. (i.e., at a dose of about 1200 mg every 3 weeks) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) on day 1 of each of the four initial dosing cycles. and a topoisomerase II inhibitor (e.g., etoposide) on days 1, 2, and 3 of each of the four initial dosing cycles. A dose of 100 mg/m ² is administered on each of the days. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on day 1 of each 21-day cycle (i.e., 600 mg every 3 weeks). A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose of about 600 mg on day 1 of each 21-day cycle (i.e., administered intravenously at a dose of 1200 mg every 3 weeks) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) at AUC = 5 mg/day 1 of each of the 4 initial dosing cycles. A topoisomerase II inhibitor (e.g., etoposide), administered at a dose sufficient to achieve ml/min, on each of days 1, 2, and 3 of each of the four initial dosing cycles Administer at a dose of 100 mg/m ² .

In some examples, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor are administered in each of four initial dosing cycles. In some examples, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg on day 1 of each of four initial dosing cycles. In some examples, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 600 mg on day 1 of each of four initial dosing cycles. In some examples, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg on day 1 of each of four initial dosing cycles. In some examples, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg on day 1 of each of four initial dosing cycles (e.g., on day 1 of each of four initial dosing cycles at a dose of about 1200 mg) to the eye). In some examples, the anti-TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg on day 1 of each of four initial dosing cycles. In some examples, the anti-TIGIT antagonist antibody is administered at a dose of 30 mg to 600 mg on day 1 of each of four initial dosing cycles. In some examples, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg on day 1 of each of four initial dosing cycles. In some examples, the PD-1 axis binding antagonist is administered at a dose of 80 mg to 1600 mg on day 1 of each of the four initial dosing cycles (e.g., on day 1 of each of the four initial dosing cycles at a dose of 1200 mg). In some examples, the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on day 1 of each of four initial dosing cycles and/or topoisomerase II Inhibitors are administered at a dose of 100 mg/ ^m2 on each of days 1, 2, and 3 of each of the four initial dosing cycles.

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

In some examples, the anti-TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg on day 1 of each of one or more additional dosing cycles (e.g., on day 1 of each of one or more additional dosing cycles). at a dose of 30 mg to 600 mg). In some examples, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg on day 1 of each of one or more additional dosing cycles. In some examples, the PD-1 axis binding antagonist is administered at a dose of 80 mg to 2000 mg on day 1 of each of one or more additional dosing cycles (e.g., 1 of each of one or more additional dosing cycles). doses of 840 mg, 1200 mg or 1680 mg per day). In some examples, additional dosing cycles include administration of a PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. . For example, in some instances, each of the one or more additional dosing cycles is 14 days, and the PD-1 axis binding antagonist (eg, atezolizumab) is administered for 1 day of each of the one or more additional dosing cycles. A dose of 840 mg is administered to the eye. In some examples, each of the one or more dosing cycles is 21 days and the PD-1 axis binding antagonist (eg, atezolizumab) is 1200 mg on day 1 of each of the one or more additional dosing cycles. administered in doses. In some examples, each of the one or more dosing cycles is 28 days and the PD-1 axis binding antagonist (eg, atezolizumab) is 1680 mg on day 1 of each of the one or more additional dosing cycles. administered in doses.

In some examples, a subject or subject population with lung cancer (eg, SCLC, eg, ES-SCLC) is administered between about 30 mg and about 1200 mg (eg, between about 30 mg and about 1100 mg, for example between about 60 mg and about 1000 mg, such as between about 100 mg and about 900 mg, such as between about 200 mg and about 800 mg, such as between about 300 mg and about 800 mg, such as between about 400 mg and about 800 mg, such as between about 400 mg and about between 750 mg, such as between about 450 mg and about 750 mg, such as between about 500 mg and about 700 mg, such as between about 550 mg and about 650 mg, such as 600 mg±10 mg, such as 600±6 mg, such as 600±5 mg, such as 600±3 mg , e.g., 600±1 mg, e.g., 600±0.5 mg, e.g., 600 mg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) on Day 1 of the dosing cycle of about between 80 mg and about 2000 mg, such as between about 100 mg and about 1600 mg, such as between about 200 mg and about 1600 mg, such as between about 300 mg and about 1600 mg, such as between about 400 mg and about 1600 mg, such as between about 500 mg and about 1600 mg between about 600 mg and about 1600 mg, such as between about 700 mg and about 1600 mg, such as between about 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as about 1050 mg and about 1350 mg, such as between about 1100 mg and about 1300 mg, such as between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg) (eg between about 30 mg and 1200 mg (eg between 30 mg and 1100 mg, such as between 60 mg and 1000 mg, such as between 100 mg and 900 mg) between 200 mg and 800 mg, such as between 300 mg and 800 mg, such as between 400 mg and 800 mg, such as between 400 mg and 750 mg, such as between 450 mg and 750 mg, such as between 500 mg and 700 mg, such as between 550 mg and 650 mg, For example 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) PD-1 axis binding antagonist (eg anti-PD-L1 antagonist) antibody (e.g., atezolizumab)), between 80 mg and 2000 mg on day 1 of each dosing cycle (e.g., between 100 mg and 1600 mg, such as between 200 mg and 1600 mg, such as between 300 mg and 1600 mg, such as between 400 mg and 1600 mg, such as between 500 mg and 1600 mg, such as between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as between 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg±5 mg, such as 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0. PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of 1-50 mg/ml/min (eg, 2-25 mg/min) on day 1 of each dosing cycle. ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 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/min A dose of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) sufficient to achieve an AUC of 5 mg/ml/min.ml/min, e.g. The eye is treated by administering one or more dosing cycles (e.g., a 21-day dosing cycle) of a topoisomerase II inhibitor (e.g., etoposide) at a dose of 100 mg/ ^m2 to the subject or subject population, wherein PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)) without TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tiragolumab), platinum-based Prolongs PFS and/or OS in a subject or subject population compared to a treatment comprising a chemotherapeutic agent (eg, carboplatin or cisplatin) and a topoisomerase II inhibitor (eg, etoposide).

In some examples, a subject or subject population (eg, SCLC, eg, ES-SCLC) with lung cancer is administered about 30 mg to 1200 mg (eg, between 30 mg and 1100 mg, such as 60 mg and 1000 mg) on Day 1 of each dosing cycle. between 100 mg and 900 mg, such as between 200 mg and 800 mg, such as between 300 mg and 800 mg, such as between 400 mg and 800 mg, such as between 400 mg and 750 mg, such as between 450 mg and 750 mg, such as between 500 mg and 700 mg such as between 550 mg and 650 mg, such as 600±10 mg, such as 600±6 mg, such as 600±5 mg, such as 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg). (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab), 80 mg to 2000 mg (eg, between 100 mg and 1600 mg, such as between 200 mg and 1600 mg, such as 300 mg and 1600 mg) on day 1 of each dosing cycle. between 400 mg and 1600 mg, such as between 500 mg and 1600 mg, such as between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as between 900 mg and 1500 mg, such as between 1000 mg and 1400 mg between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ±1.0 mg, such as 1200±0.5 mg, such as 1200 mg) PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), 1-50 mg on day 1 of each dosing cycle /ml/min (such as 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/min ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min, such as 5 mg A platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) at a dose sufficient to achieve an AUC of 100 mg/ml/min) and 100 mg/ ^m2 on days 1, 2, and 3 of each dosing cycle of a dose of a topoisomerase II inhibitor (e.g., etoposide) by administering one or more dosing cycles (e.g., 21-day dosing cycles) to the subject or subject population, wherein the treatment comprises an anti-TIGIT antagonist antibody (e.g., this PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)), platinum-based chemotherapeutic agents (e.g., carboplatin), without the anti-TIGIT antagonist antibodies disclosed herein (e.g., tiragolumab) or cisplatin), and a topoisomerase II inhibitor (eg, etoposide), prolongs PFS and/or OS in a subject or subject population.

In some examples, treatment reduces OS of a subject or population of subjects by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, eg, at least about 3.3 months; 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 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 examples, treatment reduces the OS of a subject or population of subjects by at least about 5.3 months (eg 5.3 to 120 months, 6 to 60 months 7 to 48 months 8 to 36 months or 10 to 24 months such as at least about 5.3 months 5.5 months 6.0 months 6.5 months 7. 0 months 7.5 months 8.0 months 8.5 months 9.0 months 9.5 months 10 months 10.5 months 11 months 11.5 months 12 months 13 months 14 months 15 months 16 months 17 months 18 months 19 months 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, the treatment reduces the subject's or population of subjects' PFS to at least about 2.4 months (e.g., 2.4-120 months, 2.5-100 months, 3.0-80 months, 4.0-60 months, 5.0-48 months, 6.0-36 months, 8.0-24 months, or 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months , 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months , 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10 months .5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months , 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's or population of subjects' PFS to at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9-36 months, or 10-24 months, eg, 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 months .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 subject or subject population is administered an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and about 80 mg to about 2000 mg on Day 1 of each additional dosing cycle. and carboplatin and etoposide are omitted from each of the one or more additional dosing cycles.

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

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab)) to the subject or subject population. In some examples, the method includes an intervening first observation period, eg, after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis binding antagonist. In some examples, the method further comprises a second observation period after administration of the PD-1 axis binding antagonist. In some examples, 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 examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. In examples in which the first and second observation periods are each about 60 minutes, the method comprises administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist during the first and second observation periods about 30±10 minutes. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at . In examples where the first and second observation periods are each about 30 minutes, the method includes administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist during the first and second observation periods about 15±10 minutes. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at .

In other examples, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is combined with an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab). ) to a subject or population of subjects. In some examples, the method includes an intervening first observation period, eg, after administration of the PD-1 axis binding antagonist and before administration of the anti-TIGIT antagonist antibody. In some examples, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the method includes both a first observation period following administration of the PD-1 axis binding antagonist and a second observation period following administration of the anti-TIGIT antagonist antibody. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. In examples in which the first and second observation periods are each about 60 minutes, the method includes administering the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody during the first and second observation periods about 30±10 minutes. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at . In examples in which the first and second observation periods are about 30 minutes each, the method comprises administering the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody during the first and second observation periods about 15±10 minutes. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at .

In other examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 (atezolizumab) antagonist antibody) are The subjects or populations of subjects are administered simultaneously. In some examples, the method includes an observation period, eg, after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody). In some examples, the observation period is between about 30 minutes and about 60 minutes long. If the observation period is about 60 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and an anti-TIGIT antagonist antibody during the observation period at about 30±10 minutes. , may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature). If the observation period is about 30 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and an anti-TIGIT antagonist antibody during the observation period about 15±10 minutes. , may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature).

In any method, use or composition for use described herein, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), PD-1 axial binding antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab)), platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and topoisomerase II inhibitors (e.g., etoposide)) or pharmaceutical agents thereof One or more immune co-inhibitory receptors such as additional anti-cancer therapeutic agents (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab (YERVOY®))) (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), or one or more immune co-stimulatory receptors (e.g. one or more selected from CD226, OX-40, CD28, CD27, CD137, HVEM and/or GITR) such as OX-40 agonists, e.g. chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapy, and/or anti-hormonal agents such as those listed hereinabove. ) in conjunction with (separately or together).

In some examples, the lung cancer is small cell lung cancer (SCLC), eg, extensive-stage SCLC (ES-SCLC). In some examples, the subject or subject population is treatment naive for ES-SCLC (eg, chemotherapy naive for ES-SCLC).

In some examples, lung cancers are not selected for PD-L1 expression. In another example, lung cancers are selected for PD-L1 expression. In some examples, lung cancers are selected for PD-L1 expression by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody such as SP 263, 22C3, SP 142, or 28-8. . In some examples, the anti-PD-L1 antibody is SP 263 and the IHC assay is the Ventana SP 263 IHC assay. The anti-PD-L1 antibody is 22C3, the IHC assay is the pharmDx 22C3 IHC assay, the anti-PD-L1 antibody is SP 142, the IHC assay is the Ventana SP 142 IHC assay, or the anti-PD-L1 antibody is 28-8 and the IHC assay is the pharmDx 28-8 IHC assay.

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

In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the SCLC is advanced small cell lung cancer (ES-SCLC), also called stage 4 (IV) SCLC. In some embodiments, SCLC is according to or as defined by the Veterans Administration Lung Study Group (VALG) staging system (see, e.g., Micke et al. Lung Cancer 2002, 37:271-6). In addition, ES-SCLC confirmed histologically or cytologically. In some embodiments, SCLC is classified as ES-SCLC if the individual is inoperable and cannot be classified as having limited or limited stage SCLC (L-SCLC or LS-SCLC). being classified. In some embodiments, ES-SCLC is detectable and/or has spread outside the originally affected lung. In some embodiments, ESSCLC is detectable and/or has spread further to other (eg, remote) organs such as the liver, adrenal glands, lymph nodes and/or brain. In some embodiments, ESSCLC is difficult to treat.

In some embodiments, the subject or subject population has a poor prognosis. In some embodiments, the subject or subject population is a treatment-naive subject or subject population (eg, a chemotherapy-naive subject or subject population). In some embodiments, a treatment-naive subject is, for example, a subject who has had no prior treatment for cancer, SCLC, or ES-SCLC. In some embodiments, a treatment-naive subject is a subject who has never had prior treatment for ES-SCLC. In some embodiments, the treatment-naive subject is chemotherapy-naive, e.g., a subject who has not received prior chemotherapy for treatment of cancer, SCLC and/or ES-SCLC. . In some embodiments, the subject or subject population is treatment naïve for ES-SCLC. In some embodiments, the subject or subject population has no prior systemic treatment for ES-SCLC. In some embodiments, the subject or subject population has received prior chemoradiation therapy for limited-stage SCLC (LS-SCLC) with curative intent, and the last chemotherapy since the diagnosis of ES-SCLC; Have undergone at least 6 months of treatment-free cycle from a radiotherapy or chemoradiation cycle. In some embodiments, the subject or subject population has an asymptomatic supratentorial or cerebellar central nervous system (CNS) metastasis. In some embodiments, the subject or subject population does not have metastasis to the midbrain, pons, medulla oblongata, or spinal cord. In some embodiments, the subject or subject population has CNS disease and does not require corticosteroid treatment for CNS disease. In some embodiments, the subject or subject population has new asymptomatic metastases and has undergone radiation therapy and/or surgery for CNS metastases. In some embodiments, the subject or subject population is a measurable disease. In some embodiments, the subject or subject population has no prior treatment with a CD 137 agonist or immune checkpoint blockade therapy.

In some instances, treatment results in CR or PR. In some examples, the subject or subject population's PFS is increased compared to the baseline PFS time. In some examples, the baseline PFS time is without an anti-TIGIT antagonist antibody (e.g., tiragolumab) (e.g., an anti-PD-L1 antibody (e.g., atezolizumab)), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and Median PFS time in a subject population that has received treatment with a topoisomerase II inhibitor (eg, etoposide).

In some examples, the method further comprises an additional treatment. Further treatments include radiotherapy, 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. Additional treatment may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is administration of small molecule enzyme inhibitors or antimetastatic agents. In some embodiments, the additional therapy is administration of side effect limiting agents (eg, agents intended to reduce the incidence and/or severity of side effects of treatment, such as antiemetic agents, etc.). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional treatment is surgery. In some embodiments, the additional treatment is a combination of radiation therapy and surgery. In some embodiments, the additional treatment is gamma irradiation.

Additional therapeutic antibodies contemplated for use herein include, but are not limited to, alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab ( VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar , Corixia), antibody-drug conjugate gemtuzumab ozogamicin (Myrotak®, Wyeth), apolizumab, acelizumab, atolizumab, bapinuzumab, vivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celolizumab mabpegor, sidovucituzumab, sidutuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erulizumab, felubizumab, vontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, mattuzumab, mepolizumab,モタビズマブ、モトビズマブ、ナタリズマブ、ニモツズマブ、ノロビズマブ、ヌマビズマブ、オクレリズマブ、オマリズマブ、パリビズマブ、パスコリズマブ、ペクフシツズマブ、ペクセリズマブ、ペクセリズマブ、ラリビズマブ、ラニビズマブ、レスリビズマブ、レスリズマブ、レスリビズマブ、ロベリズマブ、ルピズマブ、シブロツズマブ、シプリズマブ、ソンツズマブ、タカタツズマブTetraxetane, tadoxizumab, talizumab, tefibazumab, tocilizumab, tralizumab, tucuzumab cermoreukin, tuxituzumab, umabizumab, ultoxazumab, ustekinumab, vigilizumab, and interleukin-12 (ABT-874/J695, Wyeth Research and Abbott) mentioned.

In some embodiments, the additional therapy is a therapy targeting the PI3K/AKT/mTOR pathway, HSP 90 inhibitors, tubulin inhibitors, apoptosis inhibitors, and/or chemopreventive agents. In some embodiments, the additional therapy is CTLA-4 (also known as CD152), eg, blocking antibody, ipilimumab (also known as MDX-010, MDX-101, or Yervoy®) , tremelimumab (also known as ticilimumab or CP-675, 206), antagonists to B7-H3 (also known as CD276), such as blocking antibodies, MGA271, antagonists to TGF-beta, such as metelimumab (CAT-192 ), frezolimumab (also known as GC1008), or LY2157299, a treatment involving adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR); Treatments including adoptive transfer of T cells containing dominant-negative TGFbeta receptors, e.g., dominant-negative TGFbeta type II receptors, treatments including HERCREEM protocols (see, e.g., ClinicalTrials. -1BB, or ILA), e.g., activating antibody, Urelumab (also known as BMS-663513). activating antibody, activating antibody administered in conjunction with a different anti-OX40 antibody (eg, AgonOx), agonists to CD27, such as activating antibody, CDX-1127, indoleamine-2, 3-dioxygenase (IDO), 1-methyl-D-tryptophan (also known as 1-D-MT), antibody drug conjugates (in some embodiments, including mertansine or monomethylauristatin E (MMAE) ), anti-NAPI2B antibody-MMAE conjugate (also known as DNIB0600A or RG7599), trastuzumab emtansine (also known as TDM1, adtrastuzumab emtansine, or KADCYLA®, Genentech), DMUC5754A, endothelin B receptor Antibody drug conjugates targeting (EDNBR), e.g., antibodies to EDNBR conjugated with MMAE, angiogenesis inhibitors, antibodies against VEGF, such as VEGF-A, bevacizumab (AVASTIN®, also known as Genentech), antibodies against Angiopoietin 2 (also known as Ang2), MEDI3617, antitumor agents, CSF-1R ( M-CSFR or CD115), anti-CSF-1R (also known as IMCCS4), interferons such as interferon alpha or interferon gamma, roferon A, GM-CSF (recombinant human granulocyte-macrophage colony stimulating factor, rhu GMCSF, sargramostim, also known as Leukin®), IL-2 (also known as aldesleukin or proleukin®), IL-12, CD20 antibodies targeting CD20 (in some embodiments, the antibody targeting CD20 is obinutuzumab (also known as GA101 or Gazyva®) or rituximab), antibodies targeting GITR (some in some embodiments, the antibody targeting GITR is TRX518) in combination with a cancer vaccine (in some embodiments, the cancer vaccine is a peptide cancer vaccine; in some embodiments, personalized is a peptide vaccine; in some embodiments, the peptide cancer vaccine is a multivalent long peptide, multipeptide, peptide cocktail, hybrid peptide, or peptide-pulsed dendritic cell vaccine (eg, Yamada et al. , Cancer Sci, 104:14-21, 2013)), adjuvants, TLR agonists such as poly iCLC (also known as Hirtunol®), LPS, MPL, or CpG ODN in combination with tumor necrosis. factor (TNF) alpha, IL-1, HMGB1, IL-10 antagonists, IL-4 antagonists, IL-13 antagonists, HVEM antagonists, ICOS agonists, eg ICOS agonists by administration of ICOS-L, or directed against ICOS CX3CL1 targeting treatments, CXCL10 targeting treatments, CCL5 targeting treatments, LFA-1 or ICAM1 agonists, selectin agonists, targeted therapies, inhibitors of B-Raf, vemurafenib (Zelboraf) trademark)), dabrafenib (also known as Tafinlar®), erlotinib (also known as Tarceva®), MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2 known inhibitors of MEK. cobimetinib (also known as GDC-0973 or XL-518), trametinib (also known as Mekinist®), inhibitors of K-Ras, c-Met, onartuzumab (also known as MetMAB) ), inhibitor of Alk, AF802 (also known as CH5424802 or alectinib), phosphatidylinositol 3-kinase (PI3K), BKM120, idelalisib (also known as GS-1101 or CAL 101) ), perifosine (also known as KRX-0401), Akt, MK2206, GSKK690693, GDC-0941, mTOR, inhibitor of sirolimus (also known as rapamycin), temsirolimus (CCI-779 or Torisel (registered trademark)), everolimus (also known as RAD001), 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-BEZ235), GT226, GSK2126458, PF-04691502, PF-05212384 (also known as PKI-587). Additional therapy can be one or more of the chemotherapeutic agents described herein.

iii. Methods and uses for treating locally advanced unresectable or metastatic lung cancer Lung cancer (e.g., squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) in a subject or population of subjects ), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), small cell lung cancer (SCLC), including extensive-stage SCLC (ES-SCLC), and adenocarcinoma of the lung). Methods and uses for treatment, comprising an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab) anti-PD-L1 antagonist antibody, etc.) and one or more dosing cycles of the first and second chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents) are administered to the subject or population of subjects Provided herein are methods and uses comprising:

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). antibodies), and chemotherapeutic combinations to a subject or population in need thereof. In some embodiments, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg, , atezolizumab) is administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle). In some aspects, the present invention provides an effective amount of an antimicrobial agent based on body weight (BW) or body surface area (BSA) of a subject or subject population every three weeks (e.g., on day 1 of each 21-day dosing cycle). methods comprising administration of a TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab); Including use.

In some aspects, the invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, atezolizumab, etc.). anti-PD-L1 antagonist antibody), and a chemotherapeutic combination comprising administering to a subject or subject population in need thereof, wherein the chemotherapeutic combination comprises an effective amount of platinum-based chemotherapy and an effective amount of a non-platinum chemotherapeutic agent. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 3 weeks (eg, on Day 1 of each 21-day dosing cycle). In some examples, the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is an antimetabolite (eg, pemetrexed).

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD - administering an L1 antagonistic antibody (e.g., atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) to a subject or population of subjects in need thereof; Anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, e.g., atezolizumab) every 3 weeks (e.g., on day 1 of each 21-day dosing cycle), and a chemotherapy combination (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed) at the same frequency (e.g., every 3 weeks, e.g., on day 1 of each 21-day dosing cycle.) In some examples, dosing continues for 4-6 induction dosing cycles (e.g., 4 , 5 induction dosing cycles, or 6 induction dosing cycles) After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In embodiments of , the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

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

In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in an increase in PFS or DOR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in increased OS. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in increased progression-free survival in a subject or subject population. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. , to prolong the OS of a subject or subject population.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody) and a combination of chemotherapy to a subject or population in need thereof (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) in combination with an antimetabolite agent (e.g., pemetrexed)) Dosing improved the median PFS of the subject or subject population compared to treatment with a combination of pembrolizumab and a chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) resulting in an increase in In some examples, the treatment reduces the subject's or subject population's PFS 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, such as at least about 3.5-3.7 months, 3.7-3.9 months, 3.9-4.1 months, 4.1-4.3 months, 4.3-4.5 months, or 4.5-4.7 months).

In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab). ) to a subject or population of subjects with lung cancer (eg, NSCLC) for more than 8.8 months (eg, at least 8.9 months, at least 9.0 months, at least 9.2 months, at least 9.0 months). 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 such as about 8.9 months, about 9.0 months, about 9.2 months, about 9.5 months, about 10 months, about 11 months , about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or longer) yields a median PFS. In some examples, the treatment is for at least about 8 months (e.g., between 8 months and 36 months, such as between 8 months and 24 months (e.g., 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). Treatment is from about 12.5 months to about 14.7 months (eg, 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14 months). .1, 14.3, 14.5, or 14.7 months, such as about 12.5-13 months, 13-13.5 months, 13.5-14 months, or 14-14.7 months) In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist as disclosed herein) by any of the methods described herein antibodies, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapeutic combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolites. (e.g., in combination with pembrolizumab) to a subject or subject population with lung cancer (e.g., NSCLC) results in a median PFS of at least 10 months, hi some embodiments, described herein. an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD such as atezolizumab), by any of the methods of -L1 antagonist antibody), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab)), subjects with lung cancer (e.g., NSCLC) or Administration to the subject population results in a median PFS of at least 12 months.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- administration of a combination of L1 antagonist antibody) and chemotherapy to a subject or subject population with lung cancer (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite agent (e.g., pemetrexed)) , median OS (OS) in a subject or subject population compared to treatment with a combination of pembrolizumab and a chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) Provides an increase in value. In some examples, the treatment reduces the OS of the subject or subject population by at least about 4 months (e.g., between 4 months 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 examples, the treatment reduces the OS of the subject or subject population by at least about 5.5 months to about 8.0 months (eg, 5.5, 6.0, 6.5, 7.0, 7.5 , or 8.0 months, eg, 5.5-6.5, 6.5-7.5, or 7.5-8.0 months).

In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab). ) to a subject or population of subjects with lung cancer (e.g., NSCLC) for more 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, such as 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) results in a median OS. In some embodiments, the treatment is for at least about 24 months (eg, between 24 months and 42 months (eg, between 24 months and 36 months (eg, 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))) median OS for the subject population. In some embodiments, treatment is from about 27.5 months to about 32.0 months (eg, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.0 months). 5, 31.0, 31.5, or 32.0 months (e.g., 27.5-28.5, 28.5-29.5, 29.5-30.5, 30.5-31.5, or 31.5-32 months) in the subject population.In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibodies, such as tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapeutic combinations to a subject or subject population (e.g., platinum Administration of a systemic chemotherapeutic agent (e.g., carboplatin or cisplatin) in combination with an antimetabolite (e.g., pembrolizumab) to a subject or subject population with lung cancer (e.g., NSCLC) results in a median OS of at least 24 months In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) by any of the methods described herein , PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab). ) to a subject or subject population with lung cancer (eg, NSCLC) results in a median OS of at least 36 months.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD such as atezolizumab) - L1 antagonist antibody) and a combination of chemotherapy (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) in a subject in need thereof or for a subject. Population administration may reduce the total number of subjects or subject population compared to treatment with a combination of pembrolizumab and chemotherapy (e.g., an antimetabolite (e.g., pemetrexed) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)). Increased response rate (ORR), e.g., at least 10 compared to treatment with a combination of pembrolizumab and chemotherapy (e.g., an antimetabolite (e.g., pemetrexed) and a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) % ORR increase (eg, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%).

In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab)). of subjects or populations of subjects with lung cancer (e.g., NSCLC) is more 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%, such as about 48%, about 49%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab)). to a subject or subject population with lung cancer (eg, NSCLC) results in an ORR of at least 50%. In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab)). to a subject or subject population with lung cancer (eg, NSCLC) results in an ORR of at least 60%. In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab), and chemotherapy combinations (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and antimetabolite agents (e.g., pembrolizumab)). to a subject or subject population with lung cancer (eg, NSCLC) results in an ORR of at least 70%.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject or subject population in need thereof for four weeks (e.g., each on day 1 of a 28-day dosing cycle). In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in CR or PR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an improvement in the subject or population of subjects compared to a reference. Resulting in increased progression survival. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in an increase in DOR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject or population of subjects.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). antibody) to a subject or population in need thereof every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in increased progression-free survival in a subject or subject population. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. to prolong the OS of a subject or subject population.

In certain examples, the invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject or subject population in need thereof. Methods and uses comprising administration on a weekly basis (eg, on days 1 and 15 of each 28-day dosing cycle) are included. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in CR or PR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) reduces the number of subjects or populations of subjects compared to a reference. Resulting in increased progression survival. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject or population of subjects.

In some examples, the subject or subject population is within one month of administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (e.g., two months of administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody). prior to, within 3 months, within 4 months, within 6 months, 1, 2, 3, 4, 5, or 10 years ago) prior systemic treatment (e.g., healing No previous intended systemic therapy (e.g., chemotherapy). In some examples, the subject or subject population is chemotherapy naive.

In some embodiments, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are administered in combination with chemotherapy. For example, a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody once every two weeks (Q2W), once every three weeks (Q3W) or once every four weeks (Q4W) dosing regimen may be administered with one or more chemical It can be administered in conjunction with a therapeutic agent. The one or more chemotherapeutic agents are administered at the same frequency (Q2W, Q3W, or Q4W) or at a different frequency (e.g., 3 weeks on/1 week off) than the dosing frequency of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody. schedule). For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every 2 weeks and one or more chemotherapeutic agents are administered weekly for 3 weeks on/1 week off, 2 Administer weekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are administered every three weeks and one or more chemotherapeutic agents are administered every week, every two weeks, every three weeks, or every four weeks. Alternatively, a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody administered every 4 weeks and one or more chemotherapeutic agents weekly, on 3 weeks/1 week off, every 2 weeks, every 3 weeks, Or every 4 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). )) is administered.

In some embodiments, the dose of the chemotherapeutic agent is decreased after one or more initial doses (eg, after 1, 2, 3, 4, or more initial doses). Subsequent doses of, for example, 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)) is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25% of the initial dose , 20%, 15%, 10%, or 5%, for example, an initial dose of cisplatin of about 75 mg/m ² followed by doses of, for example, 70 mg/m ² , 65 mg/m ² . , 60 mg/m ² , 55 mg/m ² , 50 mg/m ² , or 45 mg/m ² , with an initial dose of pemetrexed of about 500 mg/m ² followed by doses of, for example, 450 mg/m 2 . ² , 400 mg/m ² , 350 mg/m ² , 300 mg/m ² , 250 mg/m ² , or 200 mg/m ² and/or sufficient to achieve AUC = 5 mg/ml/min An initial dose of carboplatin achieves subsequent doses, e.g., AUC = 4.5 mg/ml/min, 4.0 mg/ml/min, 3.5 mg/ml/min, or 3.0 mg/ml/min can be reduced to a dose sufficient to

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- Administration of L1 antagonist antibodies), platinum-based chemotherapeutic agents (eg carboplatin or cisplatin) and antimetabolites (eg pemetrexed) result in CR or PR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and antimetabolite agents (eg, pemetrexed) result in increased progression-free survival in a subject or subject population. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD- L1 antagonist antibody), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and antimetabolite agents (eg, pemetrexed) prolong OS in a subject or subject population.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies such as atezolizumab). ), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed), lung cancer, e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced undergoing treatment for sexually unresectable or metastatic non-squamous NSCLC (eg, stage IV non-squamous NSCLC).

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

Characterization of Cancer In any of the methods, uses or compositions for use described herein, lung cancer is characterized by NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous) NSCLC (eg, stage IV non-squamous NSCLC)). In some examples, the subject or subject population has never received prior systemic treatment for lung cancer.

In some examples, in any of the methods, uses or compositions for use described herein, the subject has epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumors. No abnormalities. In some examples, in any of the methods, uses or compositions for use described herein, the subject has an EGFR gene mutation (e.g., a sensitizing EGFR gene mutation) or an ALK gene rearrangement. do not. In some examples, the subject has a US East Coast Clinical Trials Group (ECOG) Performance (PS) of 0 or 1.

Methods for detecting mutational status EGFR and ALK are well known in the art and include, but are not limited to, Frampton et al. (Nature Biotechnology. 31(11): 1023-1033, 2013) using next-generation sequencing methods such as targeted gene pull-down and sequencing methods described in Clinical samples (e.g., tumor biopsies or blood samples). (eg, circulating tumor DNA in blood)). Such next-generation sequencing methods employ the use of small samples (e.g., from small core needle biopsies, fine needle aspirates, and/or cell blocks) or fixed samples (e.g., formalin-fixed paraffin-embedded (FFPE) samples). use 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 allowing be able to. Other methods for detecting EGFR and ALK mutational status include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods. An exemplary method for detecting the mutational status of ALK is disclosed in US Pat. No. 9,651,555, which is incorporated herein by reference in its entirety. In some examples, the VENTANA® Anti-ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.

In some examples 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 described in US Patent Application Publication No. 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 examples, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (eg, mutations in exon 18, exon 19, exon 20 and/or exon 21). In some examples, the sensitizing EGFR mutation is a deletion of exon 19 (del19). In another example, the sensitizing EGFR mutation is the L858R point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the G719X point mutation in exon 18, where "X" is most commonly C, A or S. In some examples, the sensitizing EGFR mutation is the G719S point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the G719A point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the S720F point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the L861Q point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the L861R point mutation in exon 21. In another example, the sensitizing EGFR mutation is the T790M point mutation. In some examples, the sensitizing EGFR mutation is the E709X point mutation, where "X" is most commonly K, A, or H. In some examples, the sensitizing EGFR mutation is the S768I point mutation.

In some examples of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are well known in the art and are described in US Pat. No. 9,651,555 and Du et al. (Thoracic Cancer. 9:423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, ALK gene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways to increase cell proliferation and survival. In some instances, the ALK gene rearrangement results in the formation of a fusion oncogene, EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC , TMP4, and MSN. In some instances, the ALK gene rearrangement is an EML4 rearrangement with ALK, resulting in the formation of the fusion oncogene EML4-ALK.

In some examples, in any of the methods, uses or compositions for use described herein, the subject does not have pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. Methods for detecting subtypes of NSCLC are well known in the art and include, but are not limited to, histopathological criteria or molecular characteristics (e.g., biomarkers (e.g., specific genes or (subtype) characterized by expression of one or a combination of proteins). In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample.

In some examples, in any of the methods, uses, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection; or no known or suspected chronic active EBV infection. Indicators of active or chronically active EBV infection for use in the methods described herein include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and subject-derived samples ( Examples include Epstein-Barr virus particles detected in blood or serum samples). To detect the presence of one or more indicators of active or chronically active EBV infection, including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from a subject are well known in the art and include serological diagnostics (e.g. detection of EBV DNA (e.g. by PCR analysis of blood samples to detect EBV virions) or detection of EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV IgM or EBV IgG using heterophilic antibodies) In some examples, the sample is a whole blood sample, a serum sample and a plasma sample. is selected from the group consisting of: In some examples, the subject is EBV IgM negative and/or is negative by EBV PCR, In some examples, the subject is EBV IgM negative and /or negative for EBV PCR and positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA) In other examples, the subject is negative for EBV IgG and/or Negative for EBNA In some instances, the subject has a PD-L1-selected tumor (e.g., minimal PD-L1-positive tumor cell fraction as determined by IHC using SP 263 or 22C3 antibody or TPS > 30% ( 50% or more), or 1% of the tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC) in the tumor sample as determined by IHC using the SP 142 antibody In some examples, the PD-L1-selected tumor has a PD-L1-positive tumor cell fraction of 30% or greater (eg, 50% or greater) or PD-L1-positive tumor cell fraction by immunohistochemistry (IHC) assay. Tumors determined to have L1 TPS In some instances, PD-L1-selected tumors have a percentage of tumor area occupied by PD-L1-expressing immune cells (IC) by immunohistochemistry (IHC) assay. A tumor determined to be greater than or equal to 1%.In some examples, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8.In some examples, the IHC assay is The anti-PD-L1 antibody SP263 is used, hi some examples, the IHC assay uses the anti-PD-L1 antibody SP142. use. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some instances, tumor samples have been determined to have a TPS of 50% or greater. In some examples, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), anti-PD- as determined by positive staining with the L1 antibody 22C3 (eg using the pharmDx assay) or by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142. In some instances, the IC has been determined to be 1% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be 5% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC has been determined to be 10% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 50% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 30% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay).

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

In some examples, the subject has 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- with squamous NSCLC)))). For example, in some instances, a subject with lung cancer has not been determined to have a PD-L1 positive tumor cell fraction of 50% (e.g., 45%, 40%, 35%, or 30% or greater) ) has not been determined to have a PD-L1 positive tumor cell fraction of ≥ For example, in some instances, the subject is 50% or more PD-L1 positive (e.g., as assessed using any of the IHC methods described herein or known in the art) For example, a subject has not been determined to have TPS greater than or equal to 45% PD-L1 positive, 40% PD-L1 positive, 35% PD-L1 positive, or 30% PD-L1 positive or higher. not

In some examples, 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)))) , less than 50% (such as 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35% or 20% to 30%, such as 1% to 5% , 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% or 45 % to 49%, such as less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8% , less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than, less than 1%, or about 0%) . For example, in certain instances, 1-49% of subjects with lung cancer (eg, 1%-5%, 5%-10%, 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, or 45%-49%). In other examples, a subject with lung cancer has been determined to have a PD-L1 positive tumor cell fraction of less than 1% (eg, about 0%, or undetectable PD-L1 expression).

For example, in some cases, 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))) Subjects are less than 50% PD-L1 positive (e.g., 1%-50%, 1%-49%, 5%-45%, 10%-40%, 15%-35%, or 20%-30% PD-L1 positive, e.g., 1%-5%, 5%-10%, 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35 %-40%, 40%-45%, or 45%-49% PD-L1 positive, e.g., <49%, <45%, <40%, <35%, <30%, <25%, 20% Less than, 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%, 1%, or about 0% PD -L1 positive) has been determined to have TPS. For example, in certain instances, subjects with lung cancer are 1-49% PD-L1 positive (eg, 1%-5%, 5%-10%, 10%-15%, 15%-20%, 20% ~25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, or 45%-49% PD-L1 positive) of TPS. In another example, a subject with lung cancer has been determined to have TPS with less than 1% PD-L1 positive (eg, about 0% or undetectable PD-L1 expression).

In certain embodiments, the subject has NSCLC that has not been evaluated for 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 instances, a subject with NSCLC has not been determined to have a PD-L1 positive tumor cell fraction of 50% (e.g., the subject is 45%, 40%, 35%, or 30% or greater) ) has not been determined to have a PD-L1 positive tumor cell fraction of ≥ For example, in some instances, the subject is 50% or more PD-L1 positive (e.g., as assessed using any of the IHC methods described herein or known in the art) For example, a subject has not been determined to have TPS greater than or equal to 45% PD-L1 positive, 40% PD-L1 positive, 35% PD-L1 positive, or 30% PD-L1 positive or higher. not

In some instances, subjects with NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) are less than 50% ( For example, 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35% or 20% to 30%, such as 1% to 5%, 5% to 10% %, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% or 45% to 49%, For example, 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%, was determined to have a PD-L1 positive tumor cell fraction of 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, 1-49% of subjects with NSCLC (eg, 1%-5%, 5%-10%, 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, or 45%-49%). In other examples, a subject with NSCLC has been determined to have a PD-L1 positive tumor cell fraction of less than 1% (eg, about 0%, or undetectable PD-L1 expression).

For example, in some instances, subjects with NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) are 50% less than PD-L1 positive (e.g., 1%-50%, 1%-49%, 5%-45%, 10%-40%, 15%-35%, or 20%-30% PD-L1 positive, For example, 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%-45%, or 45%-49% PD-L1 positive, e.g., <49%, <45%, <40%, <35%, <30%, <25%, <20%, <15% , <10%, <9%, <8%, <7%, <6%, <5%, <4%, <3%, <2%, 1%, or about 0% PD-L1 positive) Have been determined to have TPS. For example, in certain instances, subjects with NSCLC are 1-49% PD-L1 positive (eg, 1%-5%, 5%-10%, 10%-15%, 15%-20%, 20% ~25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, or 45%-49% PD-L1 positive) of TPS. In another example, a subject with NSCLC has been determined to have TPS with less than 1% PD-L1 positive (eg, about 0% or undetectable PD-L1 expression).

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

In some examples, 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)))) The resulting tumor samples have low or undetectable levels of PD-L1 nucleic acid expression. In some examples, the nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or combinations thereof. ing. In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample. In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some examples of any of the methods described herein, lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV Subjects with non-squamous NSCLC)))) have no prior systemic treatment for lung cancer (eg, no prior systemic treatment with curative intent). In certain embodiments, the subject has locally advanced lung cancer and has had no prior systemic treatment for locally advanced lung cancer. In some examples, the subject has NSCLC (e.g., non-squamous NSCLC, e.g., locally advanced unresectable or metastatic non-squamous NSCLC) and has no prior systemic treatment for NSCLC (e.g., , non-squamous NSCLC, eg locally advanced unresectable or metastatic non-squamous NSCLC). Prior systemic treatments include prior neoadjuvants, adjuvant chemotherapy, radiation therapy, and curative chemoradiation therapy for non-metastatic disease.

In other examples, 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))) is Has undergone prior systemic treatment for lung cancer and has undergone a treatment-free period of at least 12 months prior to treatment with any of the methods of the invention.

iv. Methods and Uses for Treating Resectable Lung Cancer lung cancer (e.g., early-stage lung cancer (e.g., resectable Provided herein are methods and uses for treating lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)). In some examples, at least one dosing cycle is administered as a neoadjuvant treatment. In some examples, the treatment is a neoadjuvant treatment. In some examples, at least one dosing cycle is administered as an adjuvant treatment. In some examples, the treatment is adjuvant treatment. In some examples, treatment includes neoadjuvant treatment and adjuvant treatment. In some examples, the lung cancer is resectable lung cancer. In some examples, the lung cancer is early stage lung cancer (eg, stage II, IIIA, or IIIB lung cancer). In some examples, the lung cancer is NSCLC (eg, squamous or non-squamous NSCLC). In some examples, the lung cancer is PD-L1 positive (eg, PD-L1 high). In some instances, the lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some embodiments, the subject has no prior treatment for lung cancer (eg, prior surgery, prior immunotherapy, prior chemotherapy, or prior radiation therapy). In some examples, the subject is eligible to receive a platinum-based chemotherapy regimen. In some examples, the subject is eligible for R0 resection for curative purposes. The subject is preferably human.

The invention includes methods and uses for treating a subject with resectable lung cancer (e.g., resectable NSCLC (e.g., resectable squamous or non-squamous NSCLC)), wherein the method comprises: every 3 weeks (e.g., on day 1 of each 21-day dosing cycle) a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist as disclosed herein) antibody, e.g., tiragolumab), and a PD-1 axis binding antagonist (e.g., a fixed dose) at a dose (e.g., fixed dose) of between about 80 mg and about 1600 mg every three weeks (e.g., on day 1 of each 21-day dosing cycle) , an anti-PD-L1 antagonist antibody such as atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab) to the subject. In some aspects, the method comprises administering a dose (e.g., a fixed dose) of between 30 mg and 1200 mg of an anti-TIGIT antagonist antibody (e.g., the subject antibody) every three weeks (e.g., on day 1 of each 21-day dosing cycle). anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a dose (e.g., fixed dose) of between 80 mg and 1600 mg every 3 weeks (e.g., on day 1 of each 21-day dosing cycle) (eg, an anti-PD-L1 antagonist antibody such as atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab) to the subject.

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

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab) ) is undergoing treatment for lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC))).

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

In any of the preceding examples, each dosing cycle is of any suitable length, such as about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (eg, about 12, 13 days). , 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 longer. In some examples, each dosing cycle is about 21 days.

In some examples, the PD-L1 expression level of a sample (eg, tumor sample, blood sample (eg, plasma sample), or lymph sample) obtained from the subject is determined. In some examples, the sample has been determined to have a detectable PD-L1 expression level (eg, a detectable protein and/or nucleic acid expression level of PD-L1). In some examples, the detectable PD-L1 expression level is a detectable PD-L1 protein expression level. In some examples, the detectable PD-L1 expression level is a PD-L1 positive tumor cell fraction (eg, a PD-L1 positive tumor cell fraction of 50% or greater). In some examples, detectable PD-L1 protein expression levels are determined by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining (e.g., anti-PD-L1 antibody SP 263). is determined by In some examples, the IHC assay is the Ventana SP263 IHC assay. In some examples, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some examples, the mutational status of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) is determined. In some examples, the method further comprises obtaining a sample from the subject. In some examples, the method further comprises determining the expression level of PD-L1.

In some examples, the first dosing cycle is initiated prior to surgery (eg, segmentectomy, lobectomy, bilobectomy, or pneumonectomy). In some instances, one or more dosing cycles are completed prior to surgery. In some examples, at least 1, 2, 3, or 4 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) are completed prior to surgery do. In some instances, four dosing cycles are completed prior to surgery. In some examples, 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 after surgery. In some instances, 16 dosing cycles are completed after surgery. In some examples, treatment includes surgery. In some examples, the surgery is segmentectomy, lobectomy, bilobectomy, or pneumonectomy. In some examples, treatment includes radiation therapy (eg, postoperative radiation therapy).

In some instances, the treatment results in an increased MPR rate compared to the baseline significant pathologic response (MPR) rate. In some examples, the treatment results in a pathological complete response (pCR) and/or an increase in the pCR rate compared to the baseline pCR rate. In some instances, treatment results in an increase in EFS compared to baseline symptom-free survival (EFS) time. In some examples, treatment results in an increase in OS compared to baseline OS time. In some examples, the baseline MPR rate, baseline pCR rate, and/or baseline EFS time are determined by (a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or (b) cisplatin and docetaxel or MPR rate, pCR rate, and/or EFS time in treatment-experienced subject populations including cisplatin, docetaxel, and bevacizumab. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in an increase in the MPR rate. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in pCR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in an increase in EFS. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in increased OS.

In some instances, treatment includes one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g. pemetrexed or gemcitabine) and/or taxanes (e.g. paclitaxel, e.g. nab-paclitaxel) In some examples, the neoadjuvant and/or adjuvant treatment comprises one or more chemotherapeutic agents (e.g. platinum-based chemotherapeutic agents (e.g. carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g. antimetabolites (e.g. pemetrexed or gemcitabine) and/or taxanes (e.g. paclitaxel, e.g. nab-paclitaxel) )) In some examples, the one or more chemotherapeutic agents is one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. In some examples, the platinum-based chemotherapeutic agent is carboplatin or cisplatin, hi some examples, the non-platinum-based chemotherapeutic agent is an antimetabolite (eg, pemetrexed or gemcitabine) and/or a taxane (eg, paclitaxel, such as nab-paclitaxel). In some examples, the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite agent (e.g., pemetrexed or gemcitabine). ) and/or taxanes (eg paclitaxel, eg nab-paclitaxel) In some examples, at least one or more chemotherapeutic agents are (a) carboplatin and pemetrexed; (d) carboplatin and gemcitabine, or (e) cisplatin and gemcitabine In some examples, the one or more chemotherapeutic agents used to treat non-squamous NSCLC are (a) (b) carboplatin and paclitaxel, or (c) cisplatin and pemetrexed In some examples, the one or more chemotherapeutic agents used to treat squamous NSCLC are (a) carboplatin and gemcitabine, (b) carboplatin and paclitaxel, or (c) cisplatin and gemcitabine In some examples, the treatment includes one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents). (e.g. carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g. antimetabolites (e.g. pemetrexed or gemcitabine) and/or taxanes (e.g. paclitaxel, e.g. nab-paclitaxel)) further includes In some examples, one or more chemotherapeutic agents are administered every three weeks. In some examples, one or more chemotherapeutic agents are administered at about day 1 (e.g., day -3, day -2, day -1, day 1, day 2) of one or more dosing cycles. or day 3). In some examples, one or more chemotherapeutic agents are administered at about day 1 (e.g., day −3, day −2, day −1, day 1, day 2) of one or more dosing cycles. day 3, or day 3) and about day 8 (eg, day 5, 6, 7, 8, 9, 10, or 11). In some examples, the dosing cycle is, for example, about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (eg, about 12, 13, 14, 15, or 16 days), About 21 days (eg, 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 examples, each dosing cycle is about 21 days. In some examples, one or more chemotherapeutic agents are administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, by implantation, Administration is by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some examples, the one or more chemotherapeutic agents is a PD-1 axis binding antagonist (eg, atezolizumab) and/or an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, for example, tiragolumab). In some instances, a non-platinum chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)) is combined with a platinum-based chemotherapeutic agent (e.g., carboplatin). or cisplatin).

The present invention provides methods and methods for treating subjects with resectable lung cancer (e.g., early resectable lung cancer (e.g., resectable NSCLC (e.g., resectable squamous or non-squamous NSCLC))). The method includes the use of a dose (e.g., fixed dose) of between about 30 mg and about 600 mg every three weeks of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or an anti-PD-1 antagonist such as, for example, pembrolizumab) at doses (e.g., fixed doses) of about 80 mg and about 1600 mg every 3 weeks antibodies), 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)). Including administering one or more dosing cycles to the subject. In some aspects, the method comprises administering a dose (e.g., a fixed dose) of between 30 mg and 600 mg every three weeks of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g. an anti-PD-L1 antagonist antibody such as atezolizumab or an anti-PD-1 antagonist such as e.g. antibodies), 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)). administering to the subject the above dosing cycles.

The present invention includes methods and uses for treating a subject with lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC))). is an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or e.g. pembrolizumab anti-PD-1 antagonist antibodies, etc.), 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)), wherein at least one of the dosing cycles is between about 30 mg and about 600 mg every three weeks as a neoadjuvant treatment (e.g., a fixed dose) of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80 mg and about 1600 mg every three weeks, a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin), and Including administering to the subject a non-platinum chemotherapeutic agent (eg, an antimetabolite (eg, pemetrexed or gemcitabine) or a taxane (eg, paclitaxel or nab-paclitaxel)). In some aspects, at least one of the dosing cycles is anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30 mg and 600 mg every 3 weeks, 80 mg and 1600 mg every 3 weeks as a neoadjuvant treatment. between doses (e.g., fixed dose) of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), or administering a taxane (eg, paclitaxel or nab-paclitaxel) to the subject.

The present invention provides methods and methods for treating subjects with resectable lung cancer (e.g., early resectable lung cancer (e.g., resectable NSCLC (e.g., resectable squamous or non-squamous NSCLC))). The method includes the use of a dose (e.g., fixed dose) of between about 30 mg and about 600 mg every three weeks of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or an anti-PD-L1 antagonist such as, 1 antagonist antibody) and (a)(i) a dose of a platinum-based chemotherapeutic agent (e.g., cisplatin) targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks or carboplatin); or (ii) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose of about 75 mg/m ² every 3 weeks; (b) (i) about 500 mg/m ² every 3 weeks, or an antimetabolite at ^a dose of about 1000 mg ^{/ m2} or about 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle; or administering to the subject one or more dosing cycles of the taxane at a dose of about 200 mg/m ² . In some aspects, the method comprises administering a dose (e.g., fixed dose) of between 30 mg and 600 mg every three weeks of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., , tiragolumab), and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab or an anti-PD-L1 antagonist antibody such as, 1 antagonist antibody) and (a)(i) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin); or (ii) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose of 75 mg/ ^m2 every 3 weeks; (b)(i) a dose of 500 mg/ ^m2 every 3 weeks; or antimetabolites at doses of 1000 mg/ ^m2 or 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle; or (ii) 100 mg/ ^m2 , 175 mg/ ^m2 , or 200 mg/m2 every 3 weeks. administering one or more dosing cycles of ^m2 doses of the taxane to the subject.

The present invention includes methods and uses for treating a subject with lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC))). is an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or e.g. pembrolizumab anti-PD-1 antagonist antibodies, etc.), 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 - administering to the subject one or more dosing cycles of paclitaxel), wherein at least one of the dosing cycles comprises administering to the subject: (a) a dose of between about 30 mg and about 600 mg every 3 weeks (e.g., (b) a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between about 80 mg and about 1600 mg every three weeks; (c) a platinum-based chemotherapeutic agent; (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/ ^min every 3 weeks; and (d) a non-platinum chemotherapeutic agent, which is (i) 500 mg/ ^m2 every 3 weeks, or 1000 mg/ ^m2 on days 1 and 8 of each dosing cycle, or or (ii) a dose of 100 mg/ ^{m 2 ,} 175 mg/m ² , or 200 mg/m ² of a taxane non-platinum chemotherapeutic agent every 3 weeks. and the treatment is a neoadjuvant treatment. In some embodiments, at least one of the dosing cycles comprises: (a) anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30 mg and 600 mg every 3 weeks; (b) every 3 weeks PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80 mg and 1600 mg; (c) platinum-based chemotherapeutic agent: (i) AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks or (ii) every 3 weeks at a dose of 75 mg/ ^m2 ; and (d) a non-platinum chemotherapeutic agent that (i) every 3 weeks 500 mg/ ^m2 , or 1000 mg/ ^m2 or 1250 mg/m2 on days 1 ^and 8 of each dosing cycle; or (ii) 100 mg/ ^m2 , 175 mg/m2 every 3 weeks ² , or a non-platinum chemotherapeutic agent that is a taxane, at a dose of 200 mg/m ² , and the treatment is a neoadjuvant treatment.

The present invention includes methods and uses for treating a subject with lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC))). 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 of the dosing cycles comprises about 30 mg of the anti-TIGIT antagonist antibody every 3 weeks; and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80 mg and about 1600 mg (e.g., fixed dose) every three weeks as a neoadjuvant treatment to the subject (b) at least one of the dosing cycles comprises an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between about 30 mg and about 1200 mg every three weeks; administering to the subject as an adjuvant treatment at a dose (eg, fixed dose) of between about 80 mg and about 1600 mg every 3 weeks. 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 of the dosing cycles comprises an anti-TIGIT antagonist; Neoadjuvant treatment with antibody at doses between 30 mg and 1200 mg every 3 weeks (e.g. fixed dose) and PD-1 axis binding antagonist at doses between 80 mg and 1600 mg every 3 weeks (e.g. fixed dose) (b) at least one of the dosing cycles is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every 3 weeks as a PD-1 axis binding antagonist as an adjuvant treatment to the subject at doses between 80 mg and 1600 mg (eg, fixed dose) every 3 weeks.

The present invention includes methods and uses for treating a subject with lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC))). comprises 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 a neoadjuvant treatment; a) a dose of between about 30 mg and about 1200 mg (e.g., fixed dose) of an anti-TIGIT antagonist antibody every three weeks; (c) a platinum-based chemotherapeutic agent that (i) achieves an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks or (ii) a platinum-based chemotherapeutic agent at ^a dose of about 75 mg/m every 3 weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein (i) every 3 weeks an antimetabolite at a dose of about 500 mg/ ^m2 , or about 1000 mg/ ^m2 or about 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle; or (ii) about 100 mg/ ^m2 every three weeks. (II) at least one of the dosing cycles comprises administering an anti-TIGIT antagonist antibody at a dose of about 175 mg/m ² or about 200 mg/m ² ; a PD-1 axis binding antagonist at a dose of between about 30 mg and about 1200 mg (e.g., fixed dose) every 3 weeks and an adjuvant at a dose of between about 80 mg and about 1600 mg (e.g., fixed dose) every 3 weeks Including administering to a subject as a treatment. In some aspects, the method comprises administering to the subject (a) an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every 3 weeks; (b) every 3 weeks as a neoadjuvant treatment; (c) a platinum-based chemotherapeutic agent, wherein (i) an AUC of 5 mg/mL/min every 3 weeks or or (ii) a platinum-based chemotherapeutic agent at a dose of 75 mg/ ^m2 every three weeks; and (d) a non-platinum-based chemotherapeutic agent. (i) an antimetabolite at a dose of 500 mg/ ^m2 every 3 weeks, or 1000 mg/ ^m2 or 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle; or (ii) every 3 weeks (II) at least one of the dosing cycles comprises administering a non-platinum chemotherapeutic agent that is a taxane at a dose of 100 mg/m ² , 175 mg/m ² , or 200 mg/m ² ; Subject administration of a TIGIT antagonist antibody at a dose of between 30 mg and 1200 mg (e.g., fixed dose) every 3 weeks and a PD-1 axis binding antagonist at a dose of between 80 mg and 1600 mg (e.g., fixed dose) every 3 weeks. including doing

In some examples, treatment may further include additional therapies. Any suitable additional therapy known in the art or described herein can be used. Additional treatments may include radiation therapy (e.g., postoperative radiation therapy), surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or any of these. It can be a combination.

In some instances, the additional therapy is a side effect-limiting agent (e.g., an agent intended to reduce the occurrence and/or severity of side effects of treatment, e.g., anti-nausea drugs, corticosteroids (e.g., prednisone or equivalents, eg doses of 1-2 mg/kg/day), hormone replacement drugs, etc.).

A treatment regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., antimetabolite agents (e.g., pemetrexed or gemcitabine) and/or taxanes (e.g. paclitaxel, e.g. nab-paclitaxel)))) and/or cancer therapy (e.g. surgery and/or radiation therapy). provided in the book. For example, a PD-1 axis binding antagonist may include an additional chemotherapy or chemotherapeutic agent (see definition above); a targeted therapy or targeted therapeutic agent; an immunotherapy or immunotherapeutic agent, such as a monoclonal antibody; cytotoxic agents (see definition above); or combinations thereof.

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

Characterization and Selection of Cancers In some examples, lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., , NSCLC (eg, squamous or non-squamous NSCLC)))) is resectable (eg, eligible for R0 resection with curative intent). In some examples, the lung cancer is NSCLC. In some examples, the NSCLC is squamous or non-squamous NSCLC. In some examples, the lung cancer is PD-L1 positive. In some instances, lung cancer is PD-L1 elevated. In some instances, the lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some examples, the lung cancer is stage II, IIIA or IIIB lung cancer.

In some examples, the subject is eligible for platinum-based chemotherapy in any of the methods, uses or compositions for use described herein. In some examples, the subject has a US East Coast Clinical Trials Group (ECOG) Performance (PS) of 0 or 1. In some examples, the subject has no prior lung cancer treatment (eg, immunotherapy, chemotherapy or radiation therapy).

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

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

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

Assessment of EGFR and ALK Abnormalities Methods for detecting the mutational status EGFR and ALK are described in Section III(N) herein.

Response to Treatment In some embodiments of any of the methods described herein, a subject's response to treatment can be characterized by one or more measures. In some embodiments, treatment results in an increase in severe pathologic response (MPR) rate. In some embodiments, treatment results in pCR. In some embodiments, treatment results in increased symptom-free survival (EFS). In some embodiments, treatment results in improved patient-reported outcomes. In some embodiments, treatment results in improvement in patient-reported physical functioning, role functioning, or GHS/QoL as measured by the EORTC-QLQ-C30. In some embodiments, treatment results in improvement of patient-reported lung cancer symptoms of cough, dyspnea and chest pain as measured by use of the EORTC-QLQ-LC13.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Comparatively, it results in an increase in the subject's MPR rate. In some instances, treatment includes, for example, chemotherapy (e.g., platinum-based doublet chemotherapy (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed or gemcitabine) or taxanes (e.g., paclitaxel or nab-paclitaxel)))) compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody to increase the rate of MPR in a subject Bring.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. In comparison, it results in an increase in the subject's pCR. In some instances, treatment includes, for example, chemotherapy (e.g., platinum-based doublet chemotherapy (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed or gemcitabine) or taxanes (e.g., paclitaxel or nab-paclitaxel)))) results in an increase in pCR in a subject compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody .

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Compare and extend the target OS. In some instances, treatment includes, for example, chemotherapy (e.g., platinum-based doublet chemotherapy (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (eg, pemetrexed or gemcitabine) or taxanes (eg, paclitaxel or nab-paclitaxel)))) in subjects compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. By comparison, prolong the subject's EFS. In some instances, treatment includes, for example, chemotherapy (e.g., platinum-based doublet chemotherapy (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (eg, pemetrexed or gemcitabine) or taxanes (eg, paclitaxel or nab-paclitaxel))))), prolongs the subject's EFS compared to treatment with a PD-uniaxial binding antagonist and an anti-TIGIT antagonist antibody.

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

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

In some embodiments, OS is measured as the time from initiation of treatment to death. In some examples, the treatment reduces the subject's OS by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8 months). ~36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, about 2.4 months, 2.5 months, 2.6 months, 2.7 months 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 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 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 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 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 examples, the treatment reduces the subject's OS by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-3 months). 36 months, or 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 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 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 examples, the treatment reduces the subject's OS by at least about 5.3 months (eg, 5.3-120, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months 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. Treatment and diagnostic methods and uses for cervical cancer Cervical cancer Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths. Worldwide, over 500,000 women are diagnosed with cervical cancer each year, resulting in over 300,000 deaths. Nearly 90% of deaths from cervical cancer occur in developing countries. There are 13,000 new cases of invasive cervical cancer and approximately 4000 cancer-related deaths each year in the United States.

Treatment of early and locally advanced cervical cancer consists of surgery and definitive chemoradiation, respectively, and can be very effective in inducing remission. However, if the cancer recurs or is not resolved with primary treatment, the prognosis is very poor, with a 5-year survival rate of approximately 15%, which is comparable to that of patients with de novo metastatic disease. . With a few exceptions, the standard of care for recurrent, persistent, or de novo metastatic disease is Gynecology Oncology Group 240 trial-based chemotherapy plus bevacizumab, which means that bevacizumab added to chemotherapy is less than chemotherapy alone. showed improved median OS compared to 17 months versus 13.3 months, respectively.

Currently, there is no globally accepted standard of care after relapse or progression on chemotherapy plus bevacizumab. Thus, treatment options for these patients primarily include various cytotoxic chemotherapeutic agents administered either as single agents or in combination. However, given the historically low response rate of about 10%-15%, cytotoxic chemotherapy is the best option given the impact and burden such agents can have on the patient's quality of life. There is an increasing focus on whether it represents an acceptable standard of care rather than supportive care for patients.

The historically low efficacy of existing treatments coupled with the involvement of an immune response by HPV infection of cervical epithelial cells makes cervical cancer a particularly attractive opportunity for novel immunotherapy-based approaches.

Thus, for the treatment of cancer (e.g. cervical cancer, e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or recurrent PD-1L positive cervical cancer) There is an unmet need in the art for the development of effective immunotherapies and methods of administering them.

Methods and Uses for Treating Cervical Cancer MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) detectable in a subject or subject population, comprising administering to the subject or subject population one or more dosing cycles Cancers with PD-L1 expression levels (eg, cervical cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer) Methods and uses for treating are provided herein.

Dosing Regimens and Administration The therapeutic methods and uses of the invention described herein are, in one aspect, cancers with detectable levels 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), in an effective amount of an anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody, such as tiragolumab) and an effective amount of a PD-1 axis binding antagonist (such as an anti-PD-L1 antagonist antibody (such as atezolizumab) or an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))), thereby treating the subject or population of subjects.

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

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 80 mg and about between about 80 mg and about 1900 mg, such as between about 80 mg and about 1800 mg, such as between about 100 mg and about 1700 mg, such as between about 200 mg and about 1600 mg, such as between about 300 mg and about 1400 mg, such as between about 400 mg and about 1300 mg, such as between about 500 mg and about 1200 mg, such as between about 600 mg and about 1100 mg, such as between about 700 mg and about 1000 mg, such as between about 740 mg and about 940 mg, such as between about 790 mg and about 890 mg between about 815 mg and about 865 mg, such as between about 830 mg and about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg) (eg, fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about between 2000 mg, such as between about 200 mg and about 1900 mg, such as between about 300 mg and about 1700 mg, such as between about 400 mg and about 1600 mg, such as between about 500 mg and about 1600 mg, such as between about 600 mg and about Between 1600 mg, such as between about 700 mg and about 1600 mg, such as between about 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as between about 1050 mg and about between 1350 mg, such as between about 1100 mg and about 1300 mg, such as between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as 1200 mg±5 mg; For example, a dose of 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about 2000 mg) every 4 weeks. between about 200 mg and about 2000 mg, such as between about 300 mg and about 2000 mg, such as between about 400 mg and about 2000 mg, such as between about 500 mg and about 2000 mg, such as between about 600 mg and about 1900 mg, such as about between 700 mg and about 1800 mg, such as between about 800 mg and about 1800 mg, such as between about 900 mg and about 1800 mg, such as between about 1000 mg and about 1800 mg, such as between about 1100 mg and about 1800 mg, such as between about 1200 mg and about 1800 mg between about 1300 mg and about 1800 mg, such as between about 1400 mg and about 1800 mg, such as between about 1500 mg and about 1800 mg, such as between about 1580 mg and about 1780 mg, such as between about 1630 mg and about 1730 mg, such as about 1655 mg and about 1705 mg, e.g. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between 80 mg and 2000 mg (eg, between 80 mg and 1950 mg, between 80 mg and 1900 mg, such as between 80 mg and 1800 mg, such as between 100 mg and 1700 mg, such as between 200 mg and 1600 mg, such as between 300 mg and 1400 mg, such as between 400 mg and 1300 mg, such as between 500 mg and 1200 mg, such as between 600 mg and 1100 mg, such as between 700 mg and 1000 mg, such as between 740 mg and 940 mg, such as between 790 mg and 890 mg, such as between 815 mg and 865 mg, such as between 830 mg and 850 mg, such as 840 mg±5 mg, such as 840±2 .5 mg, such as 840±1.0 mg, such as 840±0.5 mg, such as 840 mg) (eg, fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every three weeks, e.g. between 200 mg and 1900 mg, such as between 300 mg and 1700 mg, such as between 400 mg and 1600 mg, such as between 500 mg and 1600 mg, such as between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg ± 5 mg, such as 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every 4 weeks, e.g. between 200 mg and 2000 mg, such as between 300 mg and 2000 mg, such as between 400 mg and 2000 mg, such as between 500 mg and 2000 mg, such as between 600 mg and 1900 mg, such as between 700 mg and 1800 mg, such as between 800 mg and 1800 mg, such as 900 mg and 1800 mg, such as between 1000 mg and 1800 mg, such as between 1100 mg and 1800 mg, such as between 1200 mg and 1800 mg, such as between 1300 mg and 1800 mg, such as between 1400 mg and 1800 mg, such as between 1500 mg and 1800 mg, such as 1580 mg between 1780 mg, such as between 1630 mg and 1730 mg, such as between 1655 mg and 1705 mg, such as between 1670 mg and 1690 mg, such as 1680 mg±5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg , eg 1680 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a fixed dose of 1200 mg every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a fixed dose of 1200 mg every 3 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (eg, nivolumab)) can be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as monotherapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg, e.g., between about 1 mg/kg and about 35 mg/kg) such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as about 12 mg/kg. between 5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0 .1 mg/kg, eg about 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.1 mg/kg and about 15 mg/kg, e.g., between about 0.5 mg/kg and about 15 mg/kg, e.g., between about 1 mg/kg and about 15 mg/kg) between about 2.5 mg/kg and about 15 mg/kg, such as between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as about between 10 mg/kg and about 15 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg; For example, about 15±0.5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg administered every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg and 50 mg/kg of the subject's body weight every three weeks. between (e.g. between 0.01 mg/kg and 45 mg/kg, e.g. between 0.1 mg/kg and 40 mg/kg, e.g. between 1 mg/kg and 35 mg/kg, e.g. 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg /kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg, or 15±0.1 mg/kg, such as 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg and 15 mg/kg of the subject's body weight every three weeks. between (e.g. between 0.1 mg/kg and 15 mg/kg, such as between 0.5 mg/kg and 15 mg/kg, such as between 1 mg/kg and 15 mg/kg, such as between 2.5 mg/kg and 15 mg/kg between 5 mg/kg and 15 mg/kg, such as between 7.5 mg/kg and 15 mg/kg, such as between 10 mg/kg and 15 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, between 14 mg/kg and 15 mg/kg, such as 15±1 mg/kg, such as 15±0.5 mg/kg, such as 15±0.2 mg/kg, such as 15±0.1 mg/kg, such as 15 mg/kg) is the dose of In some examples, an effective amount of anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of 15 mg/kg administered every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist (e.g. , an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered as monotherapy, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist Antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) may be reduced compared to standard doses.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, penprolizumab)) is between about 20 mg and about 1000 mg (eg, about 40 mg and about 900 mg) every three weeks. between about 60 mg and about 800 mg, such as between about 80 mg and about 700 mg, such as between about 80 mg and about 600 mg, such as between about 100 mg and about 500 mg, such as between about 120 mg and about 400 mg, such as about between 140 mg and about 300 mg, such as between about 160 mg and about 350 mg, such as between about 180 mg and about 300 mg, such as between about 180 mg and about 250 mg, such as between about 180 mg and about 220 mg, such as between about 190 mg and about 210 mg between, eg 200±5 mg, eg 200±2.5 mg, eg 200±1.0 mg, eg 200±0.5 mg, eg 200 mg) (eg a fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., penprolizumab)) is between 20 mg and 1000 mg (e.g., between 40 mg and 900 mg) every three weeks, e.g. between 60 mg and 800 mg, such as between 80 mg and 700 mg, such as between 80 mg and 600 mg, such as between 100 mg and 500 mg, such as between 120 mg and 400 mg, such as between 140 mg and 300 mg, such as between 160 mg and 350 mg, such as 180 mg and 300 mg, such as between 180 mg and 250 mg, such as between 180 mg and 220 mg, such as between 190 mg and 210 mg, such as 200 mg±5 mg, such as 200±2.5 mg, such as 200±1.0 mg, such as 200±0. 5 mg, eg 200 mg) dose (eg fixed dose). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) is a dose of 200 mg (eg, fixed dose) every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-1 antagonist antibody (eg, penprolizumab)) can be reduced compared to the standard dose of anti-PD-L1 antagonist antibody administered as monotherapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is between about 20 mg and about 1000 mg (eg, about 40 mg and about 900 mg) every two weeks. between about 60 mg and about 800 mg, such as between about 80 mg and about 700 mg, such as between about 80 mg and about 600 mg, such as between about 100 mg and about 500 mg, such as between about 120 mg and about 400 mg, such as about between 140 mg and about 300 mg, such as between about 160 mg and about 350 mg, such as between about 180 mg and about 300 mg, such as between about 200 mg and about 280 mg, such as between about 220 mg and about 260 mg, such as between about 230 mg and about 250 mg between, eg 240±5 mg, eg 240±2.5 mg, eg 240±1.0 mg, eg 240±0.5 mg, eg 240 mg) (eg a fixed dose). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is between about 100 mg and about 1000 mg (eg, about 200 mg and about 900 mg) every 4 weeks. between about 300 mg and about 800 mg, such as between about 400 mg and about 700 mg, such as between about 400 mg and about 600 mg, such as between about 400 mg and about 550 mg, such as between about 420 mg and about 540 mg, such as about between 440 mg and about 520 mg, such as between about 460 mg and about 500 mg, such as between about 470 mg and about 490 mg, such as 480 mg±5 mg, such as 480±2.5 mg, such as 480±1.0 mg, such as 480±0.5 mg , eg 480 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is between 20 mg and 1000 mg (e.g., between 40 mg and 900 mg) every two weeks, e.g. between 60 mg and 800 mg, such as between 80 mg and 700 mg, such as between 80 mg and 600 mg, such as between 100 mg and 500 mg, such as between 120 mg and 400 mg, such as between 140 mg and 300 mg, such as between 160 mg and 350 mg, such as 180 mg and 300 mg, such as between 200 mg and 280 mg, such as between 220 mg and 260 mg, such as between 230 mg and 250 mg, such as 240 mg±5 mg, such as 240±2.5 mg, such as 240±1.0 mg, such as 240±0. 5 mg, eg 240 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is between 100 mg and 1000 mg (e.g., between 200 mg and 900 mg) every 4 weeks, e.g. between 300 mg and 800 mg, such as between 400 mg and 700 mg, such as between 400 mg and 600 mg, such as between 400 mg and 550 mg, such as between 420 mg and 540 mg, such as between 440 mg and 520 mg, such as between 460 mg and 500 mg, such as 470 mg and 490 mg, eg 480±5 mg, eg 480±2.5 mg, eg 480±1.0 mg, eg 480±0.5 mg, eg 480 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibodies (eg, nivolumab)) can be reduced compared to standard doses of anti-PD-1 antagonist antibodies administered as monotherapy.

In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody) (e.g., atezolizumab)) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))) is administered for 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 examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) dosing cycles may be associated with clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 14 to 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days). days, 24 days, 25 days, 26 days, 27 days or 28 days). In some examples, the dosing cycle length is about 21 days. In some examples, the dosing cycle length is about 14 days. In some examples, the dosing cycle length is about 28 days. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. be done. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., fixed dose) of about 600 mg (e.g., a fixed dose) on day 1 of each 21-day cycle ( i.e., intravenously at a dose of about 600 mg every 3 weeks). In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg (e.g., a fixed dose) on day 1 of each 21-day cycle. ) (ie, at a dose of 600 mg every 3 weeks). Similarly, in some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (e.g., Pembrolizumab))), formerly known as rambrolizumab, is administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every 3 weeks). ii) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) at a dose of about 200 mg on day 1 of each 21-day cycle (i.e., at a dose of about 200 mg every 3 weeks). ii) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) at a dose of about 240 mg on day 1 of each 14-day cycle (i.e., doses of about 240 mg every 2 weeks). in) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at about 480 mg on day 1 of each 28-day cycle (ie, at doses of about 480 mg every 4 weeks). The dose will be administered intravenously. In some examples, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., a dose of about 1200 mg every 3 weeks) is administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) at a dose of about 200 mg on day 1 of each 21-day cycle (i.e., at a dose of about 200 mg every 3 weeks). ii) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) at a dose of about 240 mg on day 1 of each 14-day cycle (i.e., doses of about 240 mg every 2 weeks). in) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at about 480 mg on day 1 of each 28-day cycle (ie, at doses of about 480 mg every 4 weeks). The dose will be administered intravenously.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) on about day 1 of each dosing cycle (e.g., 1 day day ± 3). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered at a dose (e.g., fixed dose) of about 600 mg on day 1 of each 21-day cycle (i.e. , at a fixed dose of about 600 mg every 3 weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 1200 mg (e.g., fixed dose). is administered intravenously on day 1 of each 21-day cycle (ie, at a dose of approximately 1200 mg every 3 weeks). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose of about 600 mg on day 1 of a 21-day cycle (i.e., about 600 mg) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, penprolizumab)) at a dose of approximately 200 mg on day 1 of a 21-day cycle (ie, 3 administered intravenously at doses of about 200 mg weekly). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg (e.g., a fixed dose) on day 1 of each cycle for 21 days. (i.e., a fixed dose of 600 mg every 3 weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of 1200 mg (e.g., fixed dose ) on day 1 of each 21-day cycle (ie, every 3 weeks at a dose of 1200 mg). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., atezolizumab) is administered at a dose of 600 mg on day 1 of each 21-day cycle (i.e., 600 mg every 3 weeks). and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., penprolizumab)) at a dose of 200 mg on day 1 of each 21-day cycle (i.e., 3 weeks administered intravenously at a dose of 200 mg per day).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) on about day 1 of the first dosing cycle (e.g., day 1 ± 3). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered at a dose (e.g., fixed dose) of about 600 mg on day 1 of each 21-day cycle (i.e. , at a fixed dose of about 600 mg every 3 weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab)) at a dose of about 240 mg (e.g., fixed dose). is administered intravenously on day 1 of each 14-day cycle (ie, at a dose of approximately 240 mg every 2 weeks). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose of about 600 mg on day 1 of a 21-day cycle (i.e., about 600 mg) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, nivolumab)) at a dose of about 480 mg on day 1 of a 28-day cycle (ie, 4 administered intravenously at a dose of approximately 480 mg weekly). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg (e.g., a fixed dose) on day 1 of each cycle for 21 days. (i.e., a fixed dose of 600 mg every 3 weeks) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab)) administered at a dose of 240 mg (e.g., fixed dose ) on day 1 of each 14-day cycle (ie, every 2 weeks at a dose of 240 mg). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., atezolizumab) is administered at a dose of 600 mg on day 1 of each 21-day cycle (i.e., 600 mg every 3 weeks). A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of 480 mg on day 1 of each 28-day cycle (i.e., 4 weeks administered intravenously at a dose of 480 mg per day).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) to the subject or population of subjects. In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly Pembrolizumab, formerly known as rambrolizumab))) is 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) 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, by intravenous infusion over 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). or administered to a target population.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 administered to the subject or population of subjects by intravenous infusion over 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes). In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) Pembrolizumab))) was known as )) was 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 administered to a subject or population of subjects by intravenous infusion over approximately 40 minutes).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) prior to administration to the subject or subject population. In some examples, for example, after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 ( Prior to administration of nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))), the method includes an intervening first observation period. In some examples, the method uses a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475). (pembrolizumab, formerly known as rambrolizumab)))). In some examples, the method includes a first observation period after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 Both include a second observation period following administration of an antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)). In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. If the first and second observation periods are each about 60 minutes long, the method includes the addition of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti-PD - about 30 ± 10 after administration of an L1 antagonistic antibody (e.g., atezolizumab) or an anti-PD-1 antagonistic antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)), respectively This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute. If the first and second observation periods are each about 30 minutes long, the method includes the addition of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti-PD - about 15 ± 10 after administration of an L1 antagonistic antibody (e.g., atezolizumab) or an anti-PD-1 antagonistic antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)), respectively This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute.

In other examples, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly known as lambrolizumab) Known pembrolizumab))) is administered to a subject or population of subjects prior to an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, for example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly After administration of pembrolizumab, formerly known as rambrolizumab))) and before administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some examples, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the method uses a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475). (pembrolizumab, formerly known as rambrolizumab)))) and a second observation period following administration of an anti-TIGIT antagonist antibody. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. If the first and second observation periods are each about 60 minutes long, the method includes the addition of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody ( atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody, respectively. This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute. If the first and second observation periods are each about 30 minutes long, the method includes the addition of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody ( atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody, respectively. This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute.

In other examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab ) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered to the subject or population of subjects concurrently. In some examples, for example, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or Following administration of MK-3475 (pembrolizumab, formerly known as rambrolizumab))), the method included an observation period. In some examples, the observation period is between about 30 minutes and about 60 minutes long. If the observation period is about 60 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., , MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) and an anti-TIGIT antagonist antibody at about 30±10 minutes after administration of the subject or subject population's vital signs (e.g., pulse rate , respiratory rate, blood pressure, and temperature). If the observation period is about 30 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., , MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) and an anti-TIGIT antagonist antibody at about 15±10 minutes after administration of the subject or subject population's vital signs (e.g., pulse rate , respiratory rate, blood pressure, and temperature).

In another aspect, the invention provides a method of treating a subject or subject population having stage IVB, metastatic, recurrent, or persistent cervical cancer, comprising: 3 Administering to the subject or subject population one or more dosing cycles of a dose (e.g., fixed dose) of 600 mg of anti-TIGIT antagonist antibody every week and a dose (e.g., fixed dose) of 1200 mg of atezolizumab every three weeks. wherein the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the invention provides a method of treating a subject or subject population having stage IVB, metastatic, recurrent, or persistent cervical cancer, wherein the subject or subject population is administered 600 mg every three weeks of Provided are methods of administering a dose (eg, fixed dose) of tiragolumab and one or more dosing cycles of a dose (eg, fixed dose) of 1200 mg atezolizumab every 3 weeks.

In another aspect, the invention provides a method of treating a subject or subject population having stage IVB, metastatic, recurrent, or persistent cervical cancer, wherein the subject or subject population is administered 600 mg every three weeks of Methods are provided for administering one or more dosing cycles of a dose (eg, fixed dose) of tiragolumab and a dose (eg, fixed dose) of 200 mg of penprolizumab every 3 weeks.

In another aspect, the invention provides a method of treating a subject or subject population having stage IVB, metastatic, recurrent, or persistent cervical cancer, wherein the subject or subject population is administered 600 mg every three weeks of Methods of administering a dose (eg, fixed dose) of tiragolumab and one or more dosing cycles of a dose (eg, fixed dose) of nivolumab of 240 mg every two weeks are provided.

In another aspect, the invention provides a method of treating a subject or subject population having stage IVB, metastatic, recurrent, or persistent cervical cancer, wherein the subject or subject population is administered 600 mg every three weeks of Methods of administering a dose (eg, fixed dose) of tiragolumab and one or more dosing cycles of a dose (eg, fixed dose) of nivolumab of 480 mg every 4 weeks are provided.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonistic antibodies (e.g. atezolizumab) or anti-PD-1 antagonistic antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly known as rambrolizumab) pembrolizumab))), wherein the method comprises an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody ( For example, administering one or more dosing cycles of MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) to a subject or population of subjects.

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

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 80 mg and about between about 80 mg and about 1900 mg, such as between about 80 mg and about 1800 mg, such as between about 100 mg and about 1700 mg, such as between about 200 mg and about 1600 mg, such as between about 300 mg and about 1400 mg, such as between about 400 mg and about 1300 mg, such as between about 500 mg and about 1200 mg, such as between about 600 mg and about 1100 mg, such as between about 700 mg and about 1000 mg, such as between about 740 mg and about 940 mg, such as between about 790 mg and about 890 mg between about 815 mg and about 865 mg, such as between about 830 mg and about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg) (eg, fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about between 2000 mg, such as between about 200 mg and about 1900 mg, such as between about 300 mg and about 1700 mg, such as between about 400 mg and about 1600 mg, such as between about 500 mg and about 1600 mg, such as between about 600 mg and about Between 1600 mg, such as between about 700 mg and about 1600 mg, such as between about 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as between about 1050 mg and about between 1350 mg, such as between about 1100 mg and about 1300 mg, such as between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as 1200 mg±5 mg; For example, a dose of 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about 2000 mg) every 4 weeks. between about 200 mg and about 2000 mg, such as between about 300 mg and about 2000 mg, such as between about 400 mg and about 2000 mg, such as between about 500 mg and about 2000 mg, such as between about 600 mg and about 1900 mg, such as about between 700 mg and about 1800 mg, such as between about 800 mg and about 1800 mg, such as between about 900 mg and about 1800 mg, such as between about 1000 mg and about 1800 mg, such as between about 1100 mg and about 1800 mg, such as between about 1200 mg and about 1800 mg between about 1300 mg and about 1800 mg, such as between about 1400 mg and about 1800 mg, such as between about 1500 mg and about 1800 mg, such as between about 1580 mg and about 1780 mg, such as between about 1630 mg and about 1730 mg, such as about 1655 mg and about 1705 mg, e.g. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between 80 mg and 2000 mg (eg, between 80 mg and 1950 mg, between 80 mg and 1900 mg, such as between 80 mg and 1800 mg, such as between 100 mg and 1700 mg, such as between 200 mg and 1600 mg, such as between 300 mg and 1400 mg, such as between 400 mg and 1300 mg, such as between 500 mg and 1200 mg, such as between 600 mg and 1100 mg, such as between 700 mg and 1000 mg, such as between 740 mg and 940 mg, such as between 790 mg and 890 mg, such as between 815 mg and 865 mg, such as between 830 mg and 850 mg, such as 840 mg±5 mg, such as 840±2 .5 mg, such as 840±1.0 mg, such as 840±0.5 mg, such as 840 mg) (eg, fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every three weeks, e.g. between 200 mg and 1900 mg, such as between 300 mg and 1700 mg, such as between 400 mg and 1600 mg, such as between 500 mg and 1600 mg, such as between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg ± 5 mg, such as 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every 4 weeks, e.g. between 200 mg and 2000 mg, such as between 300 mg and 2000 mg, such as between 400 mg and 2000 mg, such as between 500 mg and 2000 mg, such as between 600 mg and 1900 mg, such as between 700 mg and 1800 mg, such as between 800 mg and 1800 mg, such as 900 mg and 1800 mg, such as between 1000 mg and 1800 mg, such as between 1100 mg and 1800 mg, such as between 1200 mg and 1800 mg, such as between 1300 mg and 1800 mg, such as between 1400 mg and 1800 mg, such as between 1500 mg and 1800 mg, such as 1580 mg between 1780 mg, such as between 1630 mg and 1730 mg, such as between 1655 mg and 1705 mg, such as between 1670 mg and 1690 mg, such as 1680 mg±5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg , eg 1680 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a fixed dose of 1200 mg every 3 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (eg, atezolizumab)) can be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as monotherapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, penprolizumab)) is between about 20 mg and about 1000 mg (eg, about 40 mg and about 900 mg) every three weeks. between about 60 mg and about 800 mg, such as between about 80 mg and about 700 mg, such as between about 80 mg and about 600 mg, such as between about 100 mg and about 500 mg, such as between about 120 mg and about 400 mg, such as about between 140 mg and about 300 mg, such as between about 160 mg and about 350 mg, such as between about 180 mg and about 300 mg, such as between about 180 mg and about 250 mg, such as between about 180 mg and about 220 mg, such as between about 190 mg and about 210 mg between, eg 200±5 mg, eg 200±2.5 mg, eg 200±1.0 mg, eg 200±0.5 mg, eg 200 mg) (eg a fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., penprolizumab)) is between 20 mg and 1000 mg (e.g., between 40 mg and 900 mg) every three weeks, e.g. between 60 mg and 800 mg, such as between 80 mg and 700 mg, such as between 80 mg and 600 mg, such as between 100 mg and 500 mg, such as between 120 mg and 400 mg, such as between 140 mg and 300 mg, such as between 160 mg and 350 mg, such as 180 mg and 300 mg, such as between 180 mg and 250 mg, such as between 180 mg and 220 mg, such as between 190 mg and 210 mg, such as 200 mg±5 mg, such as 200±2.5 mg, such as 200±1.0 mg, such as 200±0. 5 mg, eg 200 mg) dose (eg fixed dose). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) is a dose of about 200 mg every 3 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) is a dose of 200 mg every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-1 antagonist antibody (eg, penprolizumab)) can be reduced compared to the standard dose of anti-PD-L1 antagonist antibody administered as monotherapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is between about 20 mg and about 1000 mg (eg, about 40 mg and about 900 mg) every two weeks. between about 60 mg and about 800 mg, such as between about 80 mg and about 700 mg, such as between about 80 mg and about 600 mg, such as between about 100 mg and about 500 mg, such as between about 120 mg and about 400 mg, such as about between 140 mg and about 300 mg, such as between about 160 mg and about 350 mg, such as between about 180 mg and about 300 mg, such as between about 200 mg and about 280 mg, such as between about 220 mg and about 260 mg, such as between about 230 mg and about 250 mg between, eg 240±5 mg, eg 240±2.5 mg, eg 240±1.0 mg, eg 240±0.5 mg, eg 240 mg) (eg a fixed dose). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of about 240 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, atezolizumab)) is between about 100 mg and about 1000 mg (eg, about 200 mg and about 900 mg) every 4 weeks. between about 300 mg and about 800 mg, such as between about 400 mg and about 700 mg, such as between about 400 mg and about 600 mg, such as between about 400 mg and about 550 mg, such as between about 420 mg and about 540 mg, such as about between 440 mg and about 520 mg, such as between about 460 mg and about 500 mg, such as between about 470 mg and about 490 mg, such as 480 mg±5 mg, such as 480±2.5 mg, such as 480±1.0 mg, such as 480±0.5 mg , eg 480 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is between 20 mg and 1000 mg (e.g., between 40 mg and 900 mg) every two weeks, e.g. between 60 mg and 800 mg, such as between 80 mg and 700 mg, such as between 80 mg and 600 mg, such as between 100 mg and 500 mg, such as between 120 mg and 400 mg, such as between 140 mg and 300 mg, such as between 160 mg and 350 mg, such as 180 mg and 300 mg, such as between 200 mg and 280 mg, such as between 220 mg and 260 mg, such as between 230 mg and 250 mg, such as 240 mg±5 mg, such as 240±2.5 mg, such as 240±1.0 mg, such as 240±0. 5 mg, eg 240 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is between 100 mg and 1000 mg (e.g., between 200 mg and 900 mg) every 4 weeks, e.g. between 300 mg and 800 mg, such as between 400 mg and 700 mg, such as between 400 mg and 600 mg, such as between 400 mg and 550 mg, such as between 420 mg and 540 mg, such as between 440 mg and 520 mg, such as between 460 mg and 500 mg, such as 470 mg and 490 mg, such as 480±5 mg, such as 480±2.5 mg, such as 480±1.0 mg, such as 480±0.5 mg, such as 480 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of about 480 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibodies (eg, nivolumab)) can be reduced compared to standard doses of anti-PD-1 antagonist antibodies administered as monotherapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg, e.g., between about 1 mg/kg and about 35 mg/kg) such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as about 12 mg/kg. between 5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0 .1 mg/kg, eg about 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.1 mg/kg and about 15 mg/kg, e.g., between about 0.5 mg/kg and about 15 mg/kg, e.g., between about 1 mg/kg and about 15 mg/kg) between about 2.5 mg/kg and about 15 mg/kg, such as between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as about between 10 mg/kg and about 15 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg; For example, about 15±0.5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg administered every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg and 50 mg/kg of the subject's body weight every three weeks. between (e.g. between 0.01 mg/kg and 45 mg/kg, e.g. between 0.1 mg/kg and 40 mg/kg, e.g. between 1 mg/kg and 35 mg/kg, e.g. 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg /kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg, or 15±0.1 mg/kg, such as 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg and 15 mg/kg of the subject's body weight every three weeks. between (e.g. between 0.1 mg/kg and 15 mg/kg, such as between 0.5 mg/kg and 15 mg/kg, such as between 1 mg/kg and 15 mg/kg, such as between 2.5 mg/kg and 15 mg/kg between 5 mg/kg and 15 mg/kg, such as between 7.5 mg/kg and 15 mg/kg, such as between 10 mg/kg and 15 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, between 14 mg/kg and 15 mg/kg, such as 15±1 mg/kg, such as 15±0.5 mg/kg, such as 15±0.2 mg/kg, such as 15±0.1 mg/kg, such as 15 mg/kg) is the dose of In some examples, an effective amount of anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of 15 mg/kg administered every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) doses PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly rambrolizumab) administered as drug therapy) may be reduced compared to the standard dose of pembrolizumab))), which was known as

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

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) to the subject or population of subjects. In some examples, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly Pembrolizumab (formerly known as lambrolizumab))) is 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) 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). or administered to a target population.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 administered to a subject or population of subjects by intravenous infusion over 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes). In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) Pembrolizumab))) was known as )) was 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 administered to a subject or population of subjects by intravenous infusion over approximately 40 minutes).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) prior to administration to the subject or subject population. In some examples, for example, after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 ( Prior to administration of nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))), the method includes an intervening first observation period. In some examples, the method uses a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475). (pembrolizumab, formerly known as rambrolizumab)))). In some examples, the method includes a first observation period after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 Both include a second observation period following administration of an antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)). In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. If the first and second observation periods are each about 60 minutes long, the method includes the addition of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti-PD - about 30 ± 10 after administration of an L1 antagonistic antibody (e.g., atezolizumab) or an anti-PD-1 antagonistic antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)), respectively This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute. When the first and second observation periods are each about 30 minutes long, the method includes the addition of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti-PD - about 15 ± 10 after administration of an L1 antagonistic antibody (e.g., atezolizumab) or an anti-PD-1 antagonistic antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)), respectively This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute.

In other examples, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly known as lambrolizumab) Known pembrolizumab))) is administered to a subject or population of subjects prior to an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, for example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab After administration of pembrolizumab))) and prior to administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some examples, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the method uses a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475). (pembrolizumab, formerly known as rambrolizumab)))) and a second observation period following administration of an anti-TIGIT antagonist antibody. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. If the first and second observation periods are each about 60 minutes long, the method includes the addition of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody ( atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody, respectively. This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute. If the first and second observation periods are each about 30 minutes long, the method includes the addition of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody ( atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody, respectively. This can include recording the subject's or subject population's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) every minute.

In other examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab ) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered to the subject or population of subjects concurrently. In some examples, for example, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or Following administration of MK-3475 (pembrolizumab, formerly known as rambrolizumab))), the method included an observation period. In some examples, the observation period is between about 30 minutes and about 60 minutes long. If the observation period is about 60 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., , MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) and an anti-TIGIT antagonist antibody at approximately 30±10 minutes after administration of the subject's vital signs (e.g., pulse rate, respiratory rate, , blood pressure, and temperature). If the observation period is about 30 minutes long, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., , MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) and an anti-TIGIT antagonist antibody at approximately 15±10 minutes after administration of the subject's vital signs (e.g., pulse rate, respiratory rate, , blood pressure, and temperature).

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), and as described in more detail below, the method comprises administering to the subject or subject population every 3 weeks administering a dose (e.g., fixed dose) of 600 mg of an anti-TIGIT antagonist antibody and one or more dosing cycles of a dose (e.g., fixed dose) of atezolizumab of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody is The VH domain comprises the amino acid sequence of SEQ ID NO:17 or 18 and the VL domain comprises the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) for use in methods of treating a subject or subject population and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., pembrolizumab)), and as described in more detail below, the method comprises administering to the subject or subject population every 3 weeks administering one or more dosing cycles of a dose (e.g., fixed dose) of 600 mg of an anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 200 mg (e.g., fixed dose) of pembrolizumab every three weeks, wherein the anti-TIGIT antagonist antibody is The VH domain comprises the amino acid sequence of SEQ ID NO:17 or 18 and the VL domain comprises the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)), and as described in more detail below, the method comprises administering to the subject or subject population every 3 weeks administering one or more dosing cycles of a dose (e.g., fixed dose) of 600 mg of an anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 240 mg every two weeks of nivolumab, wherein the anti-TIGIT antagonist antibody comprises: The VH domain comprises the amino acid sequence of SEQ ID NO:17 or 18 and the VL domain comprises the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) for use in methods of treating a subject or subject population and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)), and as described in more detail below, the method comprises administering to the subject or subject population every 3 weeks administering one or more dosing cycles of a dose (e.g., fixed dose) of 600 mg of an anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of nivolumab of 480 mg every 4 weeks, wherein the anti-TIGIT antagonist antibody is The VH domain comprises the amino acid sequence of SEQ ID NO:17 or 18 and the VL domain comprises the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (eg, atezolizumab), the method comprising administering to the subject or subject population a dose (eg, fixed dose) of 600 mg every 3 weeks for one or more dosing cycles (eg, a fixed dose), and 3 Administering a dose (eg, fixed dose) of 1200 mg weekly of atezolizumab.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MK-3475 (pembrolizumab, formerly known as lambrolizumab)), the method comprising administering to the subject or subject population one or more times administering a 600 mg dose (eg, fixed dose) of tiragolumab every 3 weeks and a 200 mg dose (eg, fixed dose) of penprolizumab every 3 weeks for a dosing cycle of .

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab)), the method comprising administering to the subject or subject population every 3 weeks for one or more dosing cycles administering a 600 mg dose (eg, fixed dose) of tiragolumab and a 240 mg dose (eg, fixed dose) of nivolumab every two weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab)), the method comprising administering to the subject or subject population every 3 weeks for one or more dosing cycles administering a 600 mg dose (eg, fixed dose) of tiragolumab and a 480 mg dose (eg, fixed dose) of nivolumab every 4 weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture or preparation of a medicament for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist disclosed herein) tiragolumab) and PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonistic antibodies (e.g. atezolizumab) or anti-PD-1 antagonistic antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly pembrolizumab))), formerly known as rambrolizumab, the method comprising administering to a subject or subject population one or more dosing cycles of a medicament, the medicament comprising an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly known as lambrolizumab) pembrolizumab))).

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer). and PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonistic antibodies (e.g. atezolizumab) or anti-PD-1 antagonistic antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly known as rambrolizumab) pembrolizumab)))), wherein the medicament comprises an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))).

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

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

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 80 mg and about 1950 mg) every two weeks. between about 80 mg and about 1900 mg, such as between about 80 mg and about 1800 mg, such as between about 100 mg and about 1700 mg, such as between about 200 mg and about 1600 mg, such as between about 300 mg and about 1400 mg, such as about between 400 mg and about 1300 mg, such as between about 500 mg and about 1200 mg, such as between about 600 mg and about 1100 mg, such as between about 700 mg and about 1000 mg, such as between about 740 mg and about 940 mg, such as between about 790 mg and about 890 mg between about 815 mg and about 865 mg, such as between about 830 mg and about 850 mg, such as between 840 mg±5 mg, such as between 840±2.5 mg, such as between 840±1.0 mg, such as 840±0. between 80 mg and 2000 mg (eg between 80 mg and 1950 mg, such as between 80 mg and 1900 mg, such as between 80 mg and 1800 mg, such as between 100 mg and 1700 mg, such as between 200 mg and 1600 mg, such as between 200 mg and 1600 mg, such as 300 mg and 1400 mg, such as between 400 mg and 1300 mg, such as between 500 mg and 1200 mg, such as between 600 mg and 1100 mg, such as between 700 mg and 1000 mg, such as between 740 mg and 940 mg, such as between 790 mg and 890 mg, such as 815 mg at a dose (e.g. fixed dose) of between 865 mg, such as between 830 mg and 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg) be. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about 2000 mg) every three weeks. between about 200 mg and about 1900 mg, such as between about 300 mg and about 1700 mg, such as between about 400 mg and about 1600 mg, such as between about 500 mg and about 1600 mg, such as between about 600 mg and about 1600 mg, such as about between 700 mg and about 1600 mg, such as between about 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as between about 1050 mg and about 1350 mg, such as between about 1100 mg and about 1300 mg between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between 100 mg and 2000 mg, such as between 200 mg and 1900 mg, such as between 300 mg and 1700 mg, such as between 400 mg and 1600 mg, such as between 500 mg and 1600 mg between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as between 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg), such as between about 1190 mg and about 1210 mg (eg between 1190 mg and 1210 mg), such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1 .0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about 2000 mg) every 4 weeks. between about 200 mg and about 2000 mg, such as between about 300 mg and about 2000 mg, such as between about 400 mg and about 2000 mg, such as between about 500 mg and about 2000 mg, such as between about 600 mg and about 1900 mg, such as about between 700 mg and about 1800 mg, such as between about 800 mg and about 1800 mg, such as between about 900 mg and about 1800 mg, such as between about 1000 mg and about 1800 mg, such as between about 1100 mg and about 1800 mg, such as between about 1200 mg and about 1800 mg between about 1300 mg and about 1800 mg, such as between about 1400 mg and about 1800 mg, such as between about 1500 mg and about 1800 mg, such as between about 1580 mg and about 1780 mg, such as between about 1630 mg and about 1730 mg, such as about 1655 mg and about 1705 mg, such as between about 1670 mg and about 1690 mg, such as between 100 mg and 2000 mg, such as between 200 mg and 2000 mg, such as between 300 mg and 2000 mg, such as between 400 mg and 2000 mg, such as between 500 mg and 2000 mg, such as 600 mg and 1900 mg, such as between 700 mg and 1800 mg, such as between 800 mg and 1800 mg, such as between 900 mg and 1800 mg, such as between 1000 mg and 1800 mg, such as between 1100 mg and 1800 mg, such as between 1200 mg and 1800 mg, such as 1300 mg between 1800 mg, such as between 1400 mg and 1800 mg, such as between 1500 mg and 1800 mg, such as between 1580 mg and 1780 mg, such as between 1630 mg and 1730 mg, such as between 1655 mg and 1705 mg, such as between 1670 mg and 1690 mg), such as 1680 mg ± 5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg, such as 1680 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a fixed dose of 1200 mg every 3 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) doses It may be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as drug therapy.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is between about 20 mg and about 1000 mg (eg, about 40 mg and about 900 mg) every three weeks. between about 60 mg and about 800 mg, such as between about 80 mg and about 700 mg, such as between about 80 mg and about 600 mg, such as between about 100 mg and about 500 mg, such as between about 120 mg and about 400 mg, such as about Between 140 mg and about 300 mg, such as between about 160 mg and about 350 mg, such as between about 180 mg and about 300 mg, such as between about 180 mg and about 250 mg, such as between about 180 mg and about 220 mg, such as between about 190 mg and about 210 mg ( between 40 mg and 900 mg, such as between 60 mg and 800 mg, such as between 80 mg and 700 mg, such as between 80 mg and 600 mg, such as between 100 mg and 500 mg, such as between 120 mg and 400 mg, such as between 140 mg and 300 mg, such as between 160 mg and 350 mg, such as between 180 mg and 300 mg, such as between 180 mg and 250 mg, such as between 180 mg and 220 mg, such as between 190 mg and 210 mg), such as 200 mg ± 5 mg, such as 200 ± 2.5 mg, such as 200 ± 1.0 mg, such as 200±0.5 mg, such as 200 mg) (eg, fixed dose). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) is a dose of about 200 mg every 3 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) is a dose of 200 mg every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-1 antagonist antibody (eg, penprolizumab)) can be reduced compared to the standard dose of anti-PD-L1 antagonist antibody administered as monotherapy.

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

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg, e.g., between about 1 mg/kg and about 35 mg/kg) such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as about 12 mg/kg. between 5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0 .1 mg/kg, eg about 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks. /kg (e.g., between about 0.1 mg/kg and about 15 mg/kg, e.g., between about 0.5 mg/kg and about 15 mg/kg, e.g., between about 1 mg/kg and about 15 mg/kg) between about 2.5 mg/kg and about 15 mg/kg, such as between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as about between 10 mg/kg and about 15 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg; For example, about 15±0.5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg administered every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) doses It may be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as drug therapy.

In any use of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) 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 examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) may provide clinical benefit (e.g., confirmation until no evidence of disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 14 to 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days). days, 24 days, 25 days, 26 days, 27 days or 28 days). In some examples, the dosing cycle length is about 21 days. In some examples, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered 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., tiragolumab) is administered in each 21-day cycle (i.e., at a dose of about 600 mg every 3 weeks) A dose of about 600 mg (eg, a fixed dose) is administered intravenously on day 1. Similarly, in some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (e.g., Medications, including pembrolizumab))), formerly known as rambrolizumab, are administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, a medicament comprising a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of about 1200 mg on day 1 of each 21-day cycle (ie, every 3 weeks at about 1200 mg) is administered intravenously. For example, a medicament comprising a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, penprolizumab)) at a dose of about 200 mg on day 1 of each 21-day cycle (i.e., about 200 mg every 3 weeks). 200 mg) is administered intravenously. For example, a medicament comprising a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) at a dose of about 240 mg on day 1 of each 14-day cycle (ie, about 240 mg) is administered intravenously. For example, a medicament comprising a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) at a dose of about 480 mg on day 1 of each 28-day cycle (ie, about 480 mg) is administered intravenously. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) or an anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) on Day 1 of each dosing cycle (e.g. , day 1 ± 3). For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered at a dose of about 600 mg on day 1 of each 21-day cycle (i.e., for 3 weeks). A medicament containing a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose of about 1200 mg every 21 days of each cycle. It is administered intravenously on day 1 (ie, at a dose of approximately 1200 mg every 3 weeks). For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., atezolizumab) is administered at a dose of about 600 mg on day 1 of each 21-day cycle (i.e., for 3 weeks). A drug containing a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., penprolizumab)) is administered intravenously at a dose of about 200 mg every 21 days of each cycle. It is administered intravenously on day 1 (ie, at a dose of approximately 200 mg every 3 weeks). For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., atezolizumab) is administered at a dose of about 600 mg on day 1 of each 21-day cycle (i.e., for 3 weeks). A drug containing a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., penprolizumab)) administered intravenously at a dose of about 600 mg per cycle for 14 days at a dose of about 240 mg. It is administered intravenously on day 1 (ie, at a dose of approximately 240 mg every two weeks). For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., atezolizumab) is administered at a dose of about 600 mg on day 1 of each 21-day cycle (i.e., for 3 weeks). A drug containing a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., penprolizumab)) is administered intravenously at a dose of about 480 mg per 28-day cycle. It is administered intravenously on day 1 (ie, at a dose of approximately 480 mg every 4 weeks).

In some examples, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) to the subject or population of subjects. In some examples, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly Pembrolizumab, formerly known as rambrolizumab))), containing 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) intravenously It is administered to a subject or population of subjects by injection.

In some examples, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) to the subject or population of subjects. In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) Pembrolizumab))) was known as pembrolizumab))) was administered for 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 minutes, or about 40 minutes) to the subject or population of subjects.

In some examples, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist Subject or subject population prior to medication containing antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) administered. In some examples, the method includes an intervening first observation period, eg, after administration of the medicament comprising the anti-TIGIT antagonist antibody and before administration of the medicament comprising the anti-PD-L1 antagonist antibody. In some examples, the method further comprises a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the method includes both a first observation period after administration of a medicament comprising an anti-TIGIT antagonist antibody and a second observation period after administration of a medicament comprising an anti-PD-L1 antagonist antibody. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. In examples where the first and second observation periods are each about 60 minutes, the method comprises administering a medicament comprising an anti-TIGIT antagonist antibody and a medicament comprising an anti-PD-L1 antagonist antibody during the first and second observation periods This may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) at about 30±10 minutes later. In examples where the first and second observation periods are each about 30 minutes, the method comprises administering a medicament comprising an anti-TIGIT antagonist antibody and a medicament comprising an anti-PD-L1 antagonist antibody during the first and second observation periods It may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) at about 15±10 minutes later.

In other examples, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly known as lambrolizumab) A medicament comprising known 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., tiragolumab). In some examples, the method includes an intervening first observation period, eg, after administration of the medicament comprising the anti-PD-L1 antagonist antibody and before administration of the medicament comprising the anti-TIGIT antagonist antibody. In some examples, the method includes a second observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody. In some examples, the method includes both a first observation period after administration of a medicament comprising an anti-PD-L1 antagonist antibody and a second observation period after administration of a medicament comprising an anti-TIGIT antagonist antibody. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. In examples where the first and second observation periods are each about 60 minutes, the method comprises administering a medicament comprising an anti-PD-L1 antagonist antibody and a medicament comprising an anti-TIGIT antagonist antibody during the first and second observation periods. This may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) at about 30±10 minutes later. In examples where the first and second observation periods are each about 30 minutes, the method comprises administering a medicament comprising an anti-PD-L1 antagonist antibody and a medicament comprising an anti-TIGIT antagonist antibody during the first and second observation periods. It may include recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) at about 15±10 minutes later.

In other examples, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) is administered concurrently to the subject or subject population. be. In some examples, the method includes an observation period, eg, after administration of the medicament comprising the anti-TIGIT antagonist antibody and the medicament comprising the anti-PD-L1 antagonist antibody. In some examples, the observation period is between about 30 minutes and about 60 minutes long. If the observation period is about 60 minutes in length, the method includes measuring the subject's vital signs at 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 during the observation period It may include recording signs (eg, pulse rate, respiration rate, blood pressure, and temperature). If the observation period is about 30 minutes long, the method includes measuring the subject's vital signs at about 15±10 minutes after administration of the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody during the observation period. It may include recording signs (eg, pulse rate, respiration rate, blood pressure, and temperature).

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture or preparation of a medicament for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist disclosed herein) Antibodies (e.g., tiragolumab) and anti-PD-L1 antagonist antibodies (e.g., atezolizumab) are provided, the methods comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every 3 weeks and between about 80 mg and about 2000 mg (e.g., PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab ) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))))

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture or preparation of a medicament for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist disclosed herein) Antibodies (e.g., tiragolumab) and anti-PD-L1 antagonist antibodies (e.g., atezolizumab) are provided, the methods comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every 3 weeks and between about 80 mg and about 2000 mg (e.g., PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab ) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))))

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture or preparation of a medicament for use in a method of treating a subject or subject population (e.g., an anti-TIGIT antagonist disclosed herein) Antibodies (e.g., tiragolumab) and anti-PD-L1 antagonist antibodies (e.g., atezolizumab) are provided, the methods comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at doses between about 30 mg and about 1200 mg (e.g., fixed dose) every 3 weeks and doses between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) every 4 weeks ( PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) at fixed doses). is formulated to administer pembrolizumab))), formerly known as

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer) in the manufacture of a medicament for use in a method of treating a subject or subject population with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), the method comprising the use of the medicament and the anti-TIGIT antagonist antibody. administering one or more dosing cycles to a subject or subject population, wherein the medicament is administered at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) every three weeks PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonist antibodies (e.g. atezolizumab) or anti-PD-1 antagonist antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) ))) and to administer the anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every three weeks. be.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture of a medicament for use in a method of treating a subject or subject population (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), the method comprising the use of the medicament and the anti-TIGIT antagonist antibody. administering one or more dosing cycles to a subject or subject population, wherein the medicament is administered at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) every 4 weeks PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonist antibodies (e.g. atezolizumab) or anti-PD-1 antagonist antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) ))) and to administer the anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every three weeks. be.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer) in the manufacture of a medicament for use in a method of treating a subject or subject population with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab ) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), the method comprising the use of the medicament and the anti-TIGIT antagonist antibody. comprising administering one or more dosing cycles to a subject or population of subjects, wherein the medicament is administered at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) every two weeks PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonist antibodies (e.g. atezolizumab) or anti-PD-1 antagonist antibodies (e.g. MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) ))) and to administer the anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every three weeks. be.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer) in the manufacture of a medicament for use in a method of treating a subject or subject population, the method comprising the medicament and the PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))) administering one or more dosing cycles to a subject or subject population, wherein the medicament is administered at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg (e.g., between 30 mg and 1200 mg) every three weeks formulated to administer the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) every three weeks. Ru

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population, described in further detail below. As such, the method comprises administering to the subject or subject population one or more dosing cycles of the medicament, wherein the medicament is an anti-TIGIT antagonist antibody at a dose of 600 mg (e.g., a fixed dose) every three weeks, and atezolizumab at a dose of 1200 mg (e.g., fixed dose) every 3 weeks, wherein the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and the amino acid sequence of SEQ ID NO: 19 contains a VL domain containing In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), use of an anti-TIGIT antagonist antibody and pembrolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population, described in further detail below. As such, the method comprises administering to the subject or subject population one or more dosing cycles of the medicament, wherein the medicament is an anti-TIGIT antagonist antibody at a dose of 600 mg (e.g., a fixed dose) every three weeks, and penprolizumab at a dose of 200 mg (e.g., fixed dose) every 3 weeks, wherein the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and the amino acid sequence of SEQ ID NO: 19 contains a VL domain containing In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

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

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), use of an anti-TIGIT antagonist antibody and nivolumab in the manufacture of a medicament for use in a method of treating a subject or subject population, described in further detail below. As such, the method comprises administering to the subject or subject population one or more dosing cycles of the medicament, wherein the medicament is an anti-TIGIT antagonist antibody at a dose of 600 mg (e.g., a fixed dose) every three weeks, and nivolumab at a dose of 480 mg (e.g., fixed dose) every 4 weeks, wherein the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and the amino acid sequence of SEQ ID NO: 19 contains a VL domain containing In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and atezolizumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every three weeks. and atezolizumab administered at a dose of 1200 mg (e.g., a fixed dose) every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and penprolizumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every three weeks. and penprolizumab administered at a dose of 200 mg every three weeks (e.g., a fixed dose), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and nivolumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every 3 weeks. and nivolumab administered at a dose of 240 mg (e.g., a fixed dose) every two weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and nivolumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every 3 weeks. and nivolumab administered at a dose of 480 mg (e.g., fixed dose) every 4 weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and atezolizumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every three weeks. and atezolizumab administered at a dose of 840 mg (e.g., fixed dose) every two weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. In addition, the method comprises administering to the subject or subject population one or more dosing cycles of a pharmaceutical agent and atezolizumab, wherein the pharmaceutical agent is administered an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600 mg every three weeks. and atezolizumab administered at a dose (e.g., fixed dose) of 1680 mg every 4 weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention has detectable levels of PD-L1 expression (eg, cervical cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population having (PD-L1-positive cervical cancer) cancer, as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and an anti-TIGIT antagonist antibody, wherein the pharmaceutical agent administers atezolizumab at a dose of 1200 mg (e.g., a fixed dose) every 3 weeks, and an anti-TIGIT antagonist antibody formulated to be administered at a dose of 600 mg (e.g., a fixed dose) every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

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

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), the use of pembrolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population, as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and an anti-TIGIT antagonist antibody, wherein the pharmaceutical agent administers pembrolizumab at a dose of 200 mg (e.g., a fixed dose) every 3 weeks, and an anti-TIGIT antagonist antibody formulated to be administered at a dose of 600 mg (e.g., a fixed dose) every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

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

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), the use of nivolumab in the manufacture of a medicament for use in a method of treating a subject or subject population, as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and an anti-TIGIT antagonist antibody, wherein the pharmaceutical agent administers nivolumab at a dose of 480 mg (e.g., a fixed dose) every 4 weeks, and an anti-TIGIT antagonist antibody formulated to be administered at a dose of 600 mg (e.g., a fixed dose) every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), the use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population, as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and an anti-TIGIT antagonist antibody, wherein the pharmaceutical agent administers atezolizumab at a dose (e.g., fixed dose) of 1680 mg every 4 weeks, and an anti-TIGIT antagonist antibody formulated to be administered at a dose of 600 mg (e.g., fixed dose) every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and SEQ ID NO: 19 A VL domain comprising the amino acid sequence of In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to the subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., a fixed dose) every 3 weeks and atezolizumab every 3 weeks is formulated for administration at a dose of 1200 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to the subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., a fixed dose) every 3 weeks and atezolizumab every 2 weeks is formulated for administration at a dose of 840 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to the subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., a fixed dose) every 3 weeks and atezolizumab every 2 weeks is formulated for administration at a dose of 840 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to the subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., a fixed dose) every 3 weeks and pembrolizumab every 3 weeks is formulated for administration at a dose of 200 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to a subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., a fixed dose) every 3 weeks and nivolumab every 2 weeks is formulated for administration at a dose of 240 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1 positive cervical cancer), as described in further detail below. , the method comprises administering to the subject or subject population one or more dosing cycles of a medicament, wherein the medicament is tiragolumab at a dose of 600 mg (e.g., fixed dose) every 3 weeks and nivolumab every 4 weeks is formulated for administration at a dose of 480 mg (eg, a fixed dose) to

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and atezolizumab, wherein the pharmaceutical agent is to administer tiragolumab at a dose of 600 mg every three weeks (e.g., a fixed dose) and atezolizumab It is formulated to be administered at a dose of 1200 mg (eg, fixed dose) every 3 weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and atezolizumab, wherein the pharmaceutical agent is to administer tiragolumab at a dose of 600 mg every three weeks (e.g., a fixed dose) and atezolizumab It is formulated to be administered at a dose of 840 mg (eg, fixed dose) every two weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical and atezolizumab, wherein the pharmaceutical is to administer tiragolumab at a dose of 600 mg every three weeks (e.g., a fixed dose) and atezolizumab It is formulated to be administered at a dose of 840 mg (eg, fixed dose) every two weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical and pembrolizumab, wherein the pharmaceutical is to administer tiragolumab at a dose of 600 mg every three weeks (e.g., a fixed dose) and pembrolizumab It is formulated to be administered at a dose of 200 mg (eg, fixed dose) every 3 weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a drug and pembrolizumab, wherein the drug is tiragolumab to be administered at a dose of 600 mg every three weeks (e.g., a fixed dose) and nivolumab It is formulated to be administered at a dose of 240 mg (eg, fixed dose) every two weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a drug and pembrolizumab, wherein the drug is tiragolumab to be administered at a dose of 600 mg every three weeks (e.g., a fixed dose) and nivolumab It is formulated to be administered at a dose of 480 mg (eg, fixed dose) every 4 weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), the use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject or subject population, as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and tiragolumab, wherein the pharmaceutical agent is to administer atezolizumab at a dose of 1200 mg (e.g., a fixed dose) every 3 weeks; It is formulated to be administered at a dose of 600 mg (eg, fixed dose) every 3 weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and tiragolumab, wherein the pharmaceutical agent is to administer atezolizumab at a dose of 1200 mg (e.g., a fixed dose) every 3 weeks; It is formulated to be administered at a dose of 840 mg (eg, fixed dose) every two weeks.

In another aspect, the present invention provides cancers with detectable levels of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or or recurrent PD-L1-positive cervical cancer), as described in more detail below. comprises administering to a subject or subject population one or more dosing cycles of a pharmaceutical agent and tiragolumab, wherein the pharmaceutical agent is to administer atezolizumab at a dose of 1200 mg (e.g., a fixed dose) every 3 weeks; It is formulated to be administered at a dose of 1680 mg (eg, fixed dose) every 4 weeks.

In any method, use or composition for use described herein, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and PD-1 axis-binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) or the medicament is one or more additional anti-cancer therapeutic agent(s) (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapy, and/or antihormonal agents (e.g., those listed herein above))) in combination (either separately or together).

In any method, use or composition for use described herein, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and PD- Uniaxial binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) ) or medicament thereof for treating a subject or subject population having cervical cancer. In some examples, the cervical cancer is stage IVB, metastatic, recurrent, or persistent cervical cancer. In some examples, the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer. Cancer can be in early or late stage.

In some examples, in any of the methods, uses or compositions for use described herein, the detectable PD-L1 expression level is a detectable PD-L1 protein expression level. In some instances, detectable PD-L1 protein expression levels have been determined by immunohistochemistry (IHC) assays. In some examples, PD-L1 protein expression levels are detected using an anti-PD-L1 antibody suitable for staining. In some examples, the tumor sample is a formalin-fixed paraffin-embedded (FFPE) tumor sample.

In some examples, in any of the methods, uses or compositions for use described herein, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some examples, the detectable PD-L1 nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or combinations thereof. has been decided.

In some examples, 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 examples, the cervical cancer is stage IVB, metastatic, recurrent, or persistent. In some examples, the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer. In some examples, the subject or subject population has received no prior treatment. In some examples, the subject or subject population has received at least one prior treatment. In some examples, the subject or subject population has received two prior treatments. In some examples, the subject or subject population has received at least one but no more than two prior systemic treatments and/or there is no acceptable standard of care for these subjects. In some examples, the subject or subject population has never received 3 or more prior treatments. In some examples, prior treatment is chemotherapy, surgery, and/or radiation therapy. In some examples, the prior treatment is immunotherapy.

In some examples, in any method, use or composition for use described herein, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) results in clinical responses. In some examples, a clinical response is an increase in objective response rate (ORR) in a subject or subject population compared to a baseline ORR. In some examples, the reference ORR is at least about 14.6% to about 26%. In some examples, the reference ORR is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median ORR of the subject population. In some examples, a clinical response is an increase in PFS for a subject or subject population when compared to a baseline PFS time. In some examples, the reference PFS is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median PFS time in a subject population. In some examples, a clinical response is an increase in duration of response (DOR) for a subject or subject population compared to baseline DOR time. In some examples, the reference DOR is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median DOR time in a subject population. In some instances the clinical response is an increase in OS.

Diagnostic methods and uses for cervical cancer A method is provided for selecting a treatment for a subject or subject population having positive cervical cancer), wherein the treatment is one or more in a sample (e.g., tumor sample or blood sample) obtained from the subject or subject population diagnostic methods comprising determining the presence and/or expression levels/amounts of biomarkers (eg, PD-L1, TIGIT, activated T cells or cytokines) of

Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly as lambrolizumab) known pembrolizumab)))) (e.g. cervical cancer, e.g. stage IVB, metastatic, recurrent or persistent cervical cancer, e.g. metastatic and/or Further provided herein are methods for identifying a subject or subject population having recurrent PD-L1 positive cervical cancer), wherein the identification is a sample obtained from the subject or subject population (e.g., a tumor sample or A diagnostic method comprising determining the presence and/or expression level/amount of one or more biomarkers (eg, PD-L1, TIGIT, activated T cells or cytokines) in a blood sample).

Further herein, cancer (eg, cervical cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer) in a sample (e.g., tumor sample or blood sample) obtained from the subject or subject population, wherein the additional treatment is one or more Guided by diagnostic methods including determining the presence and/or expression level/amount of biomarkers (eg PD-L1, TIGIT, activated T cells or cytokines).

Further herein, cancer (eg, cervical cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer) wherein the further treatment is one or more biomarkers in a sample (e.g., tumor sample or blood sample) obtained from the subject or subject population (eg PD-L1, TIGIT, activated T-cells or cytokines) is guided by diagnostic methods including determining the presence and/or expression level/amount.

Biomarkers for use in the methods described herein include, but are not limited to, PD-L1 and/or TIGIT expression in tissue (eg, tumor tissue) or blood (eg, whole blood), WGS and/or or germline and somatic mutations from tissue (e.g., tumor tissue) and/or from circulating tumor DNA in the blood (including but not limited to mutation burden, MSI and MMR defects) identified by NGS , analysis of genes (e.g., CD274) or gene signatures associated with tumor immunobiology (e.g., TEFF), HPV alterations, lymphocyte subpopulations, T-cell receptor repertoires, cytokines associated with T-cell activation, and Plasma-derived cytokines can be included, but are not limited to. In some examples, the biomarker is PD-L1. In some examples, the sample is a tumor sample (eg, a formalin-fixed paraffin-embedded (FFPE) tumor sample).

In some examples, the methods detect the presence and/or presence of a biomarker (eg, PD-L1, TIGIT, activated T cells or cytokines) in a sample (eg, a tumor sample or blood sample) from a subject or subject population. or determining expression levels/amounts and anti-TIGIT antagonist antibodies (e.g., as described herein 1 or more dosing cycles (e.g., between 80 mg and 2000 mg) of an anti-TIGIT antagonist antibody disclosed in the literature (e.g., tiragolumab) and a dose (e.g., fixed dose ) and administering to the subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, the methods detect the presence and/or presence of a biomarker (eg, PD-L1, TIGIT, activated T cells or cytokines) in a sample (eg, a tumor sample or blood sample) from a subject or subject population. or determining expression levels/amounts and anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, one or more dosing cycles of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of 840 mg every two weeks. administering one or more dosing cycles to a subject or population of subjects. In some examples, the methods detect the presence and/or presence of a biomarker (eg, PD-L1, TIGIT, activated T cells or cytokines) in a sample (eg, a tumor sample or blood sample) from a subject or subject population. or determining expression levels/amounts and anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, one or more dosing cycles of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of 1200 mg every 3 weeks. administering one or more dosing cycles to a subject or population of subjects. In some examples, the methods detect the presence and/or presence of a biomarker (eg, PD-L1, TIGIT, activated T cells or cytokines) in a sample (eg, a tumor sample or blood sample) from a subject or subject population. or determining expression levels/amounts and anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, one or more dosing cycles of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of 1680 mg every 4 weeks. administering one or more dosing cycles to a subject or population of subjects.

The presence and/or expression level/amount of biomarkers (eg, PD-L1, TIGIT, activated T cells or cytokines) include, but are not limited to, proteins, protein fragments, DNA, mRNA, cDNA and/or gene copy number. It can be determined qualitatively and/or quantitatively based on any suitable criteria known in the art, without limitation.

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

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

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

In some examples, the presence and/or expression level/ The amount is, for example, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) when detectable PD-L1 expression levels are biomarkers for selecting individuals. ) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))). In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample (eg, FFPE tumor sample). In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof. In some examples, the tumor sample is an FFPE tumor sample.

In one aspect, the present invention involves obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, protein expression of PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining, anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detected levels and PD-L1 expression in the tumor sample detected. cancer (e.g., cervical cancer) by identifying a subject or subject population as likely to benefit from treatment comprising one or more dosing cycles of atezolizumab administered in a dose (e.g., fixed dose). (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Based on detecting expression levels and PD-L1 expression in tumor samples detected, tiragolumab administered at a dose of 600 mg every 3 weeks (e.g., fixed dose) and a dose of 1200 mg every 3 weeks ( cancer (e.g., cervical cancer, cervical cancer, A method for selecting a therapy for a subject or subject population, e.g., with stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer I will provide a. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the tumor sample detected cancer (e.g., cervical Selecting a treatment for a subject or subject population with cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer The anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Based on detecting expression levels and PD-L1 expression in tumor samples detected, tiragolumab administered at a dose of 600 mg every 3 weeks (e.g., fixed dose) and a dose of 1200 mg every 3 weeks ( cancer (e.g., cervical cancer, cervical cancer, A method for selecting a therapy for a subject or subject population, e.g., with stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer I will provide a. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the tumor sample detected cancer (e.g., cervical Selecting a treatment for a subject or subject population with cancer, such as stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer The anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the detected tumor samples. cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent) by identifying a subject or subject population as likely to benefit from treatment involving one or more dosing cycles. Methods are provided for selecting a treatment for a subject or subject population with cervical cancer, eg, metastatic and/or recurrent PD-L1 positive cervical cancer. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))))). identify a subject or subject population with (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) The anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) (e.g., cervical cancer, e.g., stage IVB, metastatic, Methods are provided for identifying a subject or subject population with recurrent or persistent cervical cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., atezolizumab) by identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, Methods are provided for identifying a subject or subject population with metastatic, recurrent or persistent cervical cancer (e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the anti-TIGIT antagonist antibody is , a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) (e.g., cervical cancer, e.g., stage IVB, metastatic, Methods are provided for identifying a subject or subject population with recurrent or persistent cervical cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., atezolizumab) by identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, Methods are provided for identifying a subject or subject population with metastatic, recurrent or persistent cervical cancer (e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the anti-TIGIT antagonist antibody is , a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) (e.g., cervical cancer, e.g., stage IVB, metastatic, Methods are provided for identifying a subject or subject population with recurrent or persistent cervical cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., atezolizumab) by identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or A method is provided for assessing the responsiveness of a subject or subject population with persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer, wherein the anti-TIGIT antagonist antibody comprises SEQ ID NO: A VH domain comprising a 17 or 18 amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) Methods are provided for assessing responsiveness of a subject or population of subjects with cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., atezolizumab) by identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or A method is provided for assessing the responsiveness of a subject or subject population with persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer, wherein the anti-TIGIT antagonist antibody comprises SEQ ID NO: A VH domain comprising a 17 or 18 amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) Methods are provided for assessing responsiveness of a subject or population of subjects with cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., atezolizumab) by identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or A method of assessing the responsiveness of a subject or subject population with persistent cervical cancer (e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) is provided, wherein the anti-TIGIT antagonist antibody comprises SEQ ID NO: 17 or It includes a VH domain comprising an 18 amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))))) Methods of assessing responsiveness of a subject or population of subjects with cancer (eg, metastatic and/or recurrent PD-L1 positive cervical cancer) are provided. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. By identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody in subjects or subject populations with PD-L1-positive cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), wherein the anti-TIGIT antagonist antibody is SEQ ID NO: 17 or It includes a VH domain comprising an 18 amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. 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) in a subject or subject population with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., Methods are provided for optimizing therapy involving MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. By identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody in subjects or subject populations with PD-L1-positive cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), wherein the anti-TIGIT antagonist antibody is SEQ ID NO: 17 or It includes a VH domain comprising an 18 amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. 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) in a subject or subject population with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., Methods are provided for optimizing therapy involving MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and benefiting from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. By identifying a subject or subject population as likely to obtain cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody in subjects or subject populations with PD-L1-positive cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))), wherein the anti-TIGIT antagonist antibody is SEQ ID NO: 17 or 18 A VH domain comprising the amino acid sequence and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. 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) in a subject or subject population with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., Methods are provided for optimizing therapy involving MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab))). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, in any of the diagnostic methods or uses described herein, the cervical cancer is stage IVB metastatic, recurrent or persistent cervical cancer. Cancer can be in early or late stage.

D. Treatment Methods and Uses Related to Breast Cancer Breast Cancer Breast cancer is the most frequently diagnosed cancer in women, with an estimated global incidence of 2.08 million new cases reported in 2018. Breast cancer accounts for approximately 15% of all cancer deaths (approximately 626,700 cases) and is the most common cause of cancer-related death in women, with a 5-year survival rate of approximately 15% after diagnosis of metastasis. . The majority of patients are diagnosed with localized breast cancer. However, approximately 6% of patients exhibit de novo metastatic disease and between 10% and 40% of patients with localized breast cancer have systemic recurrence. In the early stages of breast cancer (I-III; early breast cancer), mostly asymptomatic disease is usually operable and can be treated with curative intent.

Breast cancer is a heterogeneous disease encompassing about 15 different types of carcinoma, and for therapeutic reasons, their estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 ( It is further classified according to the status of HER 2). These subgroups have important implications for selection of therapy, treatment outcome, recurrence rate, and mortality risk. Triple-negative breast cancer (TNBC) is characterized by lack of expression of ER, PR and HER2. Overall, approximately 15% to 20% of all breast cancers are classified as TNBC. Although large-scale comprehensive genomic analyzes have characterized the heterogeneity of TNBC and their diverse gene expression patterns and underlying genomic alterations, these insights are currently being used in clinical studies in laboratory and clinical studies. does not yet provide clear guidance for the identification of effective targeted therapies for

TNBC are more likely to have aggressive characteristics such as high proliferation rates. Patients with metastatic TNBC have a particularly poor clinical outcome, generally with rapid progression and a median OS rate of about 16 months. Despite recent treatment improvements, the prognosis for TNBC patients remains suboptimal, with a 5-year survival rate of approximately 15% indeed after diagnosis of metastasis.

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

Methods and Uses for Treating Lung Cancer Subjects or populations of subjects receiving chemotherapy (e.g., taxanes (e.g., nab-paclitaxel or paclitaxel)) and anti-PD-L1 antagonist antibodies such as atezolizumab are being treated for breast cancer (e.g., HER2+ breast cancer and TNBC). there is In some examples, the anti-TIGIT antagonist antibody is tiragolumab. In some examples, the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. In some examples, the anti-PD-L1 antagonist antibody is atezolizumab. In some examples, the chemotherapy is a taxane. In some examples, the taxane is nab-paclitaxel or paclitaxel. In some examples, the taxane is nab-paclitaxel. In some examples, the breast cancer is TNBC. In some examples, the TNBC is PD-L1 positive TNBC. In some instances, TNBC is unresectable, locally advanced or metastatic. In some instances, the PD-L1 positive TNBC is unresectable, locally advanced or metastatic. In some examples, the subject or subject population has never received prior systemic treatment for breast cancer. In some examples, the subject or subject population has no prior systemic treatment for metastatic breast cancer.

Methods and Uses for Treating eTNBC United States Patent Application 20070010003 Kind Code: A1 Methods and uses for treating early stage TNBC (eTNBC) in a subject or subject population, comprising an effective amount of an anti-TIGIT antagonist antibody (e.g., as disclosed herein) an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or administering to a subject or population of subjects, thereby treating the subject or population of subjects, a dosing regimen comprising one or more dosing cycles of MK-3475 (pembrolizumab, formerly known as rambrolizumab))) and uses are provided herein.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-L1, such as atezolizumab). antagonist antibody) to a subject or population in need thereof. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab) ) with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclophosphamide), taxanes (eg, paclitaxel, eg nab-paclitaxel) and/or topoisomerase II inhibitors (eg, doxorubicin))) with or without a subject or population in need thereof. In some examples, the method further comprises one or more surgeries (eg, mastectomy and/or axillary lymph node surgery). In some examples, surgery is performed after administering 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 examples, the surgery is mastectomy and/or axillary lymph node surgery. In some examples, surgery is performed between 2 weeks and 6 weeks (eg, 2 weeks, 3 weeks, 4 weeks, 5 weeks and 6 weeks) after the last administration of the dosing regimen.

In some instances, any of the methods and uses for treating eTNBC in a subject or subject population can result in pCR. In some examples, any of the methods and uses for treating eTNBC in a subject or subject population can result in increased OS or disease-free survival (EFS).

Dosing Regimens and Administration The therapeutic methods and uses of the invention described herein, in one aspect, involve administering to a subject or subject population with eTNBC an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist). antibodies (eg, atezolizumab) or anti-PD-1 antagonist antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and anti-TIGIT antagonist antibodies (eg, tiragolumab) administering a treatment regimen comprising In some examples, the treatment methods and uses of the invention described herein include one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or 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))) and/or G-CSF or GM - an effective amount of a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab)), with or without CSF or administering a treatment regimen comprising MK-3475 (pembrolizumab, formerly known as rambrolizumab)) and an anti-TIGIT antagonist antibody (eg, tiragolumab) to a subject or population of subjects with eTNBC. In some aspects, the topoisomerase II inhibitor is doxorubicin. In some aspects, doxorubicin is administered at a dose of about 60 mg/m ² .

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

Dosing of Chemotherapeutic Agents Therapeutically effective amounts of various chemotherapeutic agents are known in the art and contemplated by the present invention. In certain cases, one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclo phosphamide), taxanes (e.g. paclitaxel, e.g. nab-paclitaxel) and/or topoisomerase II inhibitors (e.g. doxorubicin))) are administered according to the doses listed in Section III(K) herein. .

Characterization and Selection of Cancer In any of the methods, uses or compositions for use described herein, the cancer can be breast cancer. In some examples, the breast cancer is TNBC. In some examples, the TNBC is eTNBC. In some examples, the eTNBC is a T2-4d TNBC at presentation. In some examples, the eTNBC are cT2-cT4, cN0-cN3, and cM0 TNBC at presentation. In some instances, eTNBC are PD-L1 positive. In some instances, eTNBC are PD-L1 negative. In some examples, the subject or subject population has not been previously treated for eTNBC. In some examples, the subject or subject population has no prior systemic treatment for breast cancer (eg, TNBC, eg, eTNBC).

In some examples, in any of the methods, uses or compositions for use described herein, the subject or subject population is PD-L1-selected tumors (e.g., PD-L1-expressing tumor-infiltrating immune cells ( IC) is greater than or equal to 1% in tumor samples as determined by IHC using the SP 142 antibody). In some examples, a PD-L1-selected tumor is one that has 1% or more of the tumor area occupied by PD-L1 expression (IC) as determined by immunohistochemistry (IHC) assay. In some examples, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3 or 28-8. In some examples, the IHC assay uses the anti-PD-L1 antibody SP142. In some instances, the IC has been determined to be 1% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, PD-L1 expression levels are detected using anti-PD-L1 antibody 22C3. In some examples, the detectable PD-L1 expression level is a composite positive score (CPS) of 1 or more in a sample from the subject.

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

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

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

In some examples, the treatment is compared to treatment with a PD-1 axis binding antagonist, e.g., without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in increased symptom-free survival in a subject or population of subjects. For example, in embodiments in which no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tiragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), treatment may include, for example, anti-TIGIT Disease-free survival of a subject or population of subjects compared to treatment with a PD-1 axis binding antagonist without an antagonist antibody or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist can result in an increase in An anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one one or more 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 in embodiments administered in combination with G-CSF or GM-CSF, the treatment may comprise, for example, (i) a PD-1 axis binding antagonist and one or more chemotherapeutic agents without an anti-TIGIT antagonist antibody and/or or compared to treatment with G-CSF or GM-CSF; (ii) an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents and/or G-CSF or GM without a PD-1 axis binding antagonist. - compared to treatment with CSF; and/or (iii) treatment with PD-1 axis binding antagonists and anti-TIGIT antagonist antibodies without one or more chemotherapeutic agents and/or G-CSF or GM-CSF. may result in increased symptom-free survival of a subject or population of subjects compared to

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Comparatively prolongs the OS of a subject or subject population. For example, in embodiments in which no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tiragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), treatment may include, for example, anti-TIGIT an increase in OS of a subject or population of subjects compared to treatment with a PD-1 axis binding antagonist without an antagonist antibody or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist can bring an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) with one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more 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 - In embodiments administered in combination with CSF or GM-CSF, the treatment is, for example, (i) a PD-1 axis binding antagonist and one or more chemotherapeutic agents without an anti-TIGIT antagonist antibody and/or G - compared to treatment with CSF or GM-CSF; (ii) treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents and/or G-CSF or GM-CSF without a PD-1 axis binding antagonist. and/or (iii) treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without one or more chemotherapeutic agents and/or G-CSF or GM-CSF , may result in an increase in OS in a subject or population of subjects.

Eisenhauer et al. , Eur. J. Cancer. 2009, 45:228-47, disease-free survival of a subject or subject population can be measured according to RECIST v 1.1 criteria. In some embodiments, EFS is measured as the time from initiation of treatment to the first occurrence of disease progression as determined by the criteria of RECIST version 1.1. In some embodiments, EFS is measured as the time from initiation of treatment to death.

In some embodiments, treatment reduces the subject's or subject population's EFS by at least 2.4 months (eg, 2.4-120 months, 2.5-100 months, 3.0-80 months, 4.0- 60 months, 5.0-48 months, 6.0-36 months, 8.0-24 months, or 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2. 7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.6 months. 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, 4.6 months. 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, treatment reduces the subject's or subject population's EFS by at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9 months). ~36 months, or 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months; 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, treatment reduces the subject's or subject population's EFS by at least about 2 months (eg, 2-120 months, 3-100 months, 4-80 months, 6-60 months, 8-48 months, 9-48 months, 36 months, or 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 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, 3.6 months. 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, 4.6 months. 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 time from initiation of treatment to death. In some examples, treatment reduces the OS of a subject or subject population by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months). months, 8-36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 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 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 examples, the treatment reduces the OS of the subject or subject population by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months). , 8 to 36 months, or 10 to 24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 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 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 examples, the treatment reduces the OS of the subject or subject population by at least about 5.3 months (eg, 5.3-120, 6-60 months, 7-48 months, 8-36 months, or 10-24 months). , e.g., 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 is for 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)) median OS for the subject population. In some embodiments, treatment results in a median OS for the subject population of about 25.0 months.

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

E. Therapeutic and Diagnostic Methods and Uses for Head and Neck Cancer Head and Neck Cancer Head and neck cancer is a cause of significant morbidity and mortality, with 890,000 new cases and 450 new cases worldwide in 2018. ,000 deaths. Head and neck cancers are a heterogeneous group that includes cancers that begin on the mucosal surfaces of the upper aerodigestive tract and affect the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx. The predominant histology is squamous cell carcinoma (SCC), which accounts for over 90% of all malignancies in the head and neck regions of the body.

Despite advances in the diagnosis and treatment of early-stage or locally advanced squamous cell carcinoma of the head and neck (SCCHN), more than 65% of these patients will develop recurrent or metastatic disease. Furthermore, approximately 10% of SCCHN patients present with metastatic SCCHN at initial diagnosis. For patients with locally recurrent disease, salvage surgery is curative only for selected patients with resectable locoregional recurrence, and reirradiation is limited to prior radiotherapy history and associated toxicities and morbidity. often limited by rates. As a result, systemic therapy is the standard of care (SOC) therapy and the mainstay of palliative care for patients with recurrent or metastatic SCCHN. For these patients, the prognosis is poor, with median survival of 6-15 months in most clinical trials, depending on patient and disease-related factors.

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

Methods and Uses for Treating Head and Neck Cancer An effective amount of a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX 1106 (nivolumab)) , MK-3475 (pembrolizumab, formerly known as rambrolizumab), MEDI-0680 (AMP-514), PDR 001 (spartalizumab), REGN 2810 (semiplimab), BGB-108, prololimab, canrelizumab, cintilimab, tislelizumab or tripalimab)) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to the subject or population of subjects. SCCHN (e.g., recurrent and/or metastatic SCCHN (e.g., PD-L1 positive and/or HPV positive recurrent and/or metastatic Provided herein are methods and uses for treating sexual SCCHN)). A method for treating a subject having SCCHN with detectable PD-L1 expression levels comprising an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a dose of about 80 mg to about 1600 mg every 3 weeks. Also provided herein are methods comprising administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist on a weekly basis. Also, a method for treating a subject having SCCHN with detectable PD-L1 expression levels comprising tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. Provided herein are methods that include administering one or more dosing cycles to a subject.

The present invention provides effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject or population in need thereof. In some examples, the present invention provides effective amounts of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody such as atezolizumab) and an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antibody as disclosed herein). Methods and uses comprising administering a TIGIT antagonist antibody (eg, tiragolumab) to a subject or subject population in need thereof.

In some instances, any of the methods and uses for treating SCCHN in a subject or subject population can result in CR or PR. In some examples, any of the methods and uses for treating SCCHN in a subject or subject population can result in an increased objective response rate (ORR) of the subject or subject population. In some examples, any of the methods and uses for treating SCCHN in a subject or subject population can result in increased PFS, duration of response (DOR) and/or OS of the subject or subject population.

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

In some instances, the treatment is first line therapy. In some examples, the subject or subject population has received no prior treatment. In some examples, the subject or subject population has not received prior systemic therapy for recurrent and/or metastatic disease.

Dosing Regimens and Administration The therapeutic methods and uses of the invention described herein, in one aspect, comprise an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD -1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an effective amount of an anti-TIGIT antagonist antibody (e.g., herein administering to a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, e.g., tiragolumab, as disclosed in including doing

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

Head and Neck Cancer Diagnostic Methods and Uses The present invention provides methods for selecting treatment (e.g., first-line therapy) for subjects or subject populations with SCCHN (e.g., recurrent and/or metastatic SCCHN). and the treatment is determined by one or more biomarkers (e.g., PD-L1 (e.g., PD-L1 protein and/or nucleic acid expression) in a sample (e.g., tumor sample or blood sample) obtained from the subject or subject population. determined) or HPV status (eg, determined by p16 IHC, ISH or PCR)).

Further herein, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX 1106 (nivolumab), MK- 3475 (pembrolizumab, formerly known as lambrolizumab), MEDI-0680 (AMP-514), PDR 001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prololimab, canrelizumab, cintilimab, tislelizumab, or tripalizumab) ) is provided for identifying a subject or subject population having SCCHN (e.g., recurrent and/or metastatic SCCHN) that can benefit from treatment, wherein the identification is obtained from the subject or subject population one or more biomarkers (eg, PD-L1 (eg, as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (eg, p 16 as determined by IHC, ISH or PCR))) is guided by diagnostic methods including determining the presence and/or expression level/amount.

A method for assessing responsiveness to treatment for a subject or subject population having SCCHN (e.g., recurrent and/or metastatic SCCHN), wherein additional treatment is administered to a sample obtained from the subject or subject population (e.g., , tumor sample or blood sample) or 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., p 16 IHC, ISH Further provided herein are methods guided by diagnostic methods comprising determining the presence and/or expression level/amount of )).

A method for optimizing treatment for a subject or subject population having SCCHN (e.g., recurrent and/or metastatic SCCHN), wherein the further treatment comprises a sample obtained from the subject or subject population (e.g., a tumor 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., p 16 IHC, ISH or PCR) in the sample or blood sample) Further provided herein are methods guided by diagnostic methods comprising determining the presence and/or expression level/amount of )) when determined by

Biomarkers for use in the methods described herein include, but are not limited to, PD-L1 expression in tissue (eg, tumor tissue) or blood (eg, whole blood), identified by WGS and/or NGS germline and somatic mutations from tissues (e.g., tumor tissue) and/or from circulating tumor DNA in the blood (including but not limited to mutation burden, MSI and MMR defects), tumor immune organisms analysis of genes or gene signatures associated with physiology, HPV alterations, lymphocyte subpopulations, T-cell receptor repertoires, cytokines associated with T-cell activation, and plasma-derived cytokines. In some examples, the biomarker is PD-L1. In some examples, a tumor sample obtained from a subject or population of subjects has a detectable PD-L1 expression level (e.g., a detectable protein and/or nucleic acid expression level of PD-L1 (e.g., 5% or more have been determined to have tumor-associated immune cells (TIC)). In some examples, a detectable PD-L1 protein expression level of 5% or more (eg, PD-L1 positive), 5% or more and less than 20% (eg, PD-L1 low), or 20% in tumor samples. Tumor-associated immune cells (TIC) above (eg, PD-L1 high). In some examples, the detectable PD-L1 protein expression level is 10% or more, 10% or more and 50% or less, or 50% or more TIC in the tumor sample. In some examples, the sample is a tumor sample (eg, a formalin-fixed paraffin-embedded (FFPE) tumor sample). In some examples, the tumor sample is a tumor tissue sample.

In some examples, the method provides a sample (e.g., a tumor sample or a blood sample) from a subject or subject population (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)) and determining the presence and/or expression level/amount (e.g., between about 30 mg and about 1200 mg (e.g., 30 mg and 1200 mg) with one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) and every 3 weeks 1 of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg (e.g., between 80 mg and 2000 mg) per administering one or more dosing cycles to a subject or population of subjects. In some examples, the method provides a sample (e.g., a tumor sample or a blood sample) from a subject or subject population (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 p 16 IHC, ISH, or PCR)) and/or the presence and/or expression level/amount of HPV status (e.g., as determined by p 16 IHC, ISH, or PCR); One or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a dose of 840 mg of a PD-1 axis binding antagonist (e.g., anti- administering one or more dosing cycles of a PD-L1 antagonist antibody (eg, atezolizumab) to the subject or population of subjects. In some examples, the method provides a sample (e.g., a tumor sample or a blood sample) from a subject or subject population (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 p 16 IHC, ISH, or PCR)) and/or the presence and/or expression level/amount of HPV status (e.g., as determined by p 16 IHC, ISH, or PCR); One or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a dose of 1200 mg of a PD-1 axis binding antagonist (e.g., anti- administering one or more dosing cycles of a PD-L1 antagonist antibody (eg, atezolizumab) to the subject or population of subjects. In some examples, the method provides a sample (e.g., a tumor sample or a blood sample) from a subject or subject population (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 p 16 IHC, ISH, or PCR)) and/or the presence and/or expression level/amount of HPV status (e.g., as determined by p 16 IHC, ISH, or PCR); One or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a dose of 1680 mg of a PD-1 axis binding antagonist (e.g., anti- administering one or more dosing cycles of a PD-L1 antagonist antibody (eg, atezolizumab) to the subject or population of subjects.

presence and/or expression of (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 p 16 IHC, ISH or PCR)) The level/amount is qualitative and/or quantitative 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. can be determined to

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

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

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

In some examples, e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status in a sample (e.g., tumor sample or blood sample) from a subject or subject population The presence and/or expression level/amount of (e.g., as determined by p 16 IHC, ISH or PCR), e.g., when detectable PD-L1 expression levels are biomarkers for selecting individuals , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab Select a subject or subject population that is eligible for treatment with pembrolizumab))), known as pembrolizumab))). In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample (eg, FFPE tumor sample). In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof. In some examples, the tissue sample is a tumor sample.

In one aspect, the present invention involves obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, protein expression of PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining, anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detected levels and PD-L1 expression in the tumor sample detected. SCCHN (e.g., relapsed and/or or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the detected tumor samples. for a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from treatment that includes one or more dosing cycles A method for selecting a treatment is provided. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the tumor sample detected SCCHN (e.g., relapsed and and/or methods for selecting a treatment for a subject or subject population with metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the detected tumor samples. for a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from treatment that includes one or more dosing cycles A method for selecting a treatment is provided. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable Anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the tumor sample detected SCCHN (e.g., relapsed and and/or methods for selecting a treatment for a subject or subject population with metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In another aspect, the present invention relates to obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, staining PD-L1 protein in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on detecting expression levels and PD-L1 expression in the detected tumor samples. for a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from treatment that includes one or more dosing cycles A method for selecting a treatment is provided. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))))) that may benefit from therapy ( For example, methods are provided for identifying a subject or subject population with recurrent and/or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX - Subjects with SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from treatment with -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)); or A method is provided for identifying a subject population. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))))) that may benefit from therapy ( For example, methods are provided for identifying a subject or subject population with recurrent and/or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and one or more doses of tiragolumab administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g. anti-PD-L1 antagonist antibodies (e.g. atezolizumab ) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) that may benefit from treatment (e.g., relapsed SCCHN) Methods are provided for identifying a subject or subject population that has cerebrospinal and/or metastatic SCCHN). In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))))) that may benefit from therapy ( For example, methods are provided for identifying a subject or subject population with recurrent and/or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX - Subjects with SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from treatment with -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)); or A method is provided for identifying a subject population. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., relapsed and/or or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) Provide a method for grading. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., relapsed and/or or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) Provide a method for grading. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies ( SCCHN (e.g., relapsed and/or or metastatic SCCHN). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)))) Provide a way to grade. In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; In a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from therapy comprising one or more dosing cycles, Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly as lambrolizumab) It provides a method for optimizing therapy involving known pembrolizumab))). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti Optimizing treatment with PD-L1 antagonistic antibodies (eg, atezolizumab) or anti-PD-1 antagonistic antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) provide a method for In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; In a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from therapy comprising one or more dosing cycles, Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly as lambrolizumab) Methods are provided for optimizing treatments involving known pembrolizumab))). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti Optimizing treatment with PD-L1 antagonistic antibodies (eg, atezolizumab) or anti-PD-1 antagonistic antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) provide a method for In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. detecting protein expression levels and anti-TIGIT antagonist antibody administered at a dose (e.g., fixed dose) of 600 mg every three weeks and atezolizumab administered at a dose (e.g., fixed dose) of 1200 mg every three weeks; In a subject or subject population with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying the subject or subject population as likely to benefit from therapy comprising one or more dosing cycles, Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab) or anti-PD-1 antagonist antibody (e.g. MDX-1106 (nivolumab) or MK-3475 (formerly as lambrolizumab) It provides a method for optimizing therapy involving known pembrolizumab))). In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 1680 mg every 4 weeks. In some examples, the treatment comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and atezolizumab at a dose of 840 mg every 2 weeks. In some examples, the present invention involves obtaining a tumor sample (e.g., a biopsy) from a subject or population of subjects, determining PD-L1 in the tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining. Detecting protein expression levels and potentially benefiting from a therapy comprising one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., anti Optimizing treatment with PD-L1 antagonistic antibodies (eg, atezolizumab) or anti-PD-1 antagonistic antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) provide a method for In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28) or an OX-40 agonist, such as an OX-40 agonist antibody , CD27, CD137, HVEM and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may further comprise or be administered in conjunction therewith (either separately or together).

In some examples, the method further comprises administering a treatment to the identified subject or subject population. In some examples, the treatment includes one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agents (e.g., CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)). one or more immune co-inhibitory receptors such as YERVOY®) (e.g., one selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that reduces or inhibits one or more co-immune co-inhibitory receptors (e.g., CD226, OX-40, CD28), or an OX-40 agonist, such as an OX-40 agonistic antibody; , CD27, CD137, HVEM, and/or GITR), chemotherapeutic agents, cytotoxic agents, growth inhibitors, radiotherapy )/radiation therapy, and/or anti-hormonal agents, such as those listed herein above), may be further included or administered in conjunction therewith (either separately or together).

In some examples, in any of the diagnostic methods or uses described herein the SCCHN is recurrent and/or metastatic SCCHN. Cancer may be in early or late stage. In some instances, the treatment is first line therapy. In some examples, the subject or subject population has received no prior treatment. In some examples, prior treatment is prior systemic treatment of recurrent and/or metastatic disease.

Characterization and Selection of Cancer In any of the methods, uses or compositions for use described herein, the cancer can be SCCHN (eg, recurrent and/or metastatic SCCHN). In some examples, the SCCHN is recurrent and/or metastatic SCCHN. In some instances SCCHN is PD-L1 positive. In some instances SCCHN is HPV positive. In some instances SCCHN is HPV negative. In some instances SCCHN is PD-L1 positive and HPV positive. In some instances SCCHN is PD-L1 positive and HPV negative. In some examples, the subject or subject population has received no prior treatment. In some examples, prior treatment is prior systemic treatment of recurrent and/or metastatic disease.

In some examples, in any of the methods, uses or compositions for use described herein, the subject or subject population is a PD-L1-selected tumor (e.g., a detectable PD-L1 expression level (e.g., a detectable PD-L1 protein expression level (e.g., 5% or more tumor-associated immune cells (TIC)).In some examples, a sample obtained from a subject or population of subjects (e.g., , a tumor sample (e.g., a tumor tissue sample) has a detectable PD-L1 protein expression level (e.g., a TIC of 5% or greater), hi some examples, a PD-L1-selected tumor has a detectable has a PD-L1 expression level (e.g., a detectable PD-L1 protein expression level (e.g., a TIC of 5% or greater), hi some examples, a detectable PD-L1 expression level is detectable PD-L1 expression level - L1 protein expression level (e.g., TIC of 5% or more) In some examples, the detectable PD-L1 protein expression level is about 5% or more (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) TIC In some examples, the detectable PD-L1 protein expression level is 5% or more and 20% or more less than (e.g., 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%) TIC, hi some examples, a TIC of 5% or more and less than 20% is defined as PD-L1 low, hi some examples, a detectable PD-L1 protein expression level is 20% or more (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%) of TIC In some examples, a TIC of 20% or more is defined as PD-L1 high, hi some examples, detectable PD-L1 protein expression levels are about 10% or more (e.g., 10% , 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 6 0%, 70%, 75%, 80%, 90% or more) TIC. In some examples, the detectable PD-L1 protein expression level is greater than or equal to 10% and less than 50% (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%) TIC. In some examples, the detectable PD-L1 protein expression level is 50% or more (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 examples, the IHC assay uses anti-PD-L1 antibodies SP263, SP142, 22C3 or 28-8. In some examples, the IHC assay uses the anti-PD-L1 antibody SP263. In some instances, the TIC has been determined to be 5% or greater (eg, using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TIC has been determined to be greater than or equal to 5% and less than 20% (eg, using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TIC has been determined to be 20% or greater (eg, using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TIC has been determined to be 10% or greater (eg, using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TIC has been determined to be greater than or equal to 10% and less than 50% (eg, using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TIC has been determined to be 50% or greater (eg, using the Ventana (SP263) PD-L1 IHC assay).

In some examples, in any of the methods, uses or compositions for use described herein, a sample obtained from a subject or subject population (e.g., a tumor sample) contains detectable PD-L1 Has a nucleic acid expression level. In some examples, the detectable PD-L1 nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or combinations thereof. has been decided. In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample. In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some examples, in any of the methods, uses or compositions for use described herein, the subject or subject population has a tumor with detectable HPV. In some examples, in any of the methods, uses or compositions for use described herein, the subject or subject population has a tumor without detectable HPV. In some examples, HPV is directly or indirectly detected. In some instances, HPV is detected by protein expression levels (eg, p16 or HPV viral proteins). In some examples, HPV is detected by nucleic acid expression levels. In some instances, HPV status is determined by p16 IHC, in situ hybridization, or PCR. In some examples, the HPV is HPV16. In some examples, the HPV is HPV18.

Response to Treatment In some embodiments of any of the methods described herein, the response of a subject or subject population to treatment can be characterized by one or more measures. In some embodiments, treatment results in CR or PR. In some examples, any of the methods and uses for treating SCCHN in a subject or subject population can result in an increased objective response rate (ORR) of the subject or subject population. In some examples, any of the methods and uses for treating SCCHN in a subject or subject population can result in increased PFS, duration of response (DOR) and/or OS of the subject or subject population.

In some examples, in any method, use or composition for use described herein, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as rambrolizumab)) results in clinical responses. In some examples, a clinical response is an increase in ORR for a subject or subject population when compared to a baseline ORR time. In some examples, the reference ORR is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median ORR of the subject population. In some examples, 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 examples, 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 examples, the reference ORR is at least about 19% to about 36%. In some examples, a clinical response is an increase in PFS for a subject or subject population when compared to a baseline PFS time. In some examples, the reference PFS is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median PFS time in a subject population. In some examples, a clinical response is an increase in DOR for a subject or subject population compared to a baseline DOR time. In some examples, the reference DOR is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)))) median DOR time in a subject population. In some examples, the baseline 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 examples, the baseline 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). months, 10.0 months, 11.0 months, or 12.0 months). In some examples, the baseline DOR time is at least about 6.7 months to about 23.4 months. In some examples, the baseline 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). months, 24 months, 25 months, 26 months, 28 months, 30 months, or 32 months). In some instances the clinical response is an increase in OS.

In some instances, treatment is 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) result in ORR. In some instances, treatment results in an ORR that is greater than the baseline ORR. In some examples, the reference ORR is 19%. In some examples, the reference ORR is 24.4%. In some examples, the reference ORR is 28.8%. In some examples, the reference ORR is 35%.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Comparatively, it results in an increase in PFS, DOR, or OS for a subject or subject population.

In some embodiments, OS is measured as the time from initiation of treatment to death. In some examples, treatment reduces the OS of a subject or subject population by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months). months, 8-36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 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 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 examples, the treatment reduces the OS of the subject or subject population by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months). , 8 to 36 months, or 10 to 24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 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 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 examples, the treatment reduces the OS of the subject or subject population by at least about 5.3 months (eg, 5.3-120, 6-60 months, 7-48 months, 8-36 months, or 10-24 months). , e.g., 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 examples, treatment results in an increase in OS compared to baseline OS time. In some examples, the baseline 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 examples, the baseline OS time is at least about 14.9 months (eg, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months). In some examples, the baseline OS time is at least about 11.6 months to about 14.9 months.

In some embodiments, treatment reduces the subject's or subject population's PFS to at least 2.4 months (eg, 2.4-120 months, 2.5-100 months, 3.0-80 months, 4.0- 60 months, 5.0-48 months, 6.0-36 months, 8.0-24 months, or 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2. 7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.6 months. 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, 4.6 months. 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, treatment reduces the subject's or subject population's PFS by at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9 months). ~36 months, or 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months; 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, treatment reduces the subject's or subject population's PFS by at least about 2 months (eg, 2-120 months, 3-100 months, 4-80 months, 6-60 months, 8-48 months, 9-48 months, 36 months, or 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 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, 3.6 months. 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, 4.6 months. 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, treatment reduces the subject's or subject population's DOR by at least 2.4 months (eg, 2.4-120 months, 2.5-100 months, 3.0-80 months, 4.0- 60 months, 5.0-48 months, 6.0-36 months, 8.0-24 months, or 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2. 7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.6 months. 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, 4.6 months. 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, treatment reduces the subject's or subject population's DOR by at least about 4 months (eg, 4-120 months, 5-100 months, 6-80 months, 7-60 months, 8-48 months, 9 months). ~36 months, or 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months; 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, treatment reduces the DOR of a subject or subject population by at least about 2 months (eg, 2-120 months, 3-100 months, 4-80 months, 6-60 months, 8-48 months, 9-48 months, 36 months, or 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 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, 3.6 months. 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, 4.6 months. 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 examples, the treatment is a patient-reported outcome measurement as measured by the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Item Bank v 2.0-Physical Function-Short Form 10 b. Resulting in improved time to documented decline in physical function (TTCD). In some examples, the treatment is according to PROMIS® Item Bank v2.0—Physical Functionaling—Short Form 10b, PROMIS® Item Bank v1.0—Fatigue—Short Form 4a, PROMIS® Item Bank v1.0—Produces improvement from baseline in physical function, fatigue, and/or pain as assessed by the Pain Interference Short Form 4a and PROMIS® Numeric Rating Scale v1.0—Pain Intensity 1a .

A. Treatment methods and uses for liver cancer Liver cancer Liver cancer is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide, with 854,000 new cases and 810,000 new cases annually. 000 deaths. At diagnosis, most patients with primary liver cancer have progressive disease, at a stage where treatment with curative therapies is not recommended. The World Health Organization estimates that more than 1 million people will die from liver cancer in 2030, highlighting a significant global public health problem.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for about 90% of all primary liver malignancies. HCC is a highly fatal disease with the highest mortality-to-incidence ratio of 0.98 of any solid tumor. Up to 80% of patients who first present with HCC have advanced unresectable or metastatic disease due to late onset of symptoms. In the United States, the 5-year OS rate for HCC patients is 17%, dropping substantially to only 3% when distant metastases are present.

Thus, there is an unmet need on the ground for the development of effective immunotherapies for the treatment of liver cancer, such as HCC, such as locally advanced HCC, metastatic HCC, or unresectable HCC.

Methods and uses for treating liver cancer Treating or delaying progression of liver cancer, such as hepatocellular carcinoma (HCC), locally advanced or metastatic and/or unresectable HCC, in a subject or population of subjects, comprising administering to the subject or population of subjects Provided herein are methods and uses for, wherein the subject or subject population has not previously undergone systemic treatment for liver cancer (eg, HCC). effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) treating or delaying progression of liver cancer, including locally advanced or metastatic and/or unresectable HCC, e.g., HCC, in a subject or subject population comprising administering to the subject or subject population a treatment regimen comprising Methods and uses for are also provided herein. In some embodiments, the treatment regimen comprises an effective amount of one or more of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, tiragolumab) Including dosing cycles. In other embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and Including one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tiragolumab).

administering to the subject or population of subjects a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab); Also provided herein are methods of enhancing immune function in a subject or population of subjects with liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC). In some embodiments, the treatment regimen comprises an effective amount of one or more of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, tiragolumab) Including dosing cycles.

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

A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) 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 (eg, atezolizumab)) are also provided herein, and treatment includes treatment regimens comprising administration of a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody (eg, tiragolumab). In some embodiments, the treatment regimen includes an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab). Including dosing cycles.

A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) 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 (e.g., atezolizumab)), wherein the treatment is PD in combination with a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) - Includes treatment regimens that include administration of a monoaxial binding antagonist. In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tiragolumab).

In another example, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., , bevacizumab)), wherein the treatment is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, tiragolumab ) in combination with treatment regimens that include administration of a VEGF antagonist. In some embodiments, the treatment regimen includes an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tiragolumab).

In another example, an anti-TIGIT antagonist antibody (e.g., tiragolumab) 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. Provided herein are pharmaceutical compositions comprising a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) ) in combination with an anti-TIGIT antagonist antibody. In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tiragolumab).

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

In some embodiments of any of the methods, uses or pharmaceutical compositions for use described herein, the treatment produces a response in the subject or subject population following treatment. For example, in some embodiments, treatment increases the likelihood of a subject or subject population having an objective response, prolongs the subject or subject population's PFS, increases the subject's or subject population's It prolongs OS, prolongs the time to radiographic progression (TTRP) of a subject or subject population, prolongs the duration of response (DOR) of a subject or subject population, and/or reduces the risk of death. In some embodiments, the treatment is for 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)). In some embodiments, the treatment is for 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). Median PFS for the subject population is provided. In some embodiments, the treatment is for at least about 5.6 months to at least about 6.83 months (eg, for at least about 5.7, 5.8, 5.9, 6.0, 6.1, 6.6 months). 2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, or 6.83 months). In some embodiments, the reference treatment comprises the current standard of care. In some embodiments, the reference treatment comprises a PD-1 axis binding antagonist (eg, atezolizumab) and a VEGF antagonist (eg, bevacizumab) without an anti-TIGIT antagonist antibody. In some embodiments, reference treatments include PD-1 axis binding antagonists and VEGF antagonists. 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 without a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody. 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 an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. In some embodiments, the reference treatment comprises an anti-TIGIT antagonist antibody that is free of VEGF antagonists and PD-1 axis binding antagonists.

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

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein , e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)), VEGF antagonists (e.g., anti-VEGF antibodies (e.g., bevacizumab)), or pharmaceuticals thereof may be used in the manufacture of a medicament, or one or more additional anti-cancer therapeutic agents (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapy, and/or or antihormonal agents (eg, those listed hereinabove)) for administration in combination (either separately or together).

In some embodiments of any of the methods, uses, or pharmaceutical compositions for uses described herein, the subject or subject population is liver cancer (e.g., locally advanced or metastatic and/or previously untreated for HCC, including unresectable HCC). In some examples, the subject or subject population has received no prior treatment. In some examples, the subject or subject population has received at least one prior treatment. In some examples, the subject or subject population has received two prior treatments. In some examples, the subject or subject population has received at least one but no more than two prior systemic treatments and/or there is no acceptable standard of care for these subjects. In some examples, the subject or subject population has never received 3 or more prior treatments. In some examples, prior treatment is chemotherapy, surgery, and/or radiation therapy. In some examples, the prior treatment is immunotherapy. In some embodiments, the subject or subject population has not been previously treated for liver cancer (eg, HCC (eg, locally advanced or metastatic and/or unresectable HCC)). In some embodiments, the subject or subject population has not been previously treated for HCC. In some embodiments, the subject or subject population 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 uses described herein, the subject or subject population is liver cancer (e.g., locally advanced or metastatic and/or No prior systemic therapy for HCC (including unresectable HCC). In some embodiments, the subject or subject population has no prior systemic therapy for liver cancer (eg, HCC).

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

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

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

Exemplary Methods In one aspect, the invention provides a method of treating a subject or subject population with HCC (e.g., locally advanced or metastatic and/or unresectable HCC), described in more detail below. subject to one or more dosing cycles of a dose (e.g., fixed dose) of 600 mg of an anti-TIGIT antagonist antibody every 3 weeks and a dose (e.g., fixed dose) of 1200 mg of atezolizumab every 3 weeks, or A method is provided by administering to a subject population, wherein the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19. In some examples, the subject or subject population has not been previously treated for HCC, eg, locally advanced or metastatic and/or unresectable HCC.

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

In another aspect, the invention provides a method of treating a subject or subject population having HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or subject population is given administering one or more dosing cycles of a 600 mg dose (eg, fixed dose) of tiragolumab and a 1200 mg dose (eg, fixed dose) of atezolizumab every 3 weeks.

In another aspect, the invention provides a method of treating a subject or subject population having HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or subject population is given 600 mg dose (e.g., fixed dose) of tiragolumab, 1200 mg dose (e.g., fixed dose) of atezolizumab every 3 weeks, and 15 mg/kg dose of bevacizumab every 3 weeks. provide a way to

In another aspect, the invention provides a method of treating a subject or subject population having HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or subject population is given administering one or more dosing cycles of a 420 mg dose (eg, fixed dose) of tiragolumab and a 840 mg dose (eg, fixed dose) of atezolizumab every two weeks.

In another aspect, the invention provides a method of treating a subject or subject population having HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or subject population is given tiragolumab at a dose (e.g., fixed dose) of 420 mg every 2 weeks, atezolizumab at a dose (e.g., fixed dose) of 840 mg every 2 weeks, and doses of 5 mg/kg, 7.5 mg/kg or 10 mg/kg every 2 weeks. Methods of administering one or more dosing cycles of bevacizumab are provided.

In another aspect, the invention provides a method of treating a subject or population of subjects with HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or population of subjects is given administering a dose (eg, fixed dose) of 840 mg of tiragolumab and one or more dosing cycles of a dose (eg, fixed dose) of 1680 mg (eg, fixed dose) of atezolizumab every 4 weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects with HCC (e.g., locally advanced or metastatic and/or unresectable HCC), wherein the subject or population of subjects is given tiragolumab at a dose (e.g., fixed dose) of 840 mg every 4 weeks; Methods of administering one or more dosing cycles of bevacizumab are provided.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) for , a method comprising administering to a subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody and an effective amount of one or more dosing cycles of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) including doing

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) and VEGF antagonists for (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method comprising an effective amount of an anti-TIGIT antagonist antibody, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) and an effective amount of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) one or more dosing cycles to the subject or population of subjects.

Exemplary Medicaments and Uses Thereof In another aspect, the invention provides a subject or subject population having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC). anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD - use of an L1 antagonistic antibody (e.g., atezolizumab), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament, wherein the medicament is about 30 mg every 3 weeks and about An anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 1200 mg and a PD-1 axis binding antagonist (e.g., an anti-PD- Uses formulated for administration of L1 antagonist antibodies (eg, atezolizumab) are provided. In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every three weeks and a dose (e.g., fixed dose) of between 80 mg and 2000 mg every three weeks PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)) are formulated for administration at .

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the method comprises administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg every three weeks, PD-1 axial binding at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg every three weeks Antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and VEGF at a dose between about 0.1 mg/kg and 50 mg/kg (eg, an anti-VEGF antibody (eg, bevacizumab)) every 3 weeks Formulated for administration of the antagonist. In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every three weeks, a dose (e.g., fixed dose) of between 80 mg and 2000 mg every three weeks A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody) at a dose between about 0.1 mg/kg and 50 mg/kg every 3 weeks (eg, bevacizumab)).

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament, wherein the medicament is administered at a dose of between about 30 mg and about 600 mg every two weeks (e.g. , fixed dose) of an anti-TIGIT antagonist antibody (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab ))). In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 600 mg every two weeks and a dose (e.g., fixed dose) of between 80 mg and 1200 mg every two weeks are formulated for administration of PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)) in patients.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the method comprises administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 600 mg every two weeks, PD-1 axial binding at a dose (e.g., fixed dose) of between about 80 mg and about 1200 mg every two weeks Antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and VEGF at a dose between about 0.1 mg/kg and 50 mg/kg (eg, an anti-VEGF antibody (eg, bevacizumab)) every two weeks Formulated for administration of the antagonist. In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 600 mg every two weeks; A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., an anti-VEGF antibody (e.g., For example, it is formulated for administration of bevacizumab)).

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) in the manufacture or preparation of a medicament for atezolizumab)), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament, wherein the medicament is dosed between about 600 mg and about 1200 mg every 4 weeks (e.g. , fixed dose) of an anti-TIGIT antagonist antibody (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab ))). In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 600 mg and 1200 mg every 4 weeks and a dose (e.g., fixed dose) of between 1200 mg and 2000 mg every 4 weeks PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)) are formulated for administration at .

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the method comprises administering to a subject or subject population one or more dosing cycles of the medicament, the medicament comprising: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 600 mg and about 1200 mg every 4 weeks, PD-1 axis binding at a dose (e.g., fixed dose) of between about 1200 mg and about 2000 mg every 4 weeks Antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and VEGF at a dose between about 0.1 mg/kg and 50 mg/kg (eg, an anti-VEGF antibody (eg, bevacizumab)) every two weeks Formulated for administration of the antagonist. In some aspects, the medicament is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 600 mg and 1200 mg every four weeks; A PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., an anti-VEGF antibody (e.g., For example, it is formulated for administration of bevacizumab)).

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) in the manufacture of medicaments for ), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament and an anti-TIGIT antagonist antibody, wherein the medicament is between about 80 mg and about 2000 mg every three weeks. to administer a dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a dose between about 30 mg and about 1200 mg (e.g., , fixed dose) of the anti-TIGIT antagonist antibody. In some aspects, the medicament administers a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose (eg, fixed dose) of between 80 mg and 2000 mg every 3 weeks. and to administer a dose of between 30 mg and 1200 mg (eg, a fixed dose) of the anti-TIGIT antagonist antibody every 3 weeks.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab), in the manufacture of medicaments for ) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method comprising administering to a subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, The medicament is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of between about 80 mg and about 2000 mg every three weeks, about An anti-TIGIT antagonist antibody at a dose of between 30 mg and about 1200 mg (e.g., a fixed dose) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., , bevacizumab)). In some aspects, the medicament is administered a dose (e.g., fixed dose) of between 80 mg and 2000 mg of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) every three weeks. anti-TIGIT antagonist antibody at doses between 30 mg and 1200 mg every 3 weeks (e.g., fixed dose) and VEGF antagonists at doses between 0.1 mg/kg and 50 mg/kg every 3 weeks (e.g., formulated to administer an anti-VEGF antibody (eg, bevacizumab).

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) in the manufacture of medicaments for ), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament and an anti-TIGIT antagonist antibody, wherein the medicament is between about 80 mg and about 1200 mg every two weeks. to administer a dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a dose of between about 30 mg and about 600 mg (e.g., , fixed dose) of the anti-TIGIT antagonist antibody. In some aspects, the medicament administers a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose (eg, fixed dose) of between 80 mg and 1200 mg every two weeks. and to administer a dose of between 30 mg and 600 mg (eg, a fixed dose) of the anti-TIGIT antagonist antibody every two weeks.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab), in the manufacture of medicaments for ) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method comprising administering to a subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, The medicament is a dose (e.g., fixed dose) of between about 80 mg and about 1200 mg of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) every two weeks, about An anti-TIGIT antagonist antibody at a dose of between 30 mg and about 600 mg (e.g., a fixed dose) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., an anti-VEGF antibody, e.g., , bevacizumab))). In some aspects, the medicament administers a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose (eg, fixed dose) of between 80 mg and 1200 mg every two weeks. anti-TIGIT antagonist antibody at doses between 30 mg and 600 mg (e.g., fixed dose) every 2 weeks and VEGF antagonists at doses between 0.1 mg/kg and 50 mg/kg every 2 weeks (e.g., formulated to administer an anti-VEGF antibody (eg, bevacizumab).

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) in the manufacture of medicaments for ), wherein the method comprises administering to a subject or subject population one or more dosing cycles of a medicament and an anti-TIGIT antagonist antibody, wherein the medicament is between about 1200 mg and about 2000 mg every 4 weeks. to administer a dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a dose between about 600 mg and about 1200 mg (e.g., , fixed dose) of the anti-TIGIT antagonist antibody. In some aspects, the medicament administers a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of between 1200 mg and 2000 mg every 4 weeks. and to administer a dose (eg, fixed dose) of between 600 mg and 1200 mg of anti-TIGIT antagonist antibody every 4 weeks.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab), in the manufacture of medicaments for ) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method comprising administering to a subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, The medicament is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose (eg, fixed dose) of between about 1200 mg and about 2000 mg every 4 weeks, about An anti-TIGIT antagonist antibody at a dose between 600 mg and about 1200 mg (e.g., a fixed dose) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., an anti-VEGF antibody (e.g., , bevacizumab))). In some aspects, the medicament administers a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose (e.g., fixed dose) of between 1200 mg and 2000 mg every 4 weeks. anti-TIGIT antagonist antibody at doses between 600 mg and 1200 mg (e.g., fixed dose) every 4 weeks and VEGF antagonists at doses between 0.1 mg/kg and 50 mg/kg every 2 weeks (e.g., formulated to administer an anti-VEGF antibody (eg, bevacizumab).

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

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) use of an anti-TIGIT antagonist antibody, atezolizumab, and bevacizumab in the manufacture of a medicament for, the method comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament administered every 3 weeks 600 mg dose (e.g., fixed dose) of anti-TIGIT antagonist antibody, 1200 mg dose (e.g., fixed dose) of atezolizumab every 3 weeks, 15 mg/kg dose of bevacizumab every 3 weeks. and the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in more detail below. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

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

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) use of an anti-TIGIT antagonist antibody, atezolizumab, and bevacizumab in the manufacture of a medicament for, the method comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament administered every two weeks anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 420 mg every 2 weeks, atezolizumab at a dose (e.g., fixed dose) of 840 mg every 2 weeks, and 5 mg/kg, 7.5 mg/kg or 10 mg/kg every 2 weeks and the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and the amino acid sequence of SEQ ID NO: 19, as described in more detail below. VL domain containing In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for , the method comprising administering one or more dosing cycles of the medicament to a subject or population of subjects, as described in more detail below. wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 840 mg every 4 weeks and atezolizumab at a dose (e.g., fixed dose) of 1680 mg every 4 weeks; The anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

In another aspect, the invention is used in a method of treating a subject or population of subjects with liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) use of an anti-TIGIT antagonist antibody, atezolizumab, and bevacizumab in the manufacture of a medicament for, the method comprising administering to a subject or subject population one or more dosing cycles of the medicament, the medicament administered every 4 weeks anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 840 mg every 4 weeks; atezolizumab at a dose (e.g., fixed dose) of 1680 mg every 4 weeks; Formulated to administer a dose of bevacizumab, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and the amino acid sequence of SEQ ID NO: 19, as described in more detail below Contains the VL domain. In some examples, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO:18 and a VL domain having the amino acid sequence of SEQ ID NO:19.

Dosing Regimens and Administration The therapeutic methods and uses of the invention described herein are, in one aspect, directed to liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC). )), an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and administering a treatment regimen comprising an anti-TIGIT antagonist antibody (eg, tiragolumab).

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

Effective Dosage In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is used in combination therapy (e.g., as described in Section III(K)). co-treatment with 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., atezolizumab)) at a dose of , may be decreased compared to standard doses of anti-TIGIT antagonist antibodies administered as monotherapy. Administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists and VEGF antagonists are described in Section III(K).

Dosing Cycle Dosing Cycle In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, anti-PD - L1 antagonist antibody (e.g., atezolizumab)) or VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) for 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 examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) ), and/or a dosing cycle of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) lacks clinical benefit (e.g., documented disease progression, drug resistance, death, or unacceptable toxicity) continue until In some examples, the length of each dosing cycle is about 14 to 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days). days, 24 days, 25 days, 26 days, 27 days or 28 days). In some examples, the dosing cycle length is about 21 days. In some examples, the dosing cycle length is about 14 days. In some examples, the dosing cycle length is about 28 days. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. be done. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., fixed dose) of about 600 mg (e.g., a fixed dose) on day 1 of each 21-day cycle ( i.e., intravenously at a dose of about 600 mg every 3 weeks). In some examples, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered about day 1 (eg, day 1±3) of each dosing cycle. For example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every 3 weeks). ii) administered intravenously. In some examples, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered about day 1 (eg, day 1±3) of each dosing cycle. For example, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) at a dose of about 15 mg/kg (i.e., at a dose of about 15 mg/kg every 3 weeks) intravenously on day 1 of each 21-day cycle. Administer internally. In some examples, for example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg on day 1 of each 21-day cycle (e.g., fixed dose) (ie, at a dose of 600 mg every 3 weeks) intravenously. In some examples, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on day 1 (eg, 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., atezolizumab)) at a dose of 1200 mg on day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every 3 weeks). It is administered intravenously. In some examples, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered on day 1 (eg, day 1±3) of each dosing cycle. For example, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) administered intravenously on day 1 of each 21-day cycle at a dose of 15 mg/kg (i.e., at a dose of 15 mg/kg every 3 weeks) do.

In some examples, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) are administered on about day 1 (eg, day 1±3) of each dosing cycle.

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

In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose of about 420 mg on day 1 of each 14-day cycle (i.e., 2 at a dose of about 420 mg every week) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 840 mg on day 1 of each 14-day cycle. (i.e., at a dose of about 840 mg every 2 weeks) and a VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) at about 5 mg/kg, 7 days on day 1 of each 14-day cycle. .5 mg/kg, or 10 mg/kg (ie, doses of about 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks) administered intravenously. In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose of 420 mg on day 1 of each 14-day cycle (i.e., 2 weeks PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab)) at a dose of 840 mg on day 1 of each 14-day cycle (i.e. , at a dose of 840 mg every 2 weeks) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) at 5 mg/kg, 7.5 mg/kg on day 1 of each 14-day cycle, or intravenously at a dose of 10 mg/kg (ie, at a dose of 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks).

In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 840 mg on day 1 of each 28-day cycle (i.e., 4 at a dose of about 840 mg every week) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 1680 mg on day 1 of each 28-day cycle. (i.e., at a dose of about 1680 mg every 4 weeks) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) at about 5 mg on days 1 and 15 of each 28-day cycle. /kg, 7.5 mg/kg, or 10 mg/kg (ie, doses of about 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks). In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 840 mg on day 1 of each 28-day cycle (i.e., for 4 weeks). PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab)) at a dose of 1680 mg on day 1 of each 28-day cycle (i.e. 7. VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) at 5 mg/kg on days 1 and 15 of each 28-day cycle; Administer intravenously at doses of 5 mg/kg, or 10 mg/kg (ie, doses of 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks).

Dosing Sequence and Observation Period In some examples, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is combined with a VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) and/or or administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, for example, after administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) or anti-TIGIT Prior to administration of an antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), the method includes an intervening first observation period. In some examples, for example, following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) A TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered to the subject or population of subjects prior to administration. In other examples, administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) followed by an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein) (eg, tiragolumab)) is administered to a subject or population of subjects prior to a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)). In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is first administered to a subject or population of subjects, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab) )) to a subject or population of subjects following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and an anti-TIGIT antagonist antibody (e.g., as disclosed herein an anti-TIGIT antagonist antibody (eg, tiragolumab) is administered to a subject or population of subjects after administration of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) antagonist. In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is first administered to a subject or population of subjects, followed by an anti-TIGIT antagonist antibody (e.g., disclosed herein). An anti-TIGIT antagonist antibody (e.g., tiragolumab) such as 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., atezolizumab)), and a VEGF antagonist (e.g., , an anti-VEGF antibody (eg, bevacizumab)) is administered to a subject or population of subjects after administration of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab).

In some examples, the method involves the use 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., tiragolumab). A second post-administration observation period is further included. In some examples, the method uses a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and an anti-TIGIT antagonist antibody. Further includes a third observation period following administration of (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab).

In some examples, the methods include a first observation period following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., , bevacizumab)) or a second observation period following administration of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) for a first observation period, 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., tiragolumab), and a second observation period following administration of the TIGIT antagonist antibody, PD-1 axis binding. A third observation period following administration of antagonist and VEGF antagonist is included. In some examples, the first, second, and/or third observation periods are each between about 30 minutes and about 120 minutes long (e.g., between about 30 minutes and 60 minutes long, between 60 and 90 minutes and/or between 90 and 120 minutes). If the first, second and third observation periods are each about 60 minutes long, the method includes treating the PD-1 axis binding antagonist (e.g., anti-PD - L1 antagonist antibody (e.g., atezolizumab)), anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), or VEGF antibody (e.g., anti-VEGF antibody (bevacizumab)) recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature) at about 30±10 minutes after administration of If the first, second and third observation periods are each about 30 minutes long, the method includes treating the PD-1 axis binding antagonist (e.g., anti-PD - L1 antagonist antibody (e.g., atezolizumab)), anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), or VEGF antibody (e.g., anti-VEGF antibody (bevacizumab)) recording the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and body temperature) at about 15±10 minutes after administration of the drug.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab)) or a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) prior to administration to the subject or population of subjects.

In some examples, for example, after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab )), the method includes an intervening first observation period. In some instances, e.g., after administration of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) acts as a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) to the subject or subject population. In other examples, for example, following administration of an anti-TIGIT antagonist antibody, a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is administered to a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). )) to a subject or population of subjects. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is first administered to a subject or population of subjects, and a PD-1 axis binding antagonist (e.g., , an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) 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., tiragolumab); A VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is administered to a subject or population of subjects after administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is first administered to a subject or population of subjects, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) 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., tiragolumab), and a PD-1 axis binding antagonist ( For example, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to a subject or population of subjects after administration of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)).

In some examples, the method includes administering a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). It further includes 2 observation periods. In some examples, the method uses an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody). (eg, atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), followed by a third observation period.

In some examples, the method includes a first observation period after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) or a VEGF antagonist (eg, , a second observation period following administration of an anti-VEGF antibody (eg, bevacizumab). In some examples, the method includes a first observation period after administration of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) or a VEGF antagonist (eg, A second observation period following administration of an anti-VEGF antibody (eg, bevacizumab)) and a third observation period following administration of a TIGIT antagonist antibody, a PD-1 axis binding antagonist and a VEGF antagonist. In some examples, the first, second, and third observation periods are each between about 30 minutes and about 60 minutes long. In examples in which the first, second, and third observation periods are each about 60 minutes long, the method includes: Vital signs of the subject or subject population at about 30 ± 10 minutes after administration of the axially bound antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) (eg, pulse rate, respiration rate, blood pressure, and temperature). In examples in which the first, second, and third observation periods are each about 30 minutes long, the method includes: Vital signs of the subject or subject population about 15 ± 10 minutes after administration of the axially bound antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) or VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) (eg, pulse rate, respiration rate, blood pressure, and temperature).

In some examples, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) or PD- A monoaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered prior to the subject or population of subjects. In some examples, for example, 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., tiragolumab ) or a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), the method includes an intervening first observation period. In some examples, for example, administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) followed by an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab ) is administered to a subject or population of subjects prior to a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In other examples, for example, following administration of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to anti-TIGIT An antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered to the subject or population of subjects prior to administration. In some examples, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is first administered to the subject or subject population, and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist as disclosed herein) is administered. An antibody (e.g., tiragolumab) is 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., atezolizumab)) is administered to a subject or population of subjects after administration of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is first administered to the subject or subject population, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered to the subject or population of subjects first. )) 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., , tiragolumab) is administered to a subject or population of subjects following administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) antagonist.

In some examples, the method uses an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) or a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody). (eg, atezolizumab)). In some examples, the method uses 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., tiragolumab) and Further includes a third observation period following administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some examples, the method includes a first observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., as disclosed herein). A second observation period following administration of both an anti-TIGIT antagonist antibody (eg, tiragolumab) or a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is included. In some examples, the method includes administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for a first observation period, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antibody as disclosed herein). A second observation period following administration of a TIGIT antagonist antibody, e.g. tiragolumab) or a PD-1 axis binding antagonist (e.g. an anti-PD-L1 antagonist antibody (e.g. atezolizumab)) and a TIGIT antagonist antibody, PD-1 axis binding A third observation period following administration of antagonist and VEGF antagonist is included. In some examples, the first, second, and third observation periods are each between about 30 minutes and about 60 minutes long. If the first, second, and third observation periods are each about 60 minutes long, the method includes administering a VEGF antagonist (e.g., an anti-VEGF antibody ( bevacizumab)), an anti-TIGIT antagonist antibody (e.g. an anti-TIGIT antagonist antibody as disclosed herein, e.g. tiragolumab), or a PD-1 axis binding antagonist (e.g. an anti-PD-L1 antagonist antibody (e.g. , atezolizumab)) at about 30±10 minutes after administration of the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature). If the first, second, and third observation periods are each about 30 minutes long, the method includes administering a VEGF antagonist (e.g., an anti-VEGF antibody ( bevacizumab)), an anti-TIGIT antagonist antibody (e.g. an anti-TIGIT antagonist antibody as disclosed herein, e.g. tiragolumab), or a PD-1 axis binding antagonist (e.g. an anti-PD-L1 antagonist antibody (e.g. , atezolizumab)) at about 15±10 minutes after administration of the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature).

In other examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a subject or subject population. administered at the same time. In some examples, the method includes an observation period, eg, after administration of the anti-TIGIT antagonist antibody and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)).

In other examples, anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, eg, tiragolumab) and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)). are administered simultaneously to a subject or population of subjects. In some examples, the method includes an observation period, eg, after administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

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

In some examples, the observation period is between about 30 minutes and about 60 minutes long. If the observation period is about 60 minutes long, the method includes recording the subject's or subject population's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30±10 minutes after administration. can contain. If the observation period is about 30 minutes long, the method includes recording the subject's vital signs cluster (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15±10 minutes after administration. obtain.

In some examples, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein; tiragolumab) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), followed by co-administration.

In some examples, the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is combined with an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and PD- It is administered after co-administration of a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)).

In some examples, e.g., VEGF antagonists (e.g., anti-VEGF antibodies (e.g., bevacizumab)), anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tiragolumab), and After administration of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), the method includes a second observation period. In some examples, 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., atezolizumab)), the method is Includes a second observation period. In some examples, the second observation period is between about 30 minutes and about 60 minutes long. If the second observation period is about 60 minutes long, the method records the subject's vital signs cluster (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30±10 minutes after administration. can include If the second observation period is about 30 minutes long, the method records the subject's vital signs cluster (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15±10 minutes after administration. can include

B. Methods of Treatment and Uses for Urothelial Cancer Urothelial Carcinoma Urothelial carcinoma (UC) is the most common cancer of the urinary system worldwide. The majority of cases originate in the bladder. UC can be diagnosed as non-muscle invasive, muscle invasive, or metastatic disease, with 1 in 3 newly diagnosed muscle invasive disease (tumor, node and metastasis (TNM) classification). cT2-T4a Nx M0). Muscle invasive UC (MIUC) collectively refers to muscle invasive bladder cancer (MIBC) and muscle invasive urothelial carcinoma (UTUC). In 2018, there were an estimated 549,393 new cases of bladder cancer and 199,922 deaths worldwide. In Europe, there were an estimated 197,110 new cases of bladder cancer and 64,970 deaths, of which 164,450 new cases and 52,930 deaths were attributed to 28 members of the European Union. in the country. In the United States, it is estimated that there will be 81,400 new cases of bladder cancer in 2020 and 17,980 deaths. The median age of patients diagnosed with UC in the United States is 73, the oldest age at diagnosis for any tumor type.

There is a particularly urgent need for therapeutic approaches for the treatment of MIBC. MIBC represents approximately 30% of new urothelial cancer cases. MIBC has a 5-year survival rate of 25-50% (European Urological Association EAU Guidelines 2013) and has seen little improvement over the past 30 years due to the lack of effective new treatments in this disease area (Surveillance, Epidemiology, and End Results (SEER) Program. Cancer stats: bladder cancer, 2020). Therefore, there is a high unmet need for improved medical interventions.

Methods and Uses for Treating Urothelial Carcinoma UC (e.g., bladder Provided herein are methods and uses for treating cancer (eg, MIBC). The subject is preferably human. In some embodiments, the subject or subject population has not been previously treated with cancer immunotherapy.

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

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

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

The present invention includes methods and uses for treating a subject or subject population with MIBC, wherein the method administers to the subject or subject population a dose of between about 30 mg and about 1200 mg (e.g., fixed dose) every three weeks. and one or more dosing cycles of a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80 mg and about 1600 mg every 3 weeks; It is a temporary measure. In some aspects, the method comprises administering an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every three weeks and a dose (e.g., fixed dose) of between 80 mg and 1600 mg every three weeks. The treatment is perioperative therapy, comprising administering to the subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist.

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

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

In some examples, the first dosing cycle is initiated prior to surgery. In some instances, one or more dosing cycles are completed prior to surgery. In some examples, at least 1, 2, or 3 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) are completed prior to surgery. In some examples, 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 after surgery. In some examples, 1 to 17 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 one dosing cycle) is completed after surgery. In some examples, at least one dosing cycle is initiated between about 4 and 6 weeks (eg, about 4 weeks, about 5 weeks, or about 6 weeks) after surgery. In some examples, treatment includes surgery. In some examples, the surgery is a cystectomy and/or a lymphadenectomy.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in pCR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in increased recurrence-free survival (RFS), eg, landmark RFS (eg, landmark RFS at 12, 18, or 24 months). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in increased symptom-free survival (EFS), eg, landmark EFS (eg, landmark EFS at 12, 18, or 24 months). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of an L1 antagonist antibody) results in an increase in OS, eg, landmark OS (eg, landmark OS at 12, 18, or 24 months). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in an increased rate of reduction of pathological progression. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in an increase in pCR in a subject or population of subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. , to extend the EFS (eg, landmark EFS) of a subject or population of subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. , extend the RFS (eg, landmark RFS) of a subject or population of subjects. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. , extends the OS (eg, landmark OS) of the subject or subject population.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject or subject population in need thereof for four weeks (e.g., each on day 1 of a 28-day dosing cycle). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 4 weeks (e.g., on day 1 of each 28-day dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab) for 2 weeks (e.g., 1 and 1 of each 28-day dosing cycle). every 3 weeks (eg, on day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on day 1 of each 28-day dosing cycle). In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in CR or PR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) reduces pCR in a subject or population of subjects compared to a reference. resulting in an increase in In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in increased EFS and/or RFS. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject or population of subjects.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist such as atezolizumab). (e.g., an anti-PD-1 antagonist antibody such as pembrolizumab) to a subject or population in need thereof every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle) including methods and uses including doing. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). Administration of L1 antagonist antibody) results in pCR. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. resulting in an increase in EFS and/or RFS in a subject or subject population. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-1, such as atezolizumab). L1 antagonist antibody), e.g., compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or compared to treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. to prolong the OS of a subject or subject population.

In certain examples, the invention provides an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject or subject population in need thereof. Methods and uses comprising administration on a weekly basis (eg, on days 1 and 15 of each 28-day dosing cycle) are included. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) results in pCR. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) improves the EFS of a subject or subject population compared to a reference. and/or result in increased RFS. In some examples, administration of an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) prolongs OS in a subject or population of subjects.

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

In some examples, treatment may further include additional therapies. Any suitable additional therapy known in the art or described herein can be used. Additional treatments include radiotherapy, surgery (e.g., cystectomy), gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma radiation, or combinations thereof. can be

In some instances, the additional therapy is a side effect-limiting agent (e.g., an agent intended to reduce the occurrence and/or severity of side effects of treatment, e.g., anti-nausea drugs, corticosteroids (e.g., prednisone or equivalents, eg, doses of 1-2 mg/kg/day), hormone replacement drugs, etc.).

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

A therapeutic regimen comprising an effective amount of a PD-1 axis binding antagonist (eg, atezolizumab) and/or an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) Also provided herein are methods for treating MIBC in a subject or population of subjects, comprising administering to the subject or population of subjects in combination with a cancer agent or cancer therapy. For example, a PD-1 axis binding antagonist may include an additional chemotherapy or chemotherapeutic agent (see definition above); a targeted therapy or targeted therapeutic agent; an immunotherapy or immunotherapeutic agent, such as a monoclonal antibody; cytotoxic agents (see definition above); or combinations thereof.

In some examples in which the patient has metastatic urothelial carcinoma (mUC) and the mUC has progressed during or after platinum-containing therapy, the methods provided herein provide that the subject or subject population has disease progression or Further comprising administering a second dosing regimen to the subject or subject population after experiencing unacceptable toxicity. In some examples, the second dosing regimen includes one or more dosing cycles of the PD-1 axis binding antagonist and an antibody-drug conjugate (ADC). In some examples, (a) the ADC is enfortumab vedotin or (b) sacituzumab govitecan.

Also provided herein are methods for treating a subject or population of subjects with mUC, the methods comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen. (a) the first dosing regimen comprises a dose (e.g., fixed dose) of about 600 mg every three weeks of tiragolumab and a dose (e.g., fixed dose) of about 1200 mg of atezolizumab every three weeks; b) the second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose (e.g., fixed dose) of about 1200 mg every 3 weeks; administered at a dose of 1.25 mg/kg weekly for 1 week off, or (ii) suctuzumab govitecan at 10 mg/kg weekly for 2 weeks on/1 week off A second dosing regimen is administered to a subject or subject population after the subject or subject population experiences 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 with mUC, the methods comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen and (a) the first dosing regimen is tiragolumab at a dose (e.g., fixed dose) of 600 mg every 3 weeks and atezolizumab at a dose (e.g., fixed dose) of 1200 mg every 3 weeks (b) the second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose (e.g., fixed dose) of 1200 mg every 3 weeks; (i) enfortumab vedotin for 2 weeks or (ii) suctuzumab govitecan at 10 mg weekly for 2 weeks on/1 week off /kg, and the second dosing regimen is administered to a subject or subject population after the subject or subject population experiences disease progression or unacceptable toxicity during the first dosing regimen.

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

In some examples, the treatment is for at least about 7.9 months (eg, 8.0 months, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, 8.5 months, 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). Bring. In some examples, the treatment is for 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). (months, 12 months, 13 months, 14 months, 15 months, or 16 months). In some examples, the treatment is from about 7.9 months to about 8.6 months (eg, about 8.0 months, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8 months .5 months, or 8.6 months).

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

In some examples, the treatment is at least about 7.9 (e.g., between about 7.9 months and about 36 months (e.g., between about 7.9 months 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 examples, the treatment is for at least about 16.3 (e.g., between about 16.3 months and about 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. 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, such as 7.9 months to 9 months, 9 months to 10 months, 10 months to 11 months months, 11 months to 12 months, 12 months to 13 months, 13 months to 14 months, 14 months to 15 months, 15 months to 16 months, or over 16 months).

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

Dosing 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 examples, in any of the methods, uses, or compositions for use described herein, UC (e.g., bladder cancer (e.g., MIBC)) is surgical. (eg, UC suitable for cystectomy (eg, bladder cancer (eg, MIBC))). In some examples, the MIBC is surgically manipulable (eg, a MIBC suitable for cystectomy) in any of the methods, uses, or compositions for use described herein.

In some examples, the subject is ineligible for platinum-based chemotherapy (eg, cisplatin ineligible) in any of the methods, uses or compositions for use described herein. In some examples, the subject is cisplatin ineligible. In some examples, the subject has creatinine clearance of less than 60 mL/min. In some examples, the subject has creatinine clearance greater than or equal to 30 mL/min. In some examples, the subject has grade 2 or greater hearing loss. In some examples, the subject has grade 2 or greater neuropathy. In some examples, subjects with creatinine clearance <60 mL/min, grade 2 or greater hearing loss, and/or grade 2 or greater neuropathy are cisplatin ineligible. In some instances, subjects with creatinine clearance less than 60 mL/min are cisplatin ineligible. In some instances, subjects with grade 2 or greater hearing loss are cisplatin ineligible. In some instances, subjects with grade 2 or greater neuropathy are cisplatin ineligible. In some instances, subjects who refuse cisplatin-based chemotherapy are cisplatin ineligible. In some examples, the subject has a US East Coast Clinical Trials Group (ECOG) Performance (PS) of 0 or 1.

In some examples, the presence or level of circulating tumor DNA (ctDNA) can be assessed in any of the methods, uses or compositions for use described herein. In some examples, ctDNA is assessed in a sample (eg, blood sample) from the subject. In some examples, ctDNA is assessed in a sample from the subject prior to day 1 of the first dosing cycle (eg, the first dosing cycle of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist). In some examples, ctDNA is assessed in samples from subjects prior to surgery (eg, cystectomy). In some examples, ctDNA is assessed in samples from subjects after surgery (eg, cystectomy). In some examples, ctDNA is assessed in a sample from the subject 4-6 weeks (eg, 4 weeks, 5 weeks, or 6 weeks) after surgery (eg, cystectomy). In some examples, ctDNA is assessed in samples from subjects 6 months after surgery (eg, cystectomy).

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

Response to Treatment In some embodiments of any of the methods described herein, a subject's response to treatment can be characterized by one or more measures. In some embodiments, treatment results in pCR. In some embodiments, treatment results in increased recurrence-free survival (RFS), disease-free survival (EFS), or OS. In some embodiments, treatment results in an increase in landmark RFS, landmark EFS, or landmark OS. In some embodiments, the treatment results in an increased rate of reduction of pathologic extent.

In some examples, treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. In comparison, it results in an increase in the subject's pCR.

In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Compare and extend the target OS. In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. By comparison, prolong the subject's EFS. In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Compare and prolong the subject's RFS. In some examples, the treatment is, for example, compared to treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or treatment with an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist. Comparatively, it increases the subject's rate of reduction in pathological progression.

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

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

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

In some embodiments, OS is measured as the time from initiation of treatment to death. In some examples, the treatment reduces the subject's OS by at least about 2 months (eg, 2-120 months, 3-110 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months,2. 7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.6 months; 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 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 examples, the treatment reduces the subject's OS by at least about 3.3 months (eg, 3.3-120 months, 4-100 months, 5-80 months, 6-60 months, 7-48 months, 8-3 months). 36 months, or 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months 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 months. 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 examples, the treatment reduces the subject's OS by at least about 5.3 months (eg, 5.3-120, 6-60 months, 7-48 months, 8-36 months, or 10-24 months, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months 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. Treatment Methods and Uses for Pancreatic Cancer Pancreatic Cancer Of patients with pancreatic cancer, 80% have progressive disease at initial diagnosis. Even patients undergoing radical surgery have disease recurrence, resulting in 5-year survival rates of 25%-30% and 10% in patients with node-negative and node-positive disease on pancreaticoduodenectomy, respectively. . Patients with locally advanced, unresectable disease often receive chemotherapy radiotherapy, resulting in median OS of 9-13 months, but rarely long-term survival.

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

Methods and Uses for Treating Pancreatic Cancer Subjects or populations of subjects receiving anti-PD-L1 antagonist antibodies, e.g., atezolizumab), antimetabolites (e.g., gemcitabine) and taxanes (e.g., paclitaxel) have pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). ), eg, metastatic PDAC (mPDAC))).

The present invention provides a method of treating a subject or subject population having pancreatic cancer, wherein the subject or subject population is administered a dose of about 420 mg tiragolumab on days 1 and 15 of each 28-day dosing cycle, each of 28 atezolizumab at a dose of about 840 mg on days 1 and 15 of each daily dosing cycle, gemcitabine at a dose of about 1000 mg/ ^m2 on days 1, 8 and 15 of each 28-day dosing cycle, and on days 1 and 15 of each 28-day dosing cycle administering a dosing regimen comprising one or more 28-day dosing cycles of nab-paclitaxel at a dose of about 125 mg/m ² on days 1, 8 and 15. . In some examples, the method comprises administering to the subject or subject population a dose of 420 mg tiragolumab on days 1 and 15 of each 28-day dosing cycle and 840 mg on days 1 and 15 of each 28-day dosing cycle. gemcitabine at a dose of 1000 mg/ ^m2 on days 1, 8 and 15 of each 28-day dosing cycle, and 28 mg/m2 on days 1, 8 and 15 of each 28-day dosing cycle. administering a dosing regimen comprising one or more 125-day dosing cycles containing ² doses of nab-paclitaxel. In some examples, the pancreatic cancer is PDAC, such as mPDAC. In some aspects, one or more subjects have no prior systemic treatment for metastatic PDAC.

In some examples, treatment is at least about 41.7% to about 46.7% (eg, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45% , 45.5%, 46%, 46.5%, or 46.7% (e.g., 41.7%-43%, 43%-45%, or 45%-46.7%) ORR of the subject population In some examples, the treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nab-paclitaxel without the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist In some examples, the treatment is for at least about 5.5 months (e.g., between 5.5 months and 14 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months). months, 13 months, or 14 months), hi some examples, the treatment results in a median PFS for the subject population of at least about 7 months (eg, between 7 months and 14 months (eg, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months. provide a median PFS for a subject population of months (e.g., 6 months, 6.2 months, 6.4 months, 6.6 months, 6.8 months, 7 months, or more than 7 months). , the treatment is for 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). months, 13 months, 14 months, 15 months, or 16 months)), hi some examples, treatment is at least about 10.6 months (e.g., about 10.6 months and results in a median OS in the subject population for about 16 months (10.6 months, 11 months, 12 months, 13 months, 14 months, 15 months, or 16 months) In some examples, the treatment includes: at least about 8.5 months to about 10.6 months (eg, 8.7 months, 9.0 months, 9.2 months, 9.4 months, 9.6 months, 9.8 months, 10 months, 10. 2 months, 10.4 months, 10.6 months, or over 10.6 months).

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

D. Therapeutic Methods and Uses for Esophageal Cancer The present invention includes methods for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the methods comprising about 30 mg and about a dose between 1200 mg (e.g. between about 550 mg and about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) (e.g., a fixed dose) of an anti-TIGIT antagonist antibody and between about 80 mg and about 1600 mg (e.g., between about 1000 mg and about 1400 mg, e.g., between about 1050 mg and about 1350 mg, e.g., about 1100 mg) on day 1 of each dosing cycle and about 1300 mg, such as between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as 1200 mg±5 mg, such as 1200±2.5 mg, such as 1200±1. administering to the subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a dose (e.g., fixed dose) of a PD-1 axis binding antagonist of 0 mg, such as 1200±0.5 mg, such as 1200 mg. include. In some examples, the method administers between about 500 mg and about 700 mg on day 1 of each dosing cycle (e.g., between about 550 mg and about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg) and between about 900 mg and about 1500 mg on day 1 of each dosing cycle ( for example between about 1000 mg and about 1400 mg, for example between about 1050 mg and about 1350 mg, for example between about 1100 mg and about 1300 mg, for example between about 1150 mg and about 1250 mg, for example between about 1175 mg and about 1225 mg, for example between about 1190 mg and about 1 of a PD-1 axis binding antagonist at a dose (eg, fixed dose) between 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg) administering to a subject or subject population a dosing regimen comprising more than one 21-day dosing cycle. In some aspects, the method administers between 500 mg and 700 mg (e.g., between 550 mg and 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, on day 1 of each dosing cycle). anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of, e.g., 600±1 mg, e.g., 600±0.5 mg, e.g., 600 mg) and between 900 mg and 1500 mg (e.g., between 1000 mg and 1400 mg) on day 1 of each dosing cycle between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 administering to the subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a dose (e.g., fixed dose) of a PD-1 axis binding antagonist of ±1.0 mg, such as 1200±0.5 mg, such as 1200 mg) including doing

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

In some examples, the subject or subject population has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some instances, the subject or subject population has experienced disease progression or unacceptable toxicity during prior treatment.

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

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

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

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

In some instances, one or more subjects have never received prior treatment for metastatic esophageal cancer.

The invention includes a method for treating a subject or subject population with advanced or metastatic esophageal cancer, wherein the method comprises administering to the subject or subject population a dose of about 600 mg on day 1 of each dosing cycle (e.g. tiragolumab at a dose of about 1200 mg (e.g., fixed dose) on Day 1 of each dosing cycle, atezolizumab at a dose of about 80 mg/ ^m2 on Day 1 of each dosing cycle, and cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle, and each 21 days administering a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of 800 mg/m ² /24 hours on days 1-5 of the cycle; cisplatin is omitted from. In some aspects, the method includes administering a dosing regimen comprising one or more 21-day dosing cycles to a subject or subject population, administering a dose (e.g., a fixed dose) of 600 mg (e.g., a fixed dose) of tiragolumab on day 1 of each dosing cycle, respectively 1200 mg dose (e.g., fixed dose) of atezolizumab on Day 1 of each dosing cycle, cisplatin at a dose of 80 mg/ ^m2 on Day 1 of each dosing cycle, and Days 1-5 of each 21-day cycle A dose of 800 mg/m ² /24 hours of 5-fluorouracil was administered on the day, and cisplatin was omitted from the dosing regimen after 6 doses.

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

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

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 80 mg and about 1950 mg) every two weeks. between about 80 mg and about 1900 mg, such as between about 80 mg and about 1800 mg, such as between about 100 mg and about 1700 mg, such as between about 200 mg and about 1600 mg, such as between about 300 mg and about 1400 mg, such as about between 400 mg and about 1300 mg, such as between about 500 mg and about 1200 mg, such as between about 600 mg and about 1100 mg, such as between about 700 mg and about 1000 mg, such as between about 740 mg and about 940 mg, such as between about 790 mg and about 890 mg between about 815 mg and about 865 mg, such as between about 830 mg and about 850 mg, such as 840 mg±5 mg, such as 840±2.5 mg, such as 840±1.0 mg, such as 840±0.5 mg, such as 840 mg dose. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, about 100 mg and about 2000 mg) every 4 weeks. between about 200 mg and about 2000 mg, such as between about 300 mg and about 2000 mg, such as between about 400 mg and about 2000 mg, such as between about 500 mg and about 2000 mg, such as between about 600 mg and about 1900 mg, such as about between 700 mg and about 1800 mg, such as between about 800 mg and about 1800 mg, such as between about 900 mg and about 1800 mg, such as between about 1000 mg and about 1800 mg, such as between about 1100 mg and about 1800 mg, such as between about 1200 mg and about 1800 mg between about 1300 mg and about 1800 mg, such as between about 1400 mg and about 1800 mg, such as between about 1500 mg and about 1800 mg, such as between about 1580 mg and about 1780 mg, such as between about 1630 mg and about 1730 mg, such as about 1655 mg and about 1705 mg, e.g. In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 80 mg and 1950 mg) every two weeks, e.g. between 80 mg and 1900 mg, such as between 80 mg and 1800 mg, such as between 100 mg and 1700 mg, such as between 200 mg and 1600 mg, such as between 300 mg and 1400 mg, such as between 400 mg and 1300 mg, such as between 500 mg and 1200 mg, such as 600 mg and 1100 mg, such as between 700 mg and 1000 mg, such as between 740 mg and 940 mg, such as between 790 mg and 890 mg, such as between 815 mg and 865 mg, such as between 830 mg and 850 mg, such as 840 mg±5 mg, such as 840±2. 5 mg, such as 840±1.0 mg, such as 840±0.5 mg, such as 840 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every 4 weeks, e.g. between 200 mg and 2000 mg, such as between 300 mg and 2000 mg, such as between 400 mg and 2000 mg, such as between 500 mg and 2000 mg, such as between 600 mg and 1900 mg, such as between 700 mg and 1800 mg, such as between 800 mg and 1800 mg, such as 900 mg and 1800 mg, such as between 1000 mg and 1800 mg, such as between 1100 mg and 1800 mg, such as between 1200 mg and 1800 mg, such as between 1300 mg and 1800 mg, such as between 1400 mg and 1800 mg, such as between 1500 mg and 1800 mg, such as 1580 mg between 1780 mg, such as between 1630 mg and 1730 mg, such as between 1655 mg and 1705 mg, such as between 1670 mg and 1690 mg, such as 1680 mg±5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg , eg 1680 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (eg, nivolumab)) can be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as monotherapy.

The present invention includes a method for treating a subject or subject population with advanced or metastatic esophageal cancer, comprising administering to the subject or subject population a first dosing regimen and a second dosing regimen. (a) the first dosing regimen comprises cisplatin at a dose of about 80 mg/m ² on Day 1 of each dosing cycle and 800 mg/m ² /on Days 1-5 of each 21-day cycle; comprising one or more 21-day dosing cycles with a 24-hour dose of 5-fluorouracil, wherein cisplatin is omitted from the dosing regimen after 6 doses; (b) a second dosing regimen is administered on Day 1 of each dosing cycle; One or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg and atezolizumab at a dose of about 1200 mg 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% of the subject population (e.g., 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 % ORR, such as 14%-16%, 16%-18%, 18%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60% resulting in ~70%, 70%-80%, 80%-90%, or 90%-100%).

E. Diagnostic methods and uses for cancer

The present invention provides 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 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., subject is stage IV previously untreated for 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). renal cancer or renal cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or MSI-Low CRC). )), wherein the treatment comprises one or more biomarkers (e.g., PD-L1, TIGIT, activated T cells or cytokines) by diagnostic methods including determining the presence and/or expression level/amount.

Additionally, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab, or anti-PD-1 Cancers (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 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., subject has not been previously 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 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 pancreatic cancer (e.g. PDAC, e.g. metastatic PDAC); kidney cancer or renal cancer (e.g. RCC); melanoma; ovarian cancer; or CRC (e.g., MSS or MSI-Low CRC)), wherein the identification is a sample obtained from the subject (e.g., a tumor sample or a blood sample). ) by a diagnostic method comprising determining the presence and/or expression level/amount of one or more biomarkers (eg, PD-L1, TIGIT, activated T cells or cytokines).

Furthermore, cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, stage IIIB NSCLC, 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., subject previously treated for stage IV NSCLC) never been treated))): 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) renal cancer 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)) Provided herein are methods for assessing responsiveness to a therapy for , a further therapy comprising one or more biomarkers in a sample (e.g., tumor sample or blood sample) obtained from a subject (eg PD-L1, TIGIT, activated T-cells or cytokines) by diagnostic methods including determining the presence and/or expression level/amount.

Furthermore, cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g., ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, stage IIIB NSCLC, 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., subject previously treated for stage IV NSCLC) never been treated))): 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) renal cancer 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)) Provided herein are methods for optimizing a therapeutic regimen for, further therapeutic regimens comprising one or more biomarkers (e.g., , PD-L1, TIGIT, activated T cells or cytokines).

Biomarkers for use in the methods described herein include, but are not limited to, PD-L1 and/or TIGIT expression in tissue (eg, tumor tissue) or blood (eg, whole blood), WGS and/or or germline and somatic mutations from tissue (e.g., tumor tissue) and/or from circulating tumor DNA in the blood (including but not limited to mutation burden, MSI and MMR defects) identified by NGS , analyzes of genes (e.g., CD274) or gene signatures associated with tumor immunobiology (e.g., TEFF), lymphocyte subpopulations, T-cell receptor repertoires, cytokines associated with T-cell activation, as well as plasma-derived cytokines may include, but are not limited to: In some examples, the biomarker is PD-L1. In some examples, the sample is a tumor sample (eg, a formalin-fixed paraffin-embedded (FFPE) tumor sample).

In some examples, the methods determine the presence and/or expression level/ An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, such as , tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as, e.g., pembrolizumab) to the subject. .

In some examples, the methods determine the presence and/or expression level/ an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of about 700 mg to about 1000 mg every 4 weeks and PD-1 at a dose (e.g., fixed dose) of about 1400 mg to 2000 mg every 4 weeks; administering to the subject a dosing regimen comprising one or more dosing cycles of the axially bound antagonist. In some examples, the dosing regimen is anti-TIGIT antagonist antibody at a dose (eg, fixed dose) of 700 mg to 1000 mg every 4 weeks and PD-1 at a dose (eg, fixed dose) of 1400 mg to 2000 mg every 4 weeks. Including one or more dosing cycles of the axially bound antagonist.

In some examples, the methods determine the presence and/or expression level/ and anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of about 300 mg to about 600 mg every two weeks and PD- at a dose (e.g., fixed dose) of about 600 mg to about 1200 mg every two weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the monoaxial binding antagonist. In some examples, the method comprises administering an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 300 mg to 600 mg every two weeks and a PD-1 axis at a dose (e.g., fixed dose) of 600 mg to 1200 mg every two weeks. administering to the subject a dosing regimen comprising one or more dosing cycles comprising the binding antagonist.

In some examples, the methods determine the presence and/or expression level/ and anti-TIGIT antagonist antibody at doses (eg, fixed dose) of about 30 mg to about 1200 mg every 3 weeks, and PD-1 at doses (eg, fixed dose) of about 80 and 1600 mg every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of an axially-linked antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. In some examples, the method comprises administering an anti-TIGIT antagonist antibody at a dose (eg, fixed dose) of 30 mg to 1200 mg every 3 weeks, PD-1 axis at a dose (eg, fixed dose) of 80 mg to 1600 mg every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

In some examples, the methods determine the presence and/or expression level/ and a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 200 mg every three weeks. and administering to the subject, the anti-PD-1 antagonist antibody is pembrolizumab. In some examples, the method comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of 30 mg to 1200 mg every three weeks and an anti-PD-1 antagonist antibody at a dose of 200 mg every three weeks. administering to the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab;

In some examples, the methods determine the presence and/or expression level/ and administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein pembrolizumab is administered at a dose of between about 100 mg and about 1000 mg every 6 weeks. be. In some examples, pembrolizumab is administered at a dose of about 400 mg every 6 weeks.

In some examples, the methods determine the presence and/or expression level/ and anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg every three weeks; a dose of between about 80 mg and about 1600 mg (e.g., fixed dose) every three weeks; ) and an antimetabolite at a dose (e.g., fixed dose) between about 10 mg/m ² and about 10,000 mg/m ² twice daily at 2-week/1-week intervals every 3 weeks administering to the subject a dosing regimen comprising one or more dosing cycles of the agent. In some examples, the method includes administering an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every three weeks, PD- a monoaxial binding antagonist and an antimetabolite at a dose (e.g., fixed dose) between 10 mg/ ^m2 and 10000 mg/ ^m2 twice daily with 2 weeks on/1 week off every 3 weeks administering to the subject a dosing regimen comprising one or more dosing cycles.

In some examples, the methods determine the presence and/or expression level/ and anti-TIGIT antagonist antibody at doses (eg, fixed dose) of about 30 mg to about 1200 mg every 3 weeks, and PD-1 at doses (eg, fixed dose) of about 80 and 1600 mg every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the axially bound antagonist, gemcitabine, and nab-paclitaxel. In some examples, the method includes anti-TIGIT antagonist antibody at doses (eg, fixed dose) of 30 mg to 1200 mg every 3 weeks, PD-1 axis at doses (eg, fixed dose) of 80 and 1600 mg every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the binding antagonist, gemcitabine and nab-paclitaxel.

In some examples, the methods determine the presence and/or expression level/ and anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30 mg and about 1200 mg every three weeks, a dose of between about 80 mg and about 1600 mg (e.g., fixed dose) every three weeks. ) and one or more dosing cycles of a VEGF antagonist at a dose between about 1 mg/kg and about 35 mg/kg every 3 weeks. . In some examples, the method includes administering an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between 30 mg and 1200 mg every three weeks; administering to the subject a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist and a VEGF antagonist at a dose between 1 mg/kg and 35 mg/kg every 3 weeks.

In some examples, the methods determine the presence and/or expression level/ and administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein (a) the induction phase is a dose of about 30 mg to about 1200 mg every 3 weeks (e.g., fixed dose ), a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of about 80 mg to 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks. (b) a maintenance phase of anti-TIGIT antagonist antibody every 3 weeks, PD-1 axis binding antagonist every 3 weeks and non-platinum chemotherapeutic agent every 3 weeks; The maintenance phase does not include administration of platinum-based chemotherapeutic agents, including one or more additional dosing cycles. In some examples, (a) the induction phase is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 30 mg to 1200 mg every three weeks; comprising one or more dosing cycles of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks; TIGIT antagonist antibody, PD-1 axis binding antagonist every 3 weeks and one or more additional dosing cycles of a non-platinum-based chemotherapeutic agent every 3 weeks, with a maintenance phase that does not include administration of a platinum-based chemotherapeutic agent .

In some examples, the methods determine the presence and/or expression level/ and administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein (a) the induction phase is a dose of about 500 mg to about 700 mg every 3 weeks (e.g., fixed dose ), a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based (b) a maintenance phase of an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of about 700 mg to about 1000 mg every 4 weeks, and about 1400 mg every 4 weeks. One or more additional dosing cycles of a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of ~2000 mg, with a maintenance phase that does not include administration of a platinum-based or non-platinum-based chemotherapeutic agent . In some examples, (a) the induction phase is an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of 500 mg to 700 mg every three weeks, a dose (e.g., fixed dose) of 900 mg to 1500 mg every three weeks; One or more dosing cycles of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks, and (b) a maintenance phase of 700 mg every 4 weeks. An anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of ~1000 mg and one or more additional dosing cycles of a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of 1400 mg to 2000 mg every 4 weeks. , the maintenance phase does not include administration of platinum-based chemotherapeutic agents or non-platinum-based chemotherapeutic agents.

The presence and/or expression level/amount of biomarkers (eg, PD-L1, TIGIT, activated T cells or cytokines) include, but are not limited to, proteins, protein fragments, DNA, mRNA, cDNA and/or gene copy number. It can be determined qualitatively and/or quantitatively based on any suitable criteria known in the art, without limitation. In some examples, the biomarker is PD-L1. PD-L1 expression can be assessed as described in Section III(L). In some examples, the biomarker is TIGIT. TIGIT expression can be assessed as described in Section III(M). In some examples, the biomarkers are EGFR and/or ALK abnormalities. EGFR and/or ALK abnormalities can be assessed as described in Section III(N).

In some examples, the biomarker expression level or amount is a detectable PD-L1 protein expression level in a tumor sample (eg, an FFPE tumor sample) from the subject. In some instances, PD-L1 protein expression levels were determined by immunohistochemistry (IHC) assays. In some examples, the tissue sample is a tumor sample.

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

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

In some examples, 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 is For example, if the detectable PD-L1 expression level is a biomarker for selecting individuals, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab, or pembrolizumab, etc.) Subjects are selected who are eligible for treatment with an anti-PD-1 antagonist antibody). In some examples, the sample is selected from the group consisting of tissue samples, whole blood samples, serum samples and plasma samples. In some examples, the tissue sample is a tumor sample (eg, FFPE tumor sample). In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof. In some examples, the tissue sample is a tumor sample.

In some examples, the method further comprises administering a treatment to the identified subject. In some examples, treatment includes one or more additional therapeutic agents (e.g., anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antibodies), VEGF antagonists, chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents or non-platinum-based chemotherapeutic agents), ADC (e.g., enfortumab vedotin or sacituzumab govitecan) or CSF (e.g., pegfilgrastim, filgrastim, or sargramostim)) It can be further included or administered in combination (separately or together).

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

F. Dosing i. Anti-TIGIT Antagonist Antibody Dosing 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., tiragolumab) administered to a human is The dosage may range from about 0.01 to about 50 mg/kg of patient body weight, whether or not with the above dosages. 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., tiragolumab) administered to a human is by one or more administrations. Regardless, it ranges from 0.01 to 50 mg/kg of patient body weight.

In some exemplary embodiments, the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 administered at a dose of to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg, e.g., daily, weekly, for two weeks administered every, every three weeks, or every four weeks. In some exemplary embodiments, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 0.01-45 mg/kg, 0.01-40 mg/kg, kg, 0.01-35 mg/kg, 0.01-30 mg/kg, 0.01-25 mg/kg, 0.01-20 mg/kg, 0.01-15 mg/kg, 0.01-10 mg/kg, Dosages of 0.01-5 mg/kg, or 0.01-1 mg/kg are administered, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

In some examples, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered at about day 1 (eg, day −3, −2) of the dosing cycle. Day 1, Day −1, Day 1, Day 2, or Day 3).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered in a graded dosing regimen (e.g., subject body weight (BW) or body surface area ( BSA)-based dosing) (eg, every 3 weeks). Such dosing regimens can be utilized in the treatment of relatively low weight subjects (eg, 40 kg or less (eg, 5 kg to 40 kg, 15 kg to 40 kg, or 5 kg to 15 kg)). , being developed through biosimulation studies based on extrapolation of pharmacokinetic parameters estimated from adult data.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is It is a tiered dose based on In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 300 mg every 3 weeks); (b) weighing more than 15 kg and 40 kg; or (c) greater than 40 kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every 3 weeks (e.g., about 400 mg every 3 weeks); , at doses between about 30 mg and about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between about 250 mg and about 350 mg every 3 weeks (e.g., about 300 mg every 3 weeks); (b) weighing more than 15 kg and 40 kg; or (c) greater than 40 kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 350 mg and about 450 mg every 3 weeks (e.g., about 400 mg every 3 weeks); , at doses between about 550 mg and about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) weighing greater than 15 kg and ≤40 kg and the anti-TIGIT antagonist antibody is administered at about or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 300 mg every 3 weeks); (b) weighing more than 15 kg and 40 kg or less; , the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 400 mg every 3 weeks); and 1200 mg (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighs 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between 250 mg and 350 mg every 3 weeks (e.g., 300 mg every 3 weeks); (b) weighs more than 15 kg and ≤40 kg; or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of between 350 mg and 450 mg every 3 weeks (e.g., 400 mg every 3 weeks); and 650 mg (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is greater than 40 kg (e.g., 40.5 kg, 41 kg, 42 kg, 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, between about 30 mg and about 1200 mg (e.g., about between 30 mg and about 1100 mg, such as between about 60 mg and about 1000 mg, such as between about 100 mg and about 900 mg, such as between about 200 mg and about 800 mg, such as between about 300 mg and about 800 mg, such as about between about 400 mg and about 800 mg, such as between about 400 mg and about 750 mg, such as between about 450 mg and about 750 mg, such as between about 500 mg and about 700 mg, such as between about 550 mg and about 650 mg, such as 600 mg ±10 mg, such as 600±6 mg, such as 600±5 mg, such as 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 600 mg every 3 weeks for a subject weighing over 40 kg. is the dose of In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is greater than 40 kg (e.g., 40.5 kg, 41 kg, 42 kg, 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, 68 kg, 69 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 150 kg or more) between 30 mg and 1200 mg (e.g., 30 mg and 1100 mg) every 3 weeks (Q3W) between 60 mg and 1000 mg, such as between 100 mg and 900 mg, such as between 200 mg and 800 mg, such as between 300 mg and 800 mg, such as between 400 mg and 800 mg, such as between 400 mg and 750 mg e.g. , 600±1 mg, such as 600±0.5 mg, such as 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is 600 mg every 3 weeks for a subject weighing over 40 kg. dose.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is greater than 15 kg and 40 kg or less (e.g., 15.1 kg, 15 .2kg, 15.3kg, 15.4kg, 15.5kg, 16kg, 17kg, 18kg, 19kg, 20kg, 21kg, 22kg, 23kg, 24kg, 25kg, 26kg, 27kg, 28kg, 29kg, 30kg, 31kg, 32kg, 33kg , 34 kg, 35 kg, 36 kg, 37 kg, 38 kg, 39 kg, or 39.5 kg) every three weeks (Q3W) between about 10 mg and about 1000 mg (e.g., between about 20 mg and about 1000 mg, e.g., about 50 mg) between about 900 mg, such as between about 100 mg and about 850 mg, such as between about 200 mg and about 700 mg, such as between about 250 mg and about 600 mg, such as between about 300 mg and about 500 mg, such as between about 350 mg and about 450 mg; eg between about 390 mg and about 410 mg, eg about 400 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is 3 weeks for a subject having a weight of greater than 15 kg but 40 kg or less. about 400 mg every 3 weeks (e.g., 400 mg ± 10 mg, such as 400 ± 6 mg, such as 400 ± 5 mg, such as 400 ± 3 mg, such as 400 ± 1 mg, such as 400 ± 0.5 mg, such as 400 mg every 3 weeks ). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is greater than 15 kg and 40 kg or less (e.g., 15.1 kg, 15.2 kg, 15 .3kg, 15.4kg, 15.5kg, 16kg, 17kg, 18kg, 19kg, 20kg, 21kg, 22kg, 23kg, 24kg, 25kg, 26kg, 27kg, 28kg, 29kg, 30kg, 31kg, 32kg, 33kg, 34kg, 35kg , 36 kg, 37 kg, 38 kg, 39 kg, or 39.5 kg) between 10 mg and 1000 mg (e.g., between 20 mg and 1000 mg, such as between 50 mg and 900 mg, such as 100 mg and 850 mg) every three weeks (Q3W) between 200 mg and 700 mg, such as between 250 mg and 600 mg, such as between 300 mg and 500 mg, such as between 350 mg and 450 mg, such as between 390 mg and 410 mg, such as 400 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is 3 weeks for a subject having a weight of greater than 15 kg but 40 kg or less. 400 mg every 3 weeks (e.g., 400 mg ± 10 mg, such as 400 ± 6 mg, such as 400 ± 5 mg, such as 400 ± 3 mg, such as 400 ± 1 mg, such as 400 ± 0.5 mg, such as 400 mg every 3 weeks) is the dose of

In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is less than or equal to 15 kg body weight (eg, 0.5 kg, 1 kg, 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, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14. 0 kg, 14.5 kg, or 15.0 kg) every three weeks (Q3W) between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 900 mg, e.g., between about 50 mg and about 900 mg; between about 100 mg and about 750 mg, such as between about 100 mg and about 600 mg, such as between about 150 mg and about 500 mg, such as between about 200 mg and about 400 mg, such as between about 250 mg and about 350 mg, For example, a dose of between about 290 mg and about 310 mg, eg, about 300 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered every 3 weeks to a subject having a weight of 15 kg or less. about 300 mg (e.g., 300±10 mg, such as 300±6 mg, such as 300±5 mg, such as 300±3 mg, such as 300±1 mg, such as 300±0.5 mg, such as 300 mg every 3 weeks) dose. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 15 kg or less of body weight (eg, 0.5 kg, 1 kg, 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, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14. between 10 mg and 1000 mg (e.g., between 10 mg and 900 mg, e.g., between 50 mg and 900 mg, e.g., 100 mg and 750 mg) every three weeks (Q3W) for subjects weighing 0 kg, 14.5 kg, or 15.0 kg). between 100 mg and 600 mg, such as between 150 mg and 500 mg, such as between 200 mg and 400 mg, such as between 250 mg and 350 mg, such as between 290 mg and 310 mg, such as 300 mg). . In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to a subject having a weight of 15 kg or less every 3 weeks. A dose of 300 mg (eg, 300±10 mg, such as 300±6 mg, such as 300±5 mg, such as 300±3 mg, such as 300±1 mg, such as 300±0.5 mg, such as 300 mg every 3 weeks) is.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is the body surface area of the subject. It is a tiered dose based on In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² or less than 0.75 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 350 mg every 3 weeks); c) greater than 0.75 m ² and less than or equal to 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or ( d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 30 mg and about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between about 250 mg and about 350 mg every three weeks (eg, about 300 mg every three weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between about 300 mg and about 400 mg every 3 weeks (e.g., about 350 mg every 3 weeks); or (c) greater than 0.75 ^m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between about 400 mg and about 500 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 550 mg and about 650 mg every three weeks (eg, about 600 mg every three weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) has a body surface area of 0.5 ^m2 or less, and the anti-TIGIT antagonist antibody is ^administered at a dose of about 300 ^mg every 3 weeks; , the anti-TIGIT antagonist antibody is administered ^at a dose of about 400 mg every 3 ^weeks ; or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is the body surface area of the subject. It is a tiered dose based on In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between 10 mg and 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 350 mg every 3 weeks); (c) 0 greater than .75 ^m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 450 mg every 3 weeks); or (d) 1.25 ^m2 and the anti-TIGIT antagonist antibody is administered at a dose between 30 mg and 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between 250 mg and 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 300 mg and 400 mg every 3 weeks (e.g., 350 mg every 3 weeks); or (c) ^greater than 0.75 m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 400 mg and 500 mg every 3 weeks (e.g., 450 mg every 3 weeks); or (d) 1.25 m greater than ² and the anti-TIGIT antagonist antibody is administered at a dose between 550 mg and 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) has a body surface area of 0.5 ^{m2 or} less, and the anti-TIGIT antagonist antibody is administered ^at a dose of 300 mg every 3 weeks; the anti-TIGIT antagonist antibody is ^{administered at} a dose of 400 mg every 3 weeks; or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) has a body surface area greater than 1.25 m ² (e.g., 1.25 m ² , ^1.35m2 , ^1.45m2 , ^1.50m2 , ^1.55m2 , ^1.60m2 , 1.65m2 ^{, 1.70m2} , ^1.75m2 , 1.80m2 ^{, 1.85m2} , 1.90 m ² , 1.95 m ² , 2.0 m ² , 2.1 m ² , 2.2 m ² , 2.3 m ² , 2.4 m ^{2 , 2.5 m 2} , 2.6 m ^{2 ,} 2.7 m ² , between about 30 mg and ^about 1200 mg (e.g. ^, between about 30 ^mg and about 1100 mg, e.g., about between 60 mg and about 1000 mg, such as between about 100 mg and about 900 mg, such as between about 200 mg and about 800 mg, such as between about 300 mg and about 800 mg, such as between about 400 mg and about 800 mg, such as about between 400 mg and about 750 mg, such as between about 450 mg and about 750 mg, such as between about 500 mg and about 700 mg, such as between about 550 mg and about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as , 600±5 mg, such as 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is 3 weeks for a subject with a body surface area greater than 1.25 ^m2 . dose of about 600 mg per dose. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is greater than 1.25 m ² (eg, 1.25 m ² , 1.35 m ² , ^1.45m2 , ^1.50m2 , ^1.55m2 , ^1.60m2 , 1.65m2, ^1.70m2 , ^1.75m2 , ^1.80m2 , ^1.85m2 , ^{1.90m 2} , 1.95 m ² , 2.0 m ² , 2.1 m ² , 2.2 m ² , 2.3 m ² , 2.4 m ² , 2.5 m 2 , 2.6 m ² , 2.7 ^{m 2 ,} 2.8 m ² , 2.9 m ² , 3.0 m ² or greater), between 30 mg and 1200 mg (e.g., between 30 mg and 1100 mg, e.g., 60 mg and 1000 mg) every three weeks (Q3W) between 100 mg and 900 mg, such as between 200 mg and 800 mg, such as between 300 mg and 800 mg, such as between 400 mg and 800 mg, such as between 400 mg and 750 mg, such as between 450 mg and 750 mg, between 500 mg and 700 mg, such as between 550 mg and 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, eg 600 mg) dose. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is 3 weeks for a subject with a body surface area greater than 1.25 ^m2 . dose of 600 mg per dose.

In some examples, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is greater than 0.75 ^m2 and no more than 1.25 ^m2 (e.g., ^0.76m2 , ^0.77m2 , ^0.78m2 , ^0.79m2 , 0.80m2, ^{0.82m2 , 0.84m2} , ^0.86m2 , 0.88m2 ^{, 0.90m2} , 0.95 m ² , 1.0 m ² , 1.05 m ² , 1.10 m ² , 1.15 m ² , 1.20 m ² , or 1.25 m ² ) every 3 weeks (Q3W) between about 10 mg and about 1000 mg, such as between about 20 mg and about 1000 mg, such as between about 50 mg and about 900 mg, such as between about 100 mg and about 850 mg, such as between about 200 mg and about 700 mg, such as , between about 250 mg and about 600 mg, such as between about 300 mg and about 500 mg, such as between about 400 mg and about 500 mg, such as between about 440 mg and about 460 mg, such as about 450 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) has a body surface area greater than 0.75 ^m2 and less than or equal to 1.25 ^m2 . about 450 mg every 3 weeks for subjects with For example, a dose of 450 mg every 3 weeks).

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is greater than 0.5 ^m2 and no more than 0.75 ^m2 (e.g., 0.51 m ² , 0.52 m ² , 0.53 ^{m 2 ,} 0.54 m ² , 0.55 m 2 , 0.56 m ² , 0.57 m ² , 0.58 m ² , 0.59 m ² , 0.60 m ² , 0.61 m ² , 0.62 m ² , 0.63 ^{m 2 ,} 0.64 m ² , 0.65 m 2 , 0.66 m ² , 0.67 m ² , 0.68 m ² , 0.69 m ² , 0.70 m ² , ^between about 10 mg and about 1000 mg every three weeks ( ^{Q3W ) (} e.g. ^, between about 20 mg and about 1000 mg, such as between about 50 mg and about 900 mg, such as between about 100 mg and about 850 mg, such as between about 200 mg and about 700 mg, such as between about 250 mg and about 600 mg, such as between about 300 mg and about 500 mg between about 300 mg and about 400 mg, such as between about 340 mg and about 360 mg, such as about 350 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) has a body surface area of greater than 0.5 ^m2 to 0.75 m2. 350 mg every ³ weeks (eg, 350 mg±10 mg, such as 350±6 mg, such as 350±5 mg, such as 350±3 mg, such as 350±1 mg, such as 350±0. 5 mg, eg 350 mg every 3 weeks).

In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 0.5 m ² or less (eg, 0.02 m 2 , 0.5 m ² or less). 04 m ² , 0.06 m ² , 0.08 m ² , 0.1 m ² , 0.15 m ² , 0.20 m ² , 0.25 m ² , 0.30 m ² , 0.35 m 2 , 0.40 m ² , 0.4 ^m 2 between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 900 mg, e.g., between about 50 mg and about 900 mg) every three weeks (Q3W) for a subject with a body surface area of 45 m ² , or 0.50 m ² ; for example between about 100 mg and about 750 mg, such as between about 100 mg and about 600 mg, such as between about 150 mg and about 500 mg, such as between about 200 mg and about 400 mg, such as between about 250 mg and about 350 mg, such as between about 290 mg and about between 310 mg, eg about 300 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is 3 to a subject having a surface area of 0.5 m ² . about 300 mg per week (e.g., 300 mg ± 10 mg, such as 300 ± 6 mg, such as 300 ± 5 mg, such as 300 ± 3 mg, such as 300 ± 1 mg, such as 300 ± 0.5 mg, such as every 3 weeks 300 mg).

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

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

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is between about 200 mg and about 2000 mg every four weeks (Q4W). (e.g. between about 200 and 300 mg, between about 300 and 400 mg, between about 400 and 500 mg, between about 500 and 600 mg, between about 600 and 700 mg, between about 700 and 800 mg, between about 800 and 900 mg between about 900 and 1000 mg, between about 1000 and 1100 mg, between about 1100 and 1200 mg, between about 1200 and 1300 mg, between about 1300 and 1400 mg, between about 1400 and 1500 mg, between about 1500 and 1600 mg; between about 1600 and 1700 mg, between about 1700 and 1800 mg, between about 1800 and 1900 mg, or between about 1900 and 2000 mg, such as between about 200 mg and about 1600 mg, such as between about 250 mg and about 1600 mg, such as about 300 mg and about 1600 mg, such as between about 400 mg and about 1500 mg, such as between about 500 mg and about 1400 mg, such as between about 600 mg and about 1200 mg, such as between about 700 mg and about 1100 mg, such as between about 800 mg and about 1000 mg for example between about 800 mg and about 900 mg, 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 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, about 1500, about 1550, about 1600 mg, about 1650 mg , about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg, such as about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880 , about 890, or about 900 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 700 mg to about 1000 mg every 4 weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 700 mg to 1000 mg every 4 weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 840 mg every 4 weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 840 mg every 4 weeks. The 840 mg Q4W dosing regimen is supported by the results of PK modeling and simulation and exposure-safety analysis. Briefly, the mean concentrations following the 840 mg Q4W dosing regimen are similar to the mean concentrations for the 600 mg every 3 weeks dosing regimen evaluated in previous studies. The Cmax of the 840 mg Q4W dosing regimen was simulated to be 28% higher at steady state compared to the Cmax of the 600 mg every 3 weeks dosing regimen, although the highest dose observed in the clinic (every 3 weeks 1200 mg per day) exposure. A preliminary analysis of the exposure-safety relationship of indicate a flat exposure-safety relationship. In summary, given that the predicted exposures are within the observed efficacious exposures and that tiragolumab exhibits a flat exposure-safety relationship, the 840 mg Q4W dosing regimen was reduced to 600 mg every 3 weeks. It may provide safety and efficacy comparable to regimens.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 840 mg (e.g., 840 mg ± 10 mg, e.g., 840 mg ± 10 mg) every 4 weeks. ±6 mg, such as 840±5 mg, such as 840±3 mg, such as 840±1 mg, such as 840±0.5 mg, such as 840 mg every 4 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is between about 200 mg and about 2000 mg every four weeks (Q4W) for between about 200 mg and about 2000 mg, such as between about 400 mg and about 1900 mg, such as between about 500 mg and about 1800 mg, such as between about 600 mg and about 1700 mg, such as between about 700 mg and about 1400 mg, such as about between 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as between about 1050 mg and about 1350 mg, such as between about 1100 mg and about 1300 mg, such as between about 1150 mg and about 1250 mg between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as between 200 mg and 2000 mg, such as between 400 mg and 1900 mg, such as between 500 mg and 1800 mg, such as between 600 mg and 1700 mg, such as between 700 mg and 1400 mg between 800 mg and 1600 mg, such as between 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg between 1190 mg and 1210 mg), such as about 1200 mg, such as 1200 mg ± 10 mg, such as 1200 ± 6 mg, such as 1200 ± 5 mg, such as 1200 ± 3 mg, such as 1200 ± 1 mg, such as 1200 ± 0.5 mg, such as 1200 mg). dose. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 1200 mg every 4 weeks.

In some examples, combination therapy (e.g., combination treatment with an anti-PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) The dose of anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered is compared to the standard dose of anti-TIGIT antagonist antibody administered as monotherapy. can decrease.

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

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

ii. PD-1 Axis Binding Antagonist Dosing As a general proposition, a therapeutically effective amount of a PD-1 axis binding antagonist (eg, atezolizumab) administered to a human, whether by one or more administrations, is It ranges from about 0.01 to about 50 mg/kg of body weight.

In some exemplary embodiments, the PD-1 axis binding antagonist is about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 45 mg/kg. 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 20 mg/kg. 01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg, eg, every day, every week, every two weeks, every three weeks, or every four weeks. In some exemplary embodiments, the PD-1 axis binding antagonist is 0.01-45 mg/kg, 0.01-40 mg/kg, 0.01-35 mg/kg, 0.01-30 mg/kg, 0 at doses of 0.01-25 mg/kg, 0.01-20 mg/kg, 0.01-15 mg/kg, 0.01-10 mg/kg, 0.01-5 mg/kg, or 0.01-1 mg/kg administered, for example, daily, weekly, every two weeks, every three weeks, or every four weeks.

In some examples, the PD-1 axis binding antagonist is administered at about day 1 (eg, day −3, day −2, day −1, day 1, day 2, or day 3) of the dosing cycle. eyes).

In some examples, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is administered every two weeks (Q2W ), between about 20 mg and about 1600 mg, such as between about 40 mg and about 1500 mg, such as between about 200 mg and about 1400 mg, such as between about 300 mg and about 1400 mg, such as between about 400 mg and about 1400 mg, such as about 500 mg between about 1300 mg, such as between about 600 mg and about 1200 mg, such as between about 700 mg and about 1100 mg, such as between about 800 mg and about 1000 mg, such as between about 800 mg and about 900 mg, such as about 800, about 810, about 820 , about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) (eg, a fixed dose). In some examples, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is administered every two weeks (Q2W) between 20 mg and 1600 mg, such as between 40 mg and 1500 mg, such as between 200 mg and 1400 mg, such as between 300 mg and 1400 mg, such as between 400 mg and 1400 mg, such as between 500 mg and 1300 mg, such as between 600 mg and 1200 mg; between 700 mg and 1100 mg, such as between 800 mg and 1000 mg, such as between 800 mg and 900 mg, such as 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, or 900 mg) (e.g., fixed dose). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is about A dose of 840 mg (e.g., 840 mg ± 10 mg, such as 840 ± 6 mg, such as 840 ± 5 mg, such as 840 ± 3 mg, such as 840 ± 1 mg, such as 840 ± 0.5 mg, such as 840 mg every 2 weeks) is. In some examples, the effective amount of atezolizumab is a dose of about 840 mg every two weeks.
In some examples, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., pembrolizumab) or an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject every two weeks between about 0.01 mg/kg and about 50 mg/kg of body weight

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

In some examples, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) to treat a subject with cancer is weight loss of the subject every three weeks. between about 0.01 mg/kg and about 50 mg/kg (e.g., between about 0.01 mg/kg and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as about Between 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg /kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0 .2 mg/kg, or about 15±0.1 mg/kg, eg about 15 mg/kg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks. between about 0.1 mg/kg and about 15 mg/kg, such as between about 0.5 mg/kg and about 15 mg/kg, such as between about 1 mg/kg and about 15 mg/kg, such as about 2. between 5 mg/kg and about 15 mg/kg, such as between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as between about 10 mg/kg and about 15 mg/kg between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg, such as about 15±0.5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) to treat a subject with cancer is weight loss of the subject every three weeks. between 0.01 mg/kg and 50 mg/kg of between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg /kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg, or 15±0.1 mg/kg, such as 15 mg/kg) is the dose of In some examples, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg and 15 mg/kg of the subject's body weight every three weeks. between (e.g. between 0.1 mg/kg and 15 mg/kg, such as between 0.5 mg/kg and 15 mg/kg, such as between 1 mg/kg and 15 mg/kg, such as between 2.5 mg/kg and 15 mg/kg between 5 mg/kg and 15 mg/kg, such as between 7.5 mg/kg and 15 mg/kg, such as between 10 mg/kg and 15 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, between 14 mg/kg and 15 mg/kg, such as 15±1 mg/kg, such as 15±0.5 mg/kg, such as 15±0.2 mg/kg, such as 15±0.1 mg/kg, such as 15 mg/kg) is the dose of In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 15 mg/kg administered every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 15 mg/kg administered every 3 weeks, with a maximum dose of is 1200 mg every 3 weeks. In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibodies (eg, atezolizumab)) may be reduced compared to standard doses of PD-1 axis binding antagonists administered as monotherapy. In some embodiments, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a maximum dose of 1200 mg every 3 weeks.

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

In some examples, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is every 3 weeks (Q3W ), between about 10 mg and about 800 mg, such as between about 10 mg and about 800 mg, such as between about 20 mg and about 700 mg, such as between about 50 mg and about 600 mg, such as between about 75 mg and about 500 mg, such as between about 100 mg between about 400 mg, such as between about 100 mg and about 300 mg, such as between about 125 mg and about 275 mg, such as between about 150 mg and about 250 mg, such as between about 175 mg and about 225 mg, such as between about 190 mg and about 210 mg; for example about 200 mg±10 mg, such as 200 mg±7.5 mg, such as 200 mg±5 mg, such as 200±2.5 mg, such as 200±1.0 mg, such as 200±0.5 mg, such as 200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is about A dose of 200 mg (eg, 200±10 mg, such as 200±6 mg, such as 200±5 mg, such as 200±3 mg, such as 200±1 mg, such as 200±0.5 mg, such as 200 mg every 3 weeks) is. In some examples, the effective amount of the anti-PD-1 antagonist antibody (eg, pembrolizumab) is about 200 mg (eg, 200 mg±10 mg, such as 200±6 mg, such as 200±5 mg, such as 200±3 mg, eg 200±1 mg, eg 200±0.5 mg, eg 200 mg every 3 weeks). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is every 3 weeks (Q3W) between 10 mg and 800 mg, such as between 10 mg and 800 mg, such as between 20 mg and 700 mg, such as between 50 mg and 600 mg, such as between 75 mg and 500 mg, such as between 100 mg and 400 mg, such as between 100 mg and 300 mg; between 125 mg and 275 mg, such as between 150 mg and 250 mg, such as between 175 mg and 225 mg, such as between 190 mg and 210 mg, such as 200 mg±10 mg, such as 200 mg±7.5 mg, such as 200 mg±5 mg, such as 200±2. 5 mg, such as 200±1.0 mg, such as 200±0.5 mg, such as 200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is 200 mg every 3 weeks at a dose of (e.g., 200±10 mg, such as 200±6 mg, such as 200±5 mg, such as 200±3 mg, such as 200±1 mg, such as 200±0.5 mg, such as 200 mg every 3 weeks) be. In some examples, the effective amount of anti-PD-1 antagonist antibody (eg, pembrolizumab) is 200 mg (eg, 200 mg±10 mg, such as 200±6 mg, such as 200±5 mg, such as 200 mg every 3 weeks). ±3 mg, eg 200±1 mg, eg 200±0.5 mg, eg 200 mg every 3 weeks). In some examples, the effective amount of pembrolizumab is a dose of 200 mg every 3 weeks. In some examples, the effective amount of pembrolizumab is a dose of 200 mg every 3 weeks.

In some examples, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is every 4 weeks (Q4W) between about 80 mg and about 3000 mg (e.g. between about 80 mg and 200 mg, between about 200 mg and 400 mg, between about 400 mg and 600 mg, between about 600 mg and 800 mg, between about 800 mg and 1000 mg, between about 1000 mg and 1200 mg) between about 1200 mg and 1400 mg between about 1400 mg and 1600 mg between about 1600 mg and 1800 mg between about 1800 mg and 2000 mg between about 2200 mg and 2400 mg between about 2400 mg and 2600 mg between about 2600 mg and 2800 mg between about 2800 mg and 3000 mg, such as between about 100 mg and about 3000 mg, such as between about 200 mg and about 2900 mg, such as between about 500 mg and about 2800 mg, such as between about 600 mg and about 2700 mg, such as between about 650 mg between about 2600 mg, such as between about 700 mg and about 2500 mg, such as between about 1000 mg and about 2400 mg, such as between about 1100 mg and about 2300 mg, such as between about 1200 mg and about 2200 mg, such as between about 1300 mg and about 2100 mg; for example between about 1400 mg and about 2000 mg, for example between about 1500 mg and about 1900 mg, for example between about 1600 mg and about 1800 mg, for example between about 1620 mg and about 1700 mg, for example between about 1640 mg and about 1690 mg, for example between about 1660 mg and about between 1680 mg, about 1680 mg, such as about 80 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2400 mg, about 2600 mg; about 2800 mg, or about 3000 mg, such as about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg). In some examples, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is every 4 weeks (Q4W) between 500 mg and 3000 mg, such as between 500 mg and 2800 mg, such as between 600 mg and 2700 mg, such as between 650 mg and 2600 mg, such as between 700 mg and 2500 mg, such as between 1000 mg and 2400 mg, such as between 1100 mg and 2300 mg; between 1200 mg and 2200 mg, such as between 1300 mg and 2100 mg, such as between 1400 mg and 2000 mg, such as between 1500 mg and 1900 mg, such as between 1600 mg and 1800 mg, such as between 1620 mg and 1700 mg, such as between 1640 mg and 1690 mg, such as between 1660 mg and 1680 mg, 1680 mg, such as 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1690 mg, or 1700 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is 1680 mg every 4 weeks at a dose of (e.g. 1680 mg ± 10 mg, such as 1680 ± 6 mg, such as 1680 ± 5 mg, such as 1680 ± 3 mg, such as 1680 ± 1 mg, such as 1680 ± 0.5 mg, such as 1680 mg every 4 weeks) be. In some examples, the effective amount of atezolizumab is a dose of about 1680 mg every 4 weeks. In some examples, the effective amount of atezolizumab is a dose of 1680 mg every 4 weeks.

In some examples, the effective amount of the anti-PD-1 antagonist antibody (eg, pembrolizumab) is between about 50 mg and about 2000 mg (eg, between about 50 mg and 100 mg, about 100 mg and 250 mg) every 6 weeks (Q6W). between about 250 mg and 500 mg, between about 500 mg and 750 mg, between about 750 mg and 1000 mg, between about 1000 mg and 1250 mg, between about 1250 mg and 1500 mg, between about 1500 mg and 1750 mg, or between about 1750 mg and 2000 mg between about 100 mg and about 1000 mg, between about 120 mg and about 900 mg, between about 150 mg and about 800 mg, between about 200 mg and about 700 mg, between about 250 mg and about 600 mg, between about 300 mg and about 500 mg between about 350 mg and about 450 mg, such as between about 50 mg and about 100 mg, between about 100 mg and about 200 mg, between about 200 mg and about 300 mg, between about 300 mg and about 400 mg, between about 400 mg and about 500 mg between about 500 mg and about 600 mg, between about 600 mg and about 700 mg, between about 700 mg and about 800 mg, or between about 800 mg and about 1000 mg, such as about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg , about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, or about 2000 mg, such as about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg , about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg, such as 400 mg). In some examples, the effective amount of the anti-PD-1 antagonist antibody (eg, pembrolizumab) is between 50 mg and 2000 mg (eg, between 100 mg and 1000 mg, between 120 mg and 900 mg, 150 mg) every 6 weeks (Q6W) and 800 mg, between 200 mg and 700 mg, between 250 mg and 600 mg, between 300 mg and 500 mg, or between 350 mg and 450 mg, such as between 50 mg and 100 mg, between 100 mg and 200 mg, between 200 mg and 300 mg, 300 mg and 400 mg, between 400 mg and 500 mg, between 500 mg and 600 mg, between 600 mg and 700 mg, between 700 mg and 800 mg, or between 800 mg and 1000 mg, such as 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg , 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg, such as 400 mg). In some examples, the effective amount of anti-PD-1 antagonist antibody (eg, pembrolizumab) is about 400 mg (eg, 400 mg±10 mg, such as 400±6 mg, such as 400±5 mg, such as 400±3 mg, such as 400±1 mg, such as 400±0.5 mg, such as 400 mg every 6 weeks). In some examples, the dose of PD-1 axis binding antagonist is a fixed dose. In some examples, the effective amount of pembrolizumab is a dose (eg, fixed dose) of about 400 mg every 6 weeks. In some examples, the effective amount of pembrolizumab is a dose of 400 mg (eg, fixed dose) every 6 weeks.

In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., penprolizumab)) is reduced compared to standard doses of PD-1 axis binding antagonists administered as monotherapy. can.

In some examples, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, penprolizumab)) is administered intravenously. Alternatively, in some embodiments, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered subcutaneously. In some examples, atezolizumab is administered intravenously to the patient at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks. In some examples, atezolizumab is administered intravenously to the patient at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

In some examples, the subject receives a total of 1 to 20 doses of the PD-1 axis binding antagonist, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 doses are administered. In some examples, the subject receives a total of 1-50 doses, such as 1-50 doses, 1-45 doses, 1-40 doses, 1-35 doses, 1-30 doses, 1-25 doses, 1 ~20 doses, 1-15 doses, 1-10 doses, 1-5 doses, 2-50 doses, 2-45 doses, 2-40 doses, 2-35 doses, 2-30 doses, 2-25 doses, 2 ~20 doses, 2-15 doses, 2-10 doses, 2-5 doses, 3-50 doses, 3-45 doses, 3-40 doses, 3-35 doses, 3-30 doses, 3-25 doses, 3 ~20 doses, 3-15 doses, 3-10 doses, 3-5 doses, 4-50 doses, 4-45 doses, 4-40 doses, 4-35 doses, 4-30 doses, 4-25 doses, 4 ~20 doses, 4-15 doses, 4-10 doses, 4-5 doses, 5-50 doses, 5-45 doses, 5-40 doses, 5-35 doses, 5-30 doses, 5-25 doses, 5 ~20 doses, 5-15 doses, 5-10 doses, 10-50 doses, 10-45 doses, 10-40 doses, 10-35 doses, 10-30 doses, 10-25 doses, 10-20 doses, 10 ~15 doses, 15-50 doses, 15-45 doses, 15-40 doses, 15-35 doses, 15-30 doses, 15-25 doses, 15-20 doses, 20-50 doses, 20-45 doses, 20 ~40 doses, 20-35 doses, 20-30 doses, 20-25 doses, 25-50 doses, 25-45 doses, 25-40 doses, 25-35 doses, 25-30 doses, 30-50 doses, 30 ~45 doses, 30-40 doses, 30-35 doses, 35-50 doses, 35-45 doses, 35-40 doses, 40-50 doses, 40-45 doses, or 45-50 doses of PD-1 axial binding An antagonist is administered. In certain instances, doses may be administered intravenously.

iii. Effective Dosages of Anti-TIGIT Antagonist Antibodies and PD-1 Axis Binding Antagonists In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is , every two weeks between about 30 mg and about 600 mg, such as between about 50 mg and 600 mg, such as between about 60 mg and about 600 mg, such as between about 100 mg and about 600 mg, such as between about 200 mg and about 600 mg, such as between about 200 mg and about 600 mg, such as between about 200 mg and about 550 mg, such as between about 250 mg and about 600 mg, such as between about 300 mg and about 500 mg, such as between about 350 mg and about 450 mg, such as between about 400 mg and about 440 mg, such as between about 410 mg and about 430 mg 420±10 mg, such as 420±6 mg, such as 420±5 mg, such as 420±3 mg, such as 420±1 mg, such as 420±0.5 mg, such as 420 mg) (e.g., fixed dose) between . In some examples, the effective amount of the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody (e.g., tiragolumab)) is between 30 mg and 600 mg (e.g., between 50 mg and 600 mg, e.g., 60 mg and 600 mg) every two weeks. between 100 mg and 600 mg, such as between 200 mg and 600 mg, such as between 200 mg and 550 mg, such as between 250 mg and 600 mg, such as between 300 mg and 500 mg, such as between 350 mg and 450 mg, such as between 400 mg and 440 mg between, such as between 410 mg and 430 mg, such as 420±10 mg, such as 420±6 mg, such as 420±5 mg, such as 420±3 mg, such as 420±1 mg, such as 420±0.5 mg, such as 420 mg) (e.g. fixed dose). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 420 mg every two weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 420 mg every two weeks.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is between about 30 mg and about 1200 mg (e.g., about 30 mg) every three weeks. and about 1100 mg, for example between about 60 mg and about 1000 mg, for example between about 100 mg and about 900 mg, for example between about 200 mg and about 800 mg, for example between about 300 mg and about 800 mg, for example about 400 mg and about 800 mg, such as between about 400 mg and about 750 mg, such as between about 450 mg and about 750 mg, such as between about 500 mg and about 700 mg, such as between about 550 mg and about 650 mg, such as 600 mg ± 10 mg, such as 600±6 mg, such as 600±5 mg, such as 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg). In some examples, the effective amount of the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody (e.g., tiragolumab)) is between 30 mg and 1200 mg (e.g., between 30 mg and 1100 mg, e.g., between 60 mg and 1000 mg) every three weeks. between 100 mg and 900 mg, such as between 200 mg and 800 mg, such as between 300 mg and 800 mg, such as between 400 mg and 800 mg, such as between 400 mg and 750 mg, such as between 450 mg and 750 mg, such as between 500 mg and 700 mg, for example between 550 mg and 650 mg, such as 600±10 mg, such as 600±6 mg, such as 600±5 mg, such as 600±3 mg, such as 600±1 mg, such as 600±0.5 mg, such as 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 600 mg every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 600 mg every 3 weeks.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is between about 600 mg and about 1200 mg (e.g., about 600 mg and about 1200 mg) every four weeks. between about 1100 mg, such as between about 600 mg and about 1000 mg, such as between about 700 mg and about 950 mg, such as between about 800 mg and about 900 mg, such as between about 820 mg and about 860 mg, such as about 840±10 mg, such as 840± 6 mg, such as 840±5 mg, such as 840±3 mg, such as 840±1 mg, such as 840±0.5 mg, such as 840 mg). In some examples, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is between 600 mg and 1200 mg (e.g., between 600 mg and 1100 mg) every four weeks. between 600 mg and 1000 mg, such as between 700 mg and 950 mg, such as between 800 mg and 900 mg, such as between 820 mg and 860 mg, such as 840±10 mg, such as 840±6 mg, such as 840±5 mg, such as 840±3 mg, such as 840±1 mg, such as 840±0.5 mg, such as 840 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 840 mg every 4 weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 840 mg every 4 weeks.

In some examples, combination therapy (e.g., PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK- 3475 (pembrolizumab, formerly known as lambrolizumab)) dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered at In some instances, combination therapy (e.g., one or more platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and /or with non-platinum chemotherapeutic agents (e.g. alkylating agents (e.g. cyclophosphamide), taxanes (e.g. paclitaxel or nab-paclitaxel) and/or topoisomerase II inhibitors (e.g. doxorubicin)) or Anti-TIGIT antagonist antibody (e.g., as disclosed herein) administered without PD-1 axis binding antagonist (e.g., co-treatment with anti-PD-L1 antagonist antibody (e.g., atezolizumab)) Anti-TIGIT antagonist antibodies (eg, tiragolumab) and/or G-CSF or GM-CSF doses are standard for anti-TIGIT antagonist antibodies (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)) administered as monotherapy. may be reduced relative to dose.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 20 mg and about 1600 mg (eg, about 20 and 100 mg) every two weeks. between about 100 and 200 mg between about 200 and 400 mg between about 400 and 600 mg between about 600 and 800 mg between about 800 and 1000 mg between about 1000 and 1200 mg between about 1200 and 1400 mg between about 1400 and 1600 mg, such as between about 80 mg and about 1200 mg, such as between about 100 mg and about 1200 mg, such as between about 200 mg and about 1200 mg, such as between about 300 mg and about 1200 mg, such as between about 400 mg between about 1200 mg, such as between about 500 mg and about 1200 mg, such as between about 600 mg and about 1100 mg, such as between about 700 mg and about 1000 mg, such as between about 740 mg and about 940 mg, such as between about 790 mg and about 890 mg; at a dose of between about 815 mg and about 865 mg, such as between about 830 mg and about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg. be. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between 80 mg and 1200 mg (eg, between 80 mg and 1200 mg) every two weeks. between 100 mg and 1200 mg, such as between 200 mg and 1200 mg, such as between 300 mg and 1200 mg, such as between 400 mg and 1200 mg, such as between 500 mg and 1200 mg, such as between 600 mg and 1100 mg, such as , between 700 mg and 1000 mg, such as between 740 mg and 940 mg, such as between 790 mg and 890 mg, such as between 815 mg and 865 mg, such as between 830 mg and 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2 .5 mg, eg 840±1.0 mg, eg 840±0.5 mg, eg 840 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is about 20 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg every two weeks , 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg or 1600 mg. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 80 mg and about 2000 mg (eg, between about 100 mg and about 2000 mg) every 3 weeks. such as between about 200 mg and about 1900 mg, such as between about 300 mg and about 1700 mg, such as between about 400 mg and about 1600 mg, such as between about 500 mg and about 1600 mg, such as between about 600 mg and about 1600 mg, such as about 700 mg between about 1600 mg, such as between about 800 mg and about 1600 mg, such as between about 900 mg and about 1500 mg, such as between about 1000 mg and about 1400 mg, such as between about 1050 mg and about 1350 mg, such as between about 1100 mg and about 1300 mg; for example between about 1150 mg and about 1250 mg, such as between about 1175 mg and about 1225 mg, such as between about 1190 mg and about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0 .5 mg, eg 1200 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 80 mg and 2000 mg (e.g., between 100 mg and 2000 mg) every three weeks, e.g. between 200 mg and 1900 mg, such as between 300 mg and 1700 mg, such as between 400 mg and 1600 mg, such as between 500 mg and 1600 mg, such as between 600 mg and 1600 mg, such as between 700 mg and 1600 mg, such as between 800 mg and 1600 mg, such as 900 mg and 1500 mg, such as between 1000 mg and 1400 mg, such as between 1050 mg and 1350 mg, such as between 1100 mg and 1300 mg, such as between 1150 mg and 1250 mg, such as between 1175 mg and 1225 mg, such as between 1190 mg and 1210 mg, such as 1200 mg ± 5 mg, such as 1200±2.5 mg, such as 1200±1.0 mg, such as 1200±0.5 mg, such as 1200 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a fixed dose of 1200 mg every 3 weeks.

In some examples, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is between about 1200 mg and about 2000 mg (eg, about 1200 mg and about 1900 mg) every 4 weeks. between about 1200 mg and about 1800 mg, such as between about 1300 mg and about 1800 mg, such as between about 1400 mg and about 1800 mg, such as between about 1500 mg and about 1800 mg, such as between about 1580 mg and about 1780 mg, such as about between 1630 mg and about 1730 mg, such as between about 1655 mg and about 1705 mg, such as between about 1670 mg and about 1690 mg, such as 1680 mg±5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg , eg 1680 mg). In some examples, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is between 1200 mg and 2000 mg (e.g., between 1200 mg and 1900 mg) every 4 weeks, e.g. between 1200 mg and 1800 mg, such as between 1300 mg and 1800 mg, such as between 1400 mg and 1800 mg, such as between 1500 mg and 1800 mg, such as between 1580 mg and 1780 mg, such as between 1630 mg and 1730 mg, such as between 1655 mg and 1705 mg, such as 1670 mg and 1690 mg, such as 1680±5 mg, such as 1680±2.5 mg, such as 1680±1.0 mg, such as 1680±0.5 mg, such as 1680 mg). In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some examples, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks.

In some examples, a PD-1 axis binding antagonist (e.g. , anti-PD-L1 antagonist antibody (eg, nivolumab)) can be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as monotherapy. In some examples, one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or 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))) and/or combination therapy with or without G-CSF or GM-CSF (e.g. anti-TIGIT antagonist antibody , e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., combination treatment with tiragolumab)) can be reduced compared to standard doses of PD-1 axis binding antagonists administered as monotherapy.

iv. Anti-TIGIT Antagonist Antibody and PD-1 Axis Binding Antagonist Dosing Cycles In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or or a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) for one or more dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 , 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) ) are continued until clinical benefit (eg, documented disease progression, drug resistance, death, or unacceptable toxicity) is lost. In some examples, the length of each dosing cycle is about 7 to 42 days (eg, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days). 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 examples, the dosing cycle length is about 14 days. In some examples, the dosing cycle length is about 21 days. In some examples, the dosing cycle length is about 28 days. In some examples, the dosing cycle length is about 42 days. In some examples, the dosing cycle length is about 7 days. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. be done. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 15 (e.g., day 15±3) of each dosing cycle. be done. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 22 (e.g., day 22±3) of each dosing cycle. be done. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 29 (e.g., day 29±3) of each dosing cycle. be done. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., fixed dose) of about 600 mg (e.g., a fixed dose) on day 1 of each 21-day cycle ( i.e., intravenously at a dose of about 600 mg every 3 weeks). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 600 mg (e.g., fixed dose) on days 1 and 15 of each 28-day cycle. dose) (ie, at a dose of about 420 mg every two weeks). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is dosed at about 600 mg on days 1, 15 and 29 of each 42-day cycle. (eg, fixed dose) (ie, at a dose of about 420 mg every two weeks) intravenously. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 600 mg (e.g., fixed dose) on days 1 and 22 of each 42-day cycle. dose) (ie, at a dose of about 600 mg every 3 weeks). In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) Pembrolizumab))) is administered on about day 1 (eg, day 1±3) of each dosing cycle. In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) pembrolizumab))) is administered on about day 15 (eg, day 15±3) of each dosing cycle. For example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every 3 weeks). ii) administered intravenously. For example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of about 1200 mg on days 1 and 15 of each 28-day cycle (i.e., a dose of about 840 mg). every 2 weeks) is administered intravenously. In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg (e.g., a fixed dose) on day 1 of each 21-day cycle. ) (ie, at a dose of 600 mg every 3 weeks). In some examples, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (formerly lambrolizumab) Pembrolizumab))) is administered on Day 1 (eg, 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., atezolizumab)) at a dose of 1200 mg on day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every 3 weeks). It is administered intravenously.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (eg, day 1±3) of each dosing cycle.

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 600 mg on day 1 of a 21-day cycle (i.e., 3 at a dose of about 600 mg weekly) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 1200 mg on day 1 of a 21-day cycle. It is administered intravenously (ie, at a dose of about 1200 mg every 3 weeks). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 600 mg on day 1 of a 21-day cycle (i.e., for 3 weeks). PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of 1200 mg on day 1 of a 21-day cycle (i.e., administered intravenously at a dose of 1200 mg every 3 weeks).

In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 420 mg on day 1 of a 14-day cycle (i.e., for 2 weeks). and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 840 mg on day 1 of a 14-day cycle ( ie, at a dose of about 840 mg every two weeks) intravenously. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 420 mg on day 1 of a 14-day cycle (i.e., for 2 weeks). PD-1 axis binding antagonist (e.g. anti-PD-L1 antagonist antibody (e.g. atezolizumab)) at a dose of 840 mg on day 1 of a 14-day cycle (i.e. , at a dose of 840 mg every 2 weeks) is administered intravenously.

In another example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of about 840 mg on day 1 of a 28-day cycle (i.e., for 4 weeks). PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of about 1680 mg on day 1 of a 28-day cycle ( i.e., intravenously at a dose of about 1680 mg every 4 weeks). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered at a dose of 840 mg on day 1 of a 28-day cycle (i.e., for 4 weeks). PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose of 1680 mg on day 1 of a 28-day cycle (i.e., administered intravenously at a dose of 1680 mg every 4 weeks).

v. Intravenous Infusion and Subcutaneous Administration of Anti-TIGIT Antagonist Antibody and PD-1 Axis Binding Antagonist Administer intravenously. Alternatively, in some embodiments, an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered subcutaneously. In some examples, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered intravenously. Alternatively, in some embodiments, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered subcutaneously.

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

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered for 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 examples, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered for about 30±10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes , about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).

vi. Order of Administration and Observation Period In some examples where both an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist are administered to a subject or population of subjects, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antibody as disclosed herein) is administered to a subject or population of subjects. A TIGIT antagonist antibody (eg, tiragolumab) is administered to the subject prior to a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)). be.

In some examples, the method includes an intervening first observation period, eg, after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis binding antagonist. In some examples, for example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to the subject after administration of the anti-TIGIT antagonist antibody. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is first administered to the subject, and an anti-TIGIT antagonist antibody (e.g., A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to the subject after administration of an anti-TIGIT antagonist antibody as disclosed (eg, tiragolumab).

In some examples, the method further comprises a second observation period following administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some examples, the method includes a first observation period after administration of an anti-TIGIT antagonist antibody and a second observation period after administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). Includes both observation periods. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. When the first and second observation periods are each about 60 minutes, the method includes anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) during the first or second observation period. (eg, atezolizumab)) at about 30±10 minutes after administration of the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature). If the first and second observation periods are each about 30 minutes, the method includes anti-TIGIT antagonist antibody or PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) between the first or second , atezolizumab)) at about 15±10 minutes after administration of the subject's vital signs (eg, pulse rate, respiratory rate, blood pressure, and temperature).

In some examples, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is an anti-TIGIT antagonist antibody (e.g., herein prior to administration of an anti-TIGIT antagonist antibody (eg, tiragolumab) as disclosed in the literature to the subject or population of subjects. In some examples, for example, after administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antibody as disclosed herein). Prior to administration of the TIGIT antagonist antibody (eg, tiragolumab), the method includes an intervening first observation period.

In some examples, the method further comprises a second observation period after administration of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab).

In some examples, the methods include a first observation period following administration of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, herein A second observation period after administration of an anti-TIGIT antagonist antibody (eg, tiragolumab) as disclosed in the literature. In some examples, the first and second observation periods are each between about 30 minutes and about 60 minutes long. If the first and second observation periods are each about 60 minutes long, the method includes the use of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab)) or the subject's vital signs (e.g., pulse rate, recording breathing rate, blood pressure, and temperature). If the first and second observation periods are each about 30 minutes long, the method includes the use of a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., , atezolizumab)), the subject's vital signs (e.g., pulse rate, recording breathing rate, blood pressure, and temperature).

In some examples, the method further comprises administration of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)). In some examples, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., pembrolizumab)) and an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some examples, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) or PD- A second observation period following administration of a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered.

In some examples, the method further comprises a third observation period after administration of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)). In some examples, the third observation period is between about 30 minutes and about 120 minutes long. In some examples, the first observation period, the second observation period, and the third observation period are each between about 30 minutes and about 120 minutes long.

Combination Administration of Anti-TIGIT Antagonist Antibody and PD-1 Axis Binding Antagonist such as anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., combination treatment with an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), an effective dose of the anti-TIGIT antagonist antibody (e.g., , an anti-TIGIT antagonist antibody (e.g., tiragolumab) as set forth herein, administered with an effective dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)). In some examples, the anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered herein In some examples, the anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(ii) of Section III(K)(ii) herein. and the PD-1 axis binding antagonist is administered every three weeks as described in Section III(K)(ii) herein. The anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered in Section III(K)(ii) herein. In some examples, the anti-TIGIT antagonist antibody is administered every 2 weeks as described in Section III(K)(i) herein. and the PD-1 axis binding antagonist is administered every 6 weeks as described in Section III(K)(ii) herein, hi some examples, the anti-TIGIT antagonist antibody is administered herein and the PD-1 axis binding antagonist is administered every 3 weeks as described in Section III(K)(i) of this specification, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. In some examples, the anti-TIGIT antagonist antibody is administered every three weeks as described in Section III(K)(i) herein, and P The D-1 axis binding antagonist is administered every three weeks as described in Section III(K)(ii) herein. In some examples, 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 in Section III(K)(i) herein. Administered every 4 weeks as described in III(K)(ii). In some examples, 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 in Section III(K)(i) herein. Administered every 6 weeks as described in III(K)(ii). In some examples, the anti-TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered in Section III(K)(i) herein. Administered every 2 weeks as described in III(K)(ii). In some examples, the anti-TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered in Section III(K)(i) herein. Administered every 3 weeks as described in III(K)(ii). In some examples, the anti-TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered in Section III(K)(i) herein. Administered every 4 weeks as described in III(K)(ii). In some examples, the anti-TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered in Section III(K)(i) herein. Administered every 6 weeks as described in III(K)(ii). In some examples, the anti-TIGIT antagonist antibody is administered every 2, 3 or 4 weeks as described in Section III(K)(i) herein and the PD-1 axis binding antagonist is administered herein. Administered every 2, 3, 4 or 6 weeks as described in Section III(K)(ii) of the specification.

In some examples, the dose of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of about 600 mg every 3 weeks. In some examples, the dose of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is a dose of 600 mg every 3 weeks. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered in a graded dosing regimen (e.g., subject body weight (BW) or body surface area ( (e.g., every 3 weeks) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezolizumab) is administered from about 0.01 mg/kg to about 50 mg/kg (eg, about 15 mg/kg), administered at doses up to 1200 mg, eg, every 3 weeks. In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered in a graded dosing regimen (e.g., subject body weight (BW) or body surface area ( BSA)-based dosing) (e.g., every 3 weeks) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody such as atezolizumab) is administered at 0.01 mg/kg to 50 mg/kg (e.g., , 15 mg/kg), at doses up to 1200 mg, eg every 3 weeks. Such dosing regimens can be utilized in the treatment of relatively low weight subjects (eg, 40 kg or less (eg, 5 kg to 40 kg, 15 kg to 40 kg, or 5 kg to 15 kg)). , being developed through biosimulation studies based on extrapolation of pharmacokinetic parameters estimated from adult data. In some examples, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is the body weight of the subject (e.g., body weight (BW) >40 kg: 600 mg; BW >15 kg and <40 kg: 400 mg; BW <15 kg: 300 mg). In some examples, the dose of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a subject weight-based dose (eg, 15 mg/kg). In some examples, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a subject's body surface area (e.g., body surface area (BSA) >1.25 m ² : 600 mg , BSA>0.75 m ² and ≦1.25 m ² : 450 mg, BSA>0.5 m ² and ≦0.75 m ² : 350 mg, and BSA ≦0.5 m ² : 300 mg). In some examples, a dose (e.g., about 600 mg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is added to a subject's body weight (e.g., 15 mg/kg ) every 3 weeks in combination with a dose of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, graded doses (e.g., body weight (BW) >40 kg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 3 weeks: 600 mg, BW>15 kg and ≦40 kg: 400 mg, BW ≦15 kg: 300 mg) to a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) based on the body weight of the subject (e.g., 15 mg/kg). In some examples, graded doses (e.g., body weight (BW) >40 kg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) every 3 weeks: 600 mg, BW>15 kg and ≦40 kg: 400 mg, BW ≦15 kg: 300 mg) to subject body surface area (e.g., BSA>1.25 m ² : 600 mg, BSA>0.75 m ² and ≦1.25 m ² : 450 mg, PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) based on BSA>0.5 m ² and ≦0.75 m ² : 350 mg, and BSA ≦0.5 m ² : 300 mg) administered in combination with In some embodiments, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a maximum dose of 1200 mg every 3 weeks. In some instances, the combination therapy includes one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or non-platinum-based chemotherapeutic agents (e.g., antimetabolite agents (e.g., pemetrexed or gemcitabine))).

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is The subject is (a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 300 mg every 3 weeks) (b) weighs more than 15 kg and less than or equal to 40 kg and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 400 mg every 3 weeks); or (c ) >40 kg, and the anti-TIGIT antagonist antibody is administered at a dose between about 30 mg and about 1200 mg every three weeks (eg, about 600 mg every three weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between about 250 mg and about 350 mg every 3 weeks (e.g., about 300 mg every 3 weeks); (b) weighing more than 15 kg and 40 kg; or (c) greater than 40 kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 350 mg and about 450 mg every 3 weeks (e.g., about 400 mg every 3 weeks); , at doses between about 550 mg and about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) weighing greater than 15 kg and ≤40 kg and the anti-TIGIT antagonist antibody is administered at about or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every three weeks. In some examples, between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg). /kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as about 10 mg/kg. kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15 ± 0.2 mg/kg or about 15 ± 0.1 mg/kg, such as about 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) administered in combination with weight-based graded doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), wherein the subject (a) weighs 15 kg or less; , the anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every 3 weeks (e.g., about 300 mg every 3 weeks); is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 400 mg every 3 weeks); or (c) weighs over 40 kg and the anti-TIGIT antagonist antibody is administered at about Administered at doses between 30 mg and about 1200 mg (eg, about 600 mg every 3 weeks). In some examples, an anti-TIGIT antagonist antibody (e.g., as disclosed herein) is administered to a subject weighing 15 kg or less at a dose of between about 10 mg and about 1000 mg every three weeks (e.g., about 300 mg every three weeks). an anti-TIGIT antagonist antibody, e.g., tiragolumab, as administered and between about 0.01 mg/kg and about 50 mg/kg of the subject's body weight (e.g., about 0.01 mg/kg and about 45 mg/kg) every 3 weeks between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg. kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) of a PD-1 axis binding antagonist (e.g., anti-PD - Administer an L1 antagonistic antibody (eg, atezolizumab). In some examples, a subject weighing more than 15 kg and less than 40 kg is administered an anti-TIGIT antagonist antibody (e.g., doses of between about 10 mg and about 1000 mg every 3 weeks (e.g., about 400 mg every 3 weeks), e.g., and between about 0.01 mg/kg and about 50 mg/kg of the subject's body weight (e.g., about 0.01 mg/kg and about 45 mg/kg) every 3 weeks. /kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as about between 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15± 1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) dose of a PD-1 axis binding antagonist (e.g., An anti-PD-L1 antagonist antibody (eg, atezolizumab) is administered. In some examples, an anti-TIGIT antagonist antibody (e.g., as disclosed herein) is administered to a subject weighing more than 40 kg at a dose of between about 30 mg and about 1200 mg every three weeks (e.g., about 600 mg every three weeks). an anti-TIGIT antagonist antibody, e.g., tiragolumab, as administered and between about 0.01 mg/kg and about 50 mg/kg of the subject's body weight (e.g., about 0.01 mg/kg and about 45 mg/kg) every 3 weeks between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg. kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) of a PD-1 axis binding antagonist (e.g., anti-PD - Administer an L1 antagonistic antibody (eg, atezolizumab).

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is ( b) weighing more than 15 kg and less than or equal to 40 kg, and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 400 mg every 3 weeks); The TIGIT antagonist antibody is administered at doses between 30 mg and 1200 mg every 3 weeks (eg 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighs 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose between 250 mg and 350 mg every 3 weeks (e.g., 300 mg every 3 weeks); (b) weighs more than 15 kg and ≤40 kg; or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of between 350 mg and 450 mg every 3 weeks (e.g., 400 mg every 3 weeks); and 650 mg (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on the weight of the subject, wherein the subject is ( a) weighing 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; or (c) greater than 40 kg, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks. In some examples, between 0.01 mg/kg and 50 mg/kg of body weight of the subject (e.g., between 0.01 mg/kg and 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as 12.5 mg/kg kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg or 15±0.1 mg/kg, such as 15 mg/kg) of a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) to a subject anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g. , tiragolumab) in combination with weight-based graded doses of the anti-TIGIT antagonist antibody (a) weighing 15 kg or less and anti-TIGIT antagonist antibody at doses of 10 mg and 1000 mg every 3 weeks (e.g. (b) weighing >15 kg and ≤40 kg and the anti-TIGIT antagonist antibody is administered at doses of 10 mg and 1000 mg every 3 weeks (e.g., 400 mg every 3 weeks); or (c ) weighs more than 40 kg and the anti-TIGIT antagonist antibody is administered at doses of 30 mg and 1200 mg every 3 weeks (eg 600 mg every 3 weeks). In some examples, subjects weighing 15 kg or less receive doses of 10 mg and 1000 mg every 3 weeks (e.g., 300 mg every 3 weeks) of an anti-TIGIT antagonist antibody (e.g., an anti TIGIT antagonist antibody, e.g., tiragolumab), and between 0.01 and 50 mg/kg of subject body weight (e.g., between 0.01 and 45 mg/kg, e.g., 0.1 mg/kg) every 3 weeks and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg, or 15±0. A dose of 1 mg/kg, eg, 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered. In some examples, a subject weighing more than 15 kg and less than 40 kg is administered an anti-TIGIT antagonist antibody (e.g., as disclosed herein) at doses of 10 mg and 1000 mg every 3 weeks (e.g., 400 mg every 3 weeks). anti-TIGIT antagonist antibody, e.g., tiragolumab), and between 0.01 mg/kg and 50 mg/kg of the subject's body weight (e.g., between 0.01 mg/kg and 45 mg/kg, e.g., 0.1 mg/kg) every 3 weeks /kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as 10 mg/kg and 20 mg /kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± A dose of 0.1 mg/kg, eg, 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered. In some examples, a subject weighing more than 40 kg is administered an anti-TIGIT antagonist antibody (e.g., as disclosed herein) at a dose between 30 mg and 1200 mg every 3 weeks (e.g., 600 mg every 3 weeks). anti-TIGIT antagonist antibody, e.g., tiragolumab), and between 0.01 mg/kg and 50 mg/kg of the subject's body weight (e.g., between 0.01 mg/kg and 45 mg/kg, e.g., 0.1 mg/kg) every 3 weeks /kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as 10 mg/kg and 20 mg /kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± A dose of 0.1 mg/kg, eg, 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) for treating a subject with cancer is the body surface area of the subject. It is a tiered dose based on In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² or less than 0.75 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 350 mg every 3 weeks); c) greater than 0.75 m ² and less than or equal to 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or ( d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 30 mg and about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between about 250 mg and about 350 mg every three weeks (eg, about 300 mg every three weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between about 300 mg and about 400 mg every 3 weeks (e.g., about 350 mg every 3 weeks); or (c) greater than 0.75 ^m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between about 400 mg and about 500 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between about 550 mg and about 650 mg every three weeks (eg, about 600 mg every three weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) has a body surface area of 0.5 ^m2 or less, and the anti-TIGIT antagonist antibody is ^administered at a dose of about 300 ^mg every 3 weeks; , the anti-TIGIT antagonist antibody is administered ^at a dose of about 400 mg every 3 ^weeks ; or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

In some examples, between about 0.01 mg/kg and about 50 mg/kg of body weight of the subject (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., between about 0.1 mg/kg and about 40 mg/kg). /kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as about 10 mg/kg. between about 20 mg/kg, such as about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg /kg or about 15±0.1 mg/kg, such as about 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) to the subject's anti-TIGIT antagonist antibody. (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) in combination with graded doses based on body surface area, wherein the subject: (a) has a body surface area of 0.5 m ² or less; and the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg and about 1000 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 ; the anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every three weeks (e.g., about 350 mg every three weeks); (c) greater than 0.75 ^m2 and less than or equal to 1.25 ^m2 ; The anti-TIGIT antagonist antibody is administered at a dose of between about 10 mg and about 1000 mg every 3 weeks (e.g., about 450 mg every 3 weeks); or (d) greater than 1.25 ^m2 and the anti-TIGIT antagonist antibody is , at doses between about 30 mg and about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some examples, an anti- ^TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and between about 0.01 mg/kg and about 50 mg/kg of body weight of a subject (e.g., about 0.01 mg/kg) every 3 weeks and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg; PD-1 axis binding antagonist at a dose of about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, anti-TIGIT at a dose between about 10 mg and about 1000 mg every 3 weeks (e.g., about 350 mg every 3 weeks) to a subject having a body surface area greater than 0.5 m ^{2 and} less than or equal to 0.75 m 2 an antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and between about 0.01 mg/kg and about 50 mg/kg of body weight of a subject (e.g., about between 0.01 mg/kg and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about Between 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15 mg/kg. PD at a dose of ±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) - Administer a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, anti-TIGIT at a dose of between about 10 mg and about 1000 mg every 3 weeks (e.g., about 450 mg every 3 weeks) to a subject having a body surface area greater than 0.75 m ^{2 and} less than or equal to 1.25 m 2 an antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and between about 0.01 mg/kg and about 50 mg/kg of body weight of a subject (e.g., about between 0.01 mg/kg and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about between about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered. In some examples, an anti- ^TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and between about 0.01 mg/kg and about 50 mg/kg of body weight of a subject (e.g., about 0.01 mg/kg) every 3 weeks and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg between about 5 mg/kg and about 25 mg/kg, such as between about 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg , about 15±1 mg/kg, about 15±0.5 mg/kg, about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg) An antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered.

In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between 10 mg and 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 350 mg every 3 weeks); (c) 0 greater than .75 ^m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 450 mg every 3 weeks); or (d) 1.25 ^m2 and the anti-TIGIT antagonist antibody is administered at a dose between 30 mg and 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) have a body surface area of 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of between 250 mg and 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 ^m2 and less than or equal to 0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 300 mg and 400 mg every 3 weeks (e.g., 350 mg every 3 weeks); or (c) ^greater than 0.75 m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 400 mg and 500 mg every 3 weeks (e.g., 450 mg every 3 weeks); or (d) 1.25 m greater than ² and the anti-TIGIT antagonist antibody is administered at a dose between 550 mg and 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a graded dose based on a subject's body surface area, wherein the subject is (a) has a body surface area of 0.5 ^{m2 or} less, and the anti-TIGIT antagonist antibody is administered ^at a dose of 300 mg every 3 weeks; the anti-TIGIT antagonist antibody is ^{administered at} a dose of 400 mg every 3 weeks; or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some examples, between 0.01 mg/kg and 50 mg/kg of body weight of the subject (e.g., between 0.01 mg/kg and 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as 12.5 mg/kg kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg or 15±0.1 mg/kg, such as 15 mg/kg) of a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) to a subject anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g. , tiragolumab) in combination with graded doses based on body surface area, subjects (a) with a body surface area of ≤ 0.5 ^m2 and anti-TIGIT antagonist antibody doses between 10 mg and 1000 mg every 3 weeks (e.g., 300 mg every 3 weeks); (b) greater than 0.5 ^m2 and ≤0.75 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose of between 10 mg and 1000 mg every 3 weeks (e.g., (c) greater than 0.75 ^m2 and less than or equal to 1.25 ^m2 , and the anti-TIGIT antagonist antibody is administered at a dose between 10 mg and 1000 mg every 3 weeks (e.g., 350 mg every 3 weeks); or (d) greater than 1.25 m ² and the anti-TIGIT antagonist antibody is administered at a dose between 30 mg and 1200 mg every 3 weeks (e.g., 600 mg every 3 weeks) . In some examples, a subject with a body surface area of 0.5 m ² or less is administered an anti-TIGIT antagonist antibody (e.g., 300 mg every 3 weeks) at a dose of between 10 mg and 1000 mg every 3 weeks (e.g., 300 mg every 3 weeks). and an anti-TIGIT antagonist antibody, such as tiragolumab, as disclosed in US Pat. between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg kg, or 15±0.1 mg/kg, eg, 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some examples, an anti-TIGIT antagonist antibody (e.g., 350 mg every ³ weeks) ^at a dose of between 10 mg and 1000 mg every 3 weeks ( For example, an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), and between 0.01 mg/kg and 50 mg/kg (e.g., 0.01 mg/kg and between 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15 A dose of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of ±0.2 mg/kg, or 15±0.1 mg/kg, eg, 15 mg/kg. In some examples, an anti-TIGIT antagonist antibody ( ^e.g. , 450 mg every 3 weeks) ^at a dose of between 10 mg and 1000 mg every 3 weeks ( For example, an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), and between 0.01 mg/kg and 50 mg/kg (e.g., 0.01 mg/kg and between 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15 A dose of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of ±0.2 mg/kg, or 15±0.1 mg/kg, eg, 15 mg/kg. In some examples, an anti-TIGIT antagonist antibody (e.g., 600 mg every ³ weeks) at a dose of between 30 mg and 1200 mg every 3 weeks (e.g., 600 mg every 3 weeks) to a subject with a body surface area greater than 1.25 m 2 and an anti-TIGIT antagonist antibody, such as tiragolumab, as disclosed in US Pat. between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg, 15±0.5 mg/kg, 15±0.2 mg/kg kg, or 15±0.1 mg/kg, eg, 15 mg/kg) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

Dosing of Chemotherapeutic Agents Therapeutically effective amounts of various chemotherapeutic agents are known in the art and contemplated by the present invention. In certain cases, one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclo phosphamide), taxanes (eg paclitaxel, eg nab-paclitaxel) and/or topoisomerase II inhibitors (eg doxorubicin)) are administered according to the doses recited herein.
platinum-based chemotherapeutic agent

In some examples, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 1-50 mg/ml/min (eg, 2-25 mg/ml/min, 3-15 mg/ml/min, 4 ~10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, sufficient to achieve an AUC of 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min) a reasonable dose. In some examples, an effective amount of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is a dose sufficient to achieve AUC=5 mg/ml/min. In some examples, an effective amount of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is a dose sufficient to achieve AUC=6 mg/ml/min. In some examples, an effective amount of carboplatin is a dose sufficient to achieve AUC=5 mg/ml/min. In some examples, an effective amount of carboplatin is a dose sufficient to achieve AUC=6 mg/ml/min. In some examples, the effective amount of carboplatin is the dose sufficient to achieve AUC=5 mg/ml/min on day 1 of a 21-day dosing cycle. In some examples, the effective amount of carboplatin is the dose sufficient to achieve AUC=6 mg/ml/min on day 1 of a 21-day dosing cycle. In some examples, the effective amount of carboplatin is a dose sufficient to achieve AUC=5 mg/ml/min when administered after pemetrexed or gemcitabine. In some examples, an effective amount of carboplatin is a dose sufficient to achieve AUC=6 mg/ml/min when administered after paclitaxel.
AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol. 1989, 7:1748-56):
Total Dose (mg) = (Target AUC) X (Glomerular Filtration Rate [GFR] + 25)

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

In some examples, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is between about 20 mg/m ² and about 200 mg/m ² (eg, between about 20 mg/m ² and about 150 mg/m ^{2 )} . between about 30 mg/m ² and about 125 mg/m ² , such as between about 40 mg/m ² and about 110 mg/m ² , such as between about 50 mg/m ² and about 100 mg/m ² , such as about 60 mg /m ² and about 90 mg/m ² , such as between about 70 mg/m ² and about 80 mg/m ² , such as about 75 mg/m ² , such as about 75 mg/m ² ). In some examples, the effective amount of platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is about 75 mg/m ² . In some examples, the effective amount of cisplatin is about 75 mg/ ^m2 . In some examples, the effective amount of cisplatin is about 75 mg/ ^m2 every 3 weeks. In some examples, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is between 20 mg/ ^m2 and 200 mg/ ^m2 (e.g., between 20 mg/ ^m2 and 150 mg/ ^m2 , e.g., 30 mg/m2). /m ² and 125 mg/m ² , such as between 40 mg/m ² and 110 mg/m ² , such as between 50 mg/m ² and 100 mg/m ² , such as between 60 mg/m ² and 90 mg/m ² , eg between 70 mg/m ² and 80 mg/m ² , eg 75 mg/m ² , eg 75 mg/m ² ). In some examples, the effective amount of platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 75 mg/m ² . In some examples, the effective amount of cisplatin is 75 mg/ ^m2 . In some examples, the effective amount of cisplatin is 75 mg/ ^m2 every 3 weeks.

In some examples, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered intravenously (eg, infused over 30-120 minutes) to the subject or population of subjects. In some examples, carboplatin is administered intravenously over 30-60 minutes. In some instances, cisplatin is administered intravenously over a 60-120 minute infusion. In some examples, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered to the subject or subject population every three weeks. In some examples, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered at about day 1 (eg, day −3, day −2, day −1, day 1) of a 21-day dosing cycle. , day 2, or day 3).

Taxanes A therapeutically effective amount of a taxane (e.g., paclitaxel or nab-paclitaxel (ABRAXANE®)) administered to humans, whether by one or more administrations, ranges from about 25 to about 300 mg/m ^{2 .} ranges (e.g., about 25 mg/m ² , about 50 mg/m ² , about 75 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 125 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 175 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 225 mg/m ² , about 250 mg/m ² , about 275 mg/m ² , or about 300 mg/m ² (e.g. 25 mg/m ² , 50 mg/m ² , 75 mg/m 2 , ² , 80 mg/ ^m2 , 90 mg/ ^m2 , 100 mg/ ^m2 , 110 mg/m2, 120 mg/ ^m2 , 125 mg/ ^m2 , 130 mg/ ^m2 , 140 mg/ ^m2 , 150 mg/ ^m2 , 160 mg/ ^{m2 2} , 170 mg/ ^m2 , 175 mg/ ^m2 , 180 mg/ ^m2 , 190 mg/m2, 200 mg/ ^m2 , 225 mg/ ^m2 , ²⁵⁰ mg/ ^m2 , 275 mg/ ^m2 , or 300 mg/ ^m2 )) and For example, in some embodiments about 175 mg/m ² of paclitaxel is administered. In some embodiments, 175 mg/m ² paclitaxel is administered. In some embodiments, paclitaxel is administered at a dose of about 175 mg/m ² to about 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of about 175 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of about 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose between 175 mg/m ² and 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of 175 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at 175 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered to subjects of Asian race/ethnicity at 175 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered at 200 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered to subjects of non-Asian race/ethnicity at 200 mg/m ² IV every 3 weeks. In some embodiments, about 100 mg/m ² nab-paclitaxel (ABRAXANE®) is administered. In some embodiments, 100 mg/m ² nab-paclitaxel (ABRAXANE®) is administered. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered weekly at 100 mg/m ² IV. In some embodiments, nab-paclitaxel (ABRAXANE®) at 100 mg/m ² IV three times every 4 weeks (eg, on days 1, 8 and 15 of each 28-day dosing cycle) Administer. In some embodiments, the taxane (eg, paclitaxel or nab-paclitaxel (ABRAXANE®)) is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, 1, 8, and 15 of each 21-day cycle. day, or days 1, 8, and 15 of each 28-day cycle.

In some embodiments, the taxane (eg, paclitaxel or nab-paclitaxel (ABRAXANE®)) is administered intravenously (eg, infusion over 3 hours) to the subject or population of subjects. In some embodiments, the taxane is administered to the subject or subject population every three weeks. In some embodiments, the taxane is administered at about day 1 (e.g., day −3, day −2, day −1, day 1, day 2, or day 3) of a 21-day dosing cycle. ) to a subject or population of subjects. In some embodiments, paclitaxel is administered to the subject every three weeks. In some embodiments, paclitaxel is administered to the subject or subject population on about day 1 of a 21-day dosing cycle. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered to the subject or population of subjects every three weeks. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered to the subject or subject population on about day 1 of a 21-day dosing cycle.

Antimetabolites In some examples, an effective amount of an antimetabolite (eg, pemetrexed or gemcitabine) administered as part of the methods described herein is 10-10000 mg/m ² (eg, 20-8000 mg/m2). m ² , 30-5000 mg/m ² , 40-2500 mg/m ² , 50-2000 mg/m ² , 100-1500 mg/m ² , or 400-1200 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/ ^m2 , about 50 mg/ ^m2 , about 60 mg/ ^m2 , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/ ^m2 , about 100 mg/ ^m2 , about 110 mg/ ^m2 , about 120 mg/ ^m2 , about 130 mg/ ^m2 , about 140 mg/ ^m2 , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/ ^m2 , about 180 mg/ ^m2 , about 190 mg/ ^m2 , about 200 mg / ^m2 , about 250 mg/ ^m2 , about 300 mg/ ^m2 , about 400 mg/m2, about 500 mg/ ^m2 , about 600 mg/ ^m2 , about 700 mg/ ^m2 , about 800 ^{mg/m2 ,} about 900 mg/m ² , about 1000 mg/ ^m2 , about 1100 mg/ ^m2 , about 1200 mg/m2, about ¹²⁵⁰ mg/ ^m2 , about 1300 mg/ ^m2 , about 1400 mg/ ^m2 , about 1500 mg/ ^m2 , about 1750 mg/ ^m2 , about 2000 mg/ ^m2 , about 3000 mg/ ^m2 , about 4000 mg/ ^m2 , about 5000 mg/ ^m2 , about 6000 mg/ ^m2 , about 7000 mg/ ^m2 , about 8000 mg/ ^m2 , about 9000 mg/ ^m2 , or about 10000 mg/m ² ). In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is between about 500 mg/m ² and about 1250 mg/m ² (eg, 20 mg/m ² , 30 mg/m ² , 40 mg/m ^{2 )} . , 50 mg/ ^m2 , 60 mg/ ^m2 , 70 mg/ ^m2 , 80 mg/m2, 90 mg/ ^m2 , 100 mg/ ^m2 , 110 mg/ ^m2 , 120 mg/ ^{m2 ,} 130 mg/ ^m2 , 140 mg/ ^m2 , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , 1000 mg/m ² , 1100 mg/m ² , 1200 mg/m ² , 1250 mg/m ² , 1300 mg/m ² , 1400 mg/m ² , 1500 mg/ ^m2 , 1750 mg/ ^m2 , 2000 mg/ ^m2 , 3000 mg/ ^m2 , 4000 mg/ ^m2 , 5000 mg/ ^m2 , 6000 mg/ ^m2 , 7000 mg/ ^m2 , 8000 mg/ ^m2 , 9000 mg/ ^m2 , or 10000 mg/m ² ). In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 500 mg/m ² . In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 1000 mg/m ² . In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 1250 mg/m ² . In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 500 mg/m ² . In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 1000 mg/m ² . In some examples, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 1250 mg/m ² .

In some examples, the effective amount of paclitaxel administered as part of the methods described herein is 10-1000 mg/m ² (eg, 20-900 mg/m ² , 30-800 mg/m ² , 40 ~700 mg/ ^m2 , 50-650 mg ^{/ m2} , 100-600 mg/m2, or 200-550 mg/ ^m2 , such as about 20 mg/ ^m2 , about 30 mg/ ^m2 , about 40 mg/ ^m2 , about 50 mg / ^m2 , about 60 mg/ ^m2 , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/m2, about 100 mg ^{/m2, about 110 mg/m2, about 120 mg/m2 , about 130} mg/m ² , about 140 mg/ ^m2 , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/ ^m2 , about 180 mg/ ^m2 , about 190 mg/ ^m2 , about 200 mg/ ^m2 , about 250 mg/ ^m2 , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² ) be. In some examples, the effective amount of pemetrexed is about 500 mg/ ^m2 . In some examples, the effective amount of pemetrexed is about 500 mg/ ^m2 every 3 weeks. In some examples, the effective amount of pemetrexed is 500 mg/ ^m2 . In some examples, the effective amount of pemetrexed is 500 mg/ ^m2 every 3 weeks.

In some embodiments, pemetrexed is administered intravenously (eg, infusion over 10 minutes) to a subject or population of subjects. In some embodiments, pemetrexed is administered to the subject or subject population every three weeks. In some embodiments, pemetrexed is administered at about day 1 (eg, day −3, day −2, day −1, day 1, day 2, or day 3) of a 21-day dosing cycle. ) to a subject or population of subjects.

In some examples, the effective amount of an antimetabolite (eg, pemetrexed or gemcitabine) administered as part of the methods described herein is 10-10000 mg/m ² (eg, 20-8000 mg/m ² , 30-5000 mg/m ² , 40-2500 mg/m ² , 50-2000 mg/m ² , 100-1500 mg/m ² , or 400-1250 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/ ^m2 , about 50 mg/ ^m2 , about 60 mg/ ^m2 , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/ ^m2 , about 100 mg/ ^m2 , about 110 mg/ ^m2 , about 120 mg/m2 ^m2 , about 130 mg/ ^m2 , about 140 mg/ ^m2 , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/ ^m2 , about 180 mg/ ^m2 , about 190 mg/ ^m2 , about 200 mg/ ^m2 , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , about 1000 mg/ ^m2 , about 1100 mg/ ^m2 , about 1200 mg/ ^m2 , about 1250 mg/m2, about 1300 mg/ ^m2 , about 1400 mg/ ^m2 , about 1500 mg/ ^m2 , about 1750 mg/ ^m2 , about 2000 mg/ ^{m2 m2} , about 3000 mg/ ^m2 , about 4000 mg/ ^m2 , about 5000 mg/ ^m2 , about 6000 mg/ ^m2 , about 7000 mg/ ^m2 , about 8000 mg/ ^m2 , about 9000 mg/ ^m2 , or about 10000 mg/m2 ² (e.g. 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m 2 , 110 mg/m ² ) ^m2 , 120 mg/ ^m2 , 130 mg/ ^m2 , 140 mg/m2, 150 mg/ ^m2 , 160 mg/ ^m2 , 170 mg/ ^m2 , 180 mg/ ^m2 , 190 mg/ ^m2 , 200 mg/ ^m2 , 250 mg/ ^m2 m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 9 00 mg/m ² , 1000 mg/m ² , 1100 mg/m ² , 1200 mg/m ² , 1250 mg/m ² , 1300 mg/m ² , 1400 mg/m ² , 1500 mg/m ² , 1750 mg/m ² , 2000 mg/m ² , 3000 mg/ ^m2 , 4000 mg/ ^m2 , 5000 mg/ ^m2 , 6000 mg/ ^m2 , 7000 mg/ ^m2 , 8000 mg/ ^m2 , 9000 mg/ ^m2 , or 10000 mg/ ^m2 )). In some examples, the effective amount of gemcitabine is between about 500 mg/m ² and about 1250 mg/m ² . In some examples, the effective amount of gemcitabine is about 500 mg/ ^m2 . In some examples, the effective amount of gemcitabine is about 1000 mg/ ^m2 . In some examples, the effective amount of gemcitabine is about 1000 mg/m ² when given before carboplatin. In some examples, the effective amount of gemcitabine is about 1250 mg/m ² . In some examples, the effective amount of gemcitabine is about 1250 mg/m ² when given before cisplatin. In some examples, the effective amount of gemcitabine is about 1000 mg/m ² on days 1 and 8 of a 21-day dosing cycle. In some examples, the effective amount of gemcitabine is about 1250 mg/m ² on days 1 and 8 of a 21-day dosing cycle. In some examples, the effective amount of gemcitabine is 1000 mg/ ^m2 . In some examples, the effective amount of gemcitabine is 1000 mg/m ² when given before carboplatin. In some examples, the effective amount of gemcitabine is 1250 mg/ ^m2 . In some examples, the effective amount of gemcitabine is 1250 mg/m ² when administered prior to cisplatin. In some examples, the effective amount of gemcitabine is 1000 mg/m ² on days 1 and 8 of a 21-day dosing cycle. In some examples, the effective amount of gemcitabine is 1250 mg/m ² on days 1 and 8 of a 21-day dosing cycle.

In some embodiments, gemcitabine is administered intravenously (eg, infused over 30 minutes) to a subject or population of subjects. In some examples, gemcitabine is administered at about day 1 (e.g., day -3, day -2, day -1, day 1, day 2, or day 3) of a 21-day dosing cycle administered to a subject or population of subjects. In some examples, gemcitabine is administered on about day 1 and about day 8 of a 21-day dosing cycle (e.g., day 5, day 6, day 7, day 8, day 9, day 10, or day 11) to the subject or subject population.
Topoisomerase II inhibitor

In some examples, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m ² , 50 ~300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/ ^m2 , about 100 mg/ ^m2 , about 110 mg/ ^m2 , about 120 mg/ ^m2 , about 130 mg/ ^m2 , about 140 mg/ ^m2 , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/ ^m2 , about 180 mg/m2, about 190 mg/ ^m2 , about 200 mg/ ^m2 , about 250 mg/ ^m2 , about 300 ^{mg/m2 ,} about 400 mg /m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² (e.g. 20 mg/m ² , 30 mg/m 2 ² , 40 mg/ ^m2 , 50 mg/ ^m2 , 60 mg/ ^m2 , 70 mg/m2, 80 mg/ ^m2 , 90 mg/ ^m2 , 100 mg/ ^m2 , 110 mg/ ^m2 , 120 mg/ ^m2 , ¹³⁰ mg/m2 ² , 140 mg/ ^m2 , 150 mg/ ^m2 , 160 mg/m2, 170 mg/ ^m2 , 180 mg/ ^m2 , 190 mg/ ^m2 , 200 mg/ ^m2 , 250 mg ^{/m2 ,} 300 mg/ ^m2 , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , or 1000 mg/m ² )). In some examples, an effective amount of topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² . In some examples, the effective amount of a topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² on days 1-3 every 3 weeks. In some examples, the effective amount of a topoisomerase II inhibitor (eg, etoposide) is 100 mg/m ² on days 1-3 every 3 weeks.

In some embodiments, the topoisomerase II inhibitor (eg, etoposide) is administered to the subject intravenously (eg, infusion over 60 minutes).

In some examples, an effective amount of a topoisomerase II inhibitor (eg, doxorubicin) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m ² , 50 ~300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/ ^m2 , about 80 mg/ ^m2 , about 90 mg/ ^m2 , about 100 mg/ ^m2 , about 110 mg/ ^m2 , about 120 mg/ ^m2 , about 130 mg/ ^m2 , about 140 mg/ ^m2 , about 150 mg/ ^m2 , about 160 mg/ ^m2 , about 170 mg/ ^m2 , about 180 mg/m2, about 190 mg/ ^m2 , about 200 mg/ ^m2 , about 250 mg/ ^m2 , about 300 ^{mg/m2 ,} about 400 mg /m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² (e.g. 20 mg/m ² , 30 mg/m 2 ² , 40 mg/ ^m2 , 50 mg/ ^m2 , 60 mg/ ^m2 , 70 mg/m2, 80 mg/ ^m2 , 90 mg/ ^m2 , 100 mg/ ^m2 , 110 mg/ ^m2 , 120 mg/ ^m2 , ¹³⁰ mg/m2 ² , 140 mg/ ^m2 , 150 mg/ ^m2 , 160 mg/m2, 170 mg/ ^m2 , 180 mg/ ^m2 , 190 mg/ ^m2 , 200 mg/ ^m2 , 250 mg ^{/m2 ,} 300 mg/ ^m2 , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , or 1000 mg/m ² )). In some examples, the effective amount of topoisomerase II inhibitor (eg, doxorubicin) is about 60 mg/m ² . In some examples, the effective amount of topoisomerase II inhibitor (eg, doxorubicin) is 60 mg/m ² . In some examples, an effective amount of topoisomerase II inhibitor (eg, doxorubicin) is about 100 mg/m ² . In some examples, the effective amount of topoisomerase II inhibitor (eg, doxorubicin) is 100 mg/m ² . In some instances, the dose of the topoisomerase II inhibitor (eg, doxorubicin) is reduced or delayed to avoid toxicity.

In some embodiments, the topoisomerase II inhibitor (e.g., doxorubicin) is administered weekly, every two weeks, every three weeks, every four weeks, on days 1, 8 and 15 of each 21-day cycle, or every 28 days. It can be administered on days 1, 8 and 15 of a daily cycle. In some embodiments, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) may be administered every two weeks.

In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject as an IV bolus over 3-5 minutes. In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered as an IV infusion over 15-30 minutes. In some embodiments, the topoisomerase II inhibitor (eg, doxorubicin) is administered to the subject intravenously (eg, infusion over 60 minutes).

Alkylating Agents A therapeutically effective amount of an alkylating agent (eg, cyclophosphamide) administered to a human is from about 400 to about 800 mg/m ² (eg, about 400 mg/m2), whether or not by one or more administrations. ^m2 , about 425 mg/ ^m2 , about 450 mg/ ^m2 , about 475 mg/ ^m2 , about 500 mg/ ^m2 , about 525 mg/ ^m2 , about 550 mg/ ^m2 , about 575 mg/ ^m2 , about 600 mg/ ^m2 , about 625 mg/m ² , about 650 mg/m ² , about 675 mg/m ² , about 700 mg/m ² , about 725 mg/m ² , about 750 mg/m ² , about 775 mg/m ² , or about 800 mg/m ² ( For example, 400 mg/m ² , 425 mg/m ² , 450 mg/m ² , 475 mg/m ² , 500 mg/m ² , 525 mg/m ² , 550 mg/m ² , 575 mg/m ² , 600 mg/m ² , 625 mg/m ²⁾ , 650 mg/m ² , 675 mg/m ² , 700 mg/m ² , 725 mg/m ² , 750 mg/m ² , 775 mg/m ² , or 800 mg/m ^{2 )} . For example, in some embodiments about 600 mg/m ² of alkylating agent (eg, cyclophosphamide) is administered. In some embodiments, about 600 mg/m ² of alkylating agent (eg, cyclophosphamide) is administered every two weeks. In some embodiments, about 600 mg/m ² of cyclophosphamide is administered. In some embodiments, about 600 mg/m ² of cyclophosphamide is administered every two weeks. In some embodiments, 600 mg/m ² of alkylating agent (eg, cyclophosphamide) is administered every two weeks. In some embodiments, the alkylating agent (e.g., cyclophosphamide) is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks on days 1, 8 and 15 of each 21-day cycle for 28 days each. Administration can be on days 1 and 22 of a daily cycle, or on days 1, 8 and 15 of each 28-day cycle.

In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject as an IV bolus over 3-5 minutes. In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered as an IV infusion.

Colony Stimulating Factor Dosing A therapeutically effective amount of a colony stimulating factor (CSF) (e.g., G-CSF (e.g., pegfilgrastim or filgrastim) and GM-CSF (e.g., sargramostim)) administered to a human is about 1 to about 100 mg (eg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg). For example, in some embodiments about 6 mg is administered. In some aspects, a therapeutically effective amount of colony stimulating factor (CSF) (e.g., G-CSF (e.g., pegfilgrastim or filgrastim) and GM-CSF (e.g., sargramostim)) administered to a human is , in the range of 1-100 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg). In some embodiments, 6 mg of pegfilgrastim is administered. In some embodiments, the colony stimulating factor is pegfilgrastim. In some embodiments, the colony stimulating factor is filgrastim. In some embodiments, about 6 mg pegfilgrastim is administered.

A therapeutically effective amount of a colony-stimulating factor (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sargramostim)) administered to humans ranges from about 1 to about 400 mcg/kg/kg. daily range (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/day kg/day, about 75 mcg/kg/day, about 100 mcg/kg/day, about 125 mcg/kg/day, about 150 mcg/kg/day, about 175 mcg/kg/day, about 200 mcg/kg/day, about 225 mcg/kg /day, about 250 mcg/kg/day, about 275 mcg/kg/day, about 300 mcg/kg/day, about 325 mcg/kg/day, about 350 mcg/kg/day, about 375 mcg/kg/day, or about 400 mcg/kg / day). For example, in some embodiments about 250 mcg/m ² /day is administered. In some embodiments, the therapeutically effective amount of colony-stimulating factors (e.g., G-CSF (e.g., pegfilgrastim or filgrastim) and GM-CSF (e.g., sargramostim)) administered to humans is 1 ~400 mcg/kg/day range (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, 8mcg/kg/day, 9mcg/kg/day, 10mcg/kg/day, 15mcg/kg/day, 20mcg/kg/day, 25mcg/kg/day, 50mcg/kg/day, 75mcg/kg/day , 100 mcg/kg/day, 125 mcg/kg/day, 150 mcg/kg/day, 175 mcg/kg/day, 200 mcg/kg/day, 225 mcg/kg/day, 250 mcg/kg/day, 275 mcg/kg/day, 300 mcg /kg/day, 325 mcg/kg/day, 350 mcg/kg/day, 375 mcg/kg/day, or 400 mcg/kg/day). For example, in some embodiments 250 mcg/m ² /day is administered. In some embodiments, the colony-stimulating factor (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sargramostim)) is administered as a subcutaneous injection. In some embodiments, the colony stimulating factor is sargramostim. In some embodiments, sargramostim is administered to humans at a dose of about 250 mcg/m 2 /day. In some embodiments, sargramostim is administered to humans at a dose of 250 mcg/m 2 /day.

Administration of VEGF Antagonist In some examples, an effective amount of 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 (e.g., day 1 between about 0.01 mg/kg and about 50 mg/kg of the subject's body weight (e.g., between about 0.01 mg/kg and about 45 mg/kg, e.g., about 0.1 mg/kg) between about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg, such as between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as about between 10 mg/kg and about 20 mg/kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as about 15±2 mg/kg, about 15±1 mg/kg, about 15±0.5 mg/kg; about 15±0.2 mg/kg, or about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, the effective amount of the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every three weeks (e.g., between about 0.1 mg/kg and about 15 mg/kg, such as between about 0.5 mg/kg and about 15 mg/kg, such as between about 1 mg/kg and about 15 mg/kg, such as about 2.5 mg between about 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 15 mg/kg, such as between about 10 mg/kg and about 15 mg/kg. kg, such as between about 12.5 mg/kg and about 15 mg/kg, such as between about 14 mg/kg and about 15 mg/kg, such as about 15±1 mg/kg, such as about 15±0. 5 mg/kg, such as about 15±0.2 mg/kg, such as about 15±0.1 mg/kg, such as about 15 mg/kg). In some examples, an effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 15 mg/kg administered every 3 weeks. In some examples, the effective amount of the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is administered every two weeks (e.g., on day 1 of each 14-day dosing cycle (e.g., day 1 ± 3 days)). day), or about 0.01 mg of the subject's body weight on Day 1 (e.g., Day 1 ± Day 3) and Day 28 (e.g., Day 15 ± 3)) of each 15-day dosing cycle between about 0.01 mg/kg and about 45 mg/kg, such as between about 0.1 mg/kg and about 40 mg/kg, such as between about 1 mg/kg and about 35 mg/kg between about 2.5 mg/kg and about 30 mg/kg, such as between about 5 mg/kg and about 25 mg/kg, such as between about 7.5 mg/kg and about 20 mg/kg, such as between about 7.5 mg/kg and about 20 mg/kg. Between 5 mg/kg and about 15 mg/kg, such as between about 7.5 mg/kg and about 12.5 mg/kg, such as about 10±2 mg/kg, about 10±1 mg/kg, about 10±0.5 mg/kg kg, about 10±0.2 mg/kg, or about 10±0.1 mg/kg, such as about 10 mg/kg). In some examples, the effective amount of the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01 mg/kg and about 15 mg/kg of body weight of the subject every two weeks (e.g., between about 0.1 mg/kg and about 15 mg/kg, such as between about 0.5 mg/kg and about 15 mg/kg, such as between about 1 mg/kg and about 15 mg/kg, such as about 2.5 mg /kg and about 15 mg/kg, for example between about 5 mg/kg and about 15 mg/kg, for example between about 7.5 mg/kg and about 12.5 mg/kg, for example between about 8 mg/kg and about Between 12 mg/kg, such as between about 9 mg/kg and about 11 mg/kg, such as between about 9.5 mg/kg and about 10.5 mg/kg, such as about 10±1 mg/kg, such as about 10±0.5 mg/kg, such as about 10±0.2 mg/kg, such as about 10±0.1 mg/kg, such as about 10 mg/kg). In some examples, an effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 10 mg/kg administered every two weeks. In some examples, an effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 5 mg/kg administered every two weeks. In some examples, an effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 7.5 mg/kg administered every two weeks.

In some examples, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is between 0.01 mg/kg and 50 mg/kg of body weight (eg, 0.5 mg/kg) of the subject's body weight every three weeks. between 0.1 mg/kg and 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg; between 5 mg/kg and 25 mg/kg, such as between 10 mg/kg and 20 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as 15±2 mg/kg, 15±1 mg/kg kg, 15±0.5 mg/kg, 15±0.2 mg/kg, or 15±0.1 mg/kg, such as 15 mg/kg). In some examples, the effective amount of the EGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is between 0.01 mg/kg and 15 mg/kg of body weight of the subject (e.g., 0.1 mg/kg) every three weeks. between 0.5 mg/kg and 15 mg/kg, such as between 1 mg/kg and 15 mg/kg, such as between 2.5 mg/kg and 15 mg/kg, such as between 5 mg/kg between 15 mg/kg, such as between 7.5 mg/kg and 15 mg/kg, such as between 10 mg/kg and 15 mg/kg, such as between 12.5 mg/kg and 15 mg/kg, such as between 14 mg/kg and 15 mg/kg kg, such as 15±1 mg/kg, such as 15±0.5 mg/kg, such as 15±0.2 mg/kg, such as 15±0.1 mg/kg, such as 15 mg/kg). In some examples, an effective amount of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is a dose of 15 mg/kg administered every 3 weeks. In some examples, the effective amount of the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is between 0.01 mg/kg and 50 mg/kg of body weight of the subject (e.g., 0.01 mg/kg) every two weeks. /kg and 45 mg/kg, such as between 0.1 mg/kg and 40 mg/kg, such as between 1 mg/kg and 35 mg/kg, such as between 2.5 mg/kg and 30 mg/kg, such as 5 mg/kg and 25 mg/kg, such as between 7.5 mg/kg and 20 mg/kg, such as between 7.5 mg/kg and 15 mg/kg, such as between 7.5 mg/kg and 12.5 mg/kg, such as 10 ±2 mg/kg, 10±1 mg/kg, 10±0.5 mg/kg, 10±0.2 mg/kg, or 10±0.1 mg/kg, such as 10 mg/kg). In some examples, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is between 0.01 mg/kg and 15 mg/kg of body weight of the subject (eg, 0.01 mg/kg) every two weeks. between 1 mg/kg and 15 mg/kg, such as between 0.5 mg/kg and 15 mg/kg, such as between 1 mg/kg and 15 mg/kg, such as between 2.5 mg/kg and 15 mg/kg; between 5 mg/kg and 15 mg/kg, such as between 7.5 mg/kg and 12.5 mg/kg, such as between 8 mg/kg and 12 mg/kg, such as between 9 mg/kg and 11 mg/kg between, such as between 9.5 mg/kg and 10.5 mg/kg, such as 10±1 mg/kg, such as 10±0.5 mg/kg, such as 10±0.2 mg/kg, such as 10± 0.1 mg/kg, eg 10 mg/kg). In some examples, an effective amount of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is a dose of 10 mg/kg administered every two weeks. In some examples, an effective amount of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is a dose of 5 mg/kg administered every two weeks. In some examples, an effective amount of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is a dose of 7.5 mg/kg administered every two weeks.

In some examples, combination therapy (e.g., an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist A dose of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) administered with an antibody (e.g., atezolizumab) or co-treatment with an anti-PD-1 antagonist antibody (e.g., pembrolizumab) is administered as monotherapy. may be reduced compared to standard doses of PD-1 axis binding antagonists.

In some examples, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered intravenously. In some examples, the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) is administered for 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 min). Alternatively, in some embodiments, a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered subcutaneously.

G. Assessment of PD-L1 expression

PD-L1 expression can be assessed in a subject treated according to any of the methods, uses and compositions for use described herein. Methods, uses and compositions for use can include determining the expression level of PD-L1 in a biological sample (eg, tumor sample) obtained from a subject. In some examples, the patient has bladder cancer and the sample is a transurethral resection of bladder tumor (TURBT) sample. In some examples, the sample is a cystectomy or nephroureterectomy sample. In some examples, the sample is a segmentectomy, lobectomy, bilobectomy, or pneumonectomy sample. In some examples, the sample is a lymphadenectomy sample. In other examples, the level of expression of PD-L1 in a biological sample (eg, tumor sample) obtained from the subject has been determined before treatment or after treatment is initiated. PD-L1 expression can be determined using any suitable approach. For example, PD-L1 expression can be determined as described in US Patent Application Publication No. 20180030138A1 and US Patent Application Publication No. 20180037655A1. Any suitable tumor sample can be used, such as formalin-fixed paraffin-embedded (FFPE) tumor samples, archived tumor samples, fresh or frozen tumor samples.

For example, the expression of PD-L1 is relative to the percentage of tumor samples that are comprised of tumor-infiltrating immune cells that express detectable levels of PD-L1 expression, relative to tumor infiltration in tumor samples that express detectable levels of PD-L1 expression. It can be determined as a percentage of immune cells and/or as a percentage of tumor cells in a tumor sample that express a detectable level of PD-L1 expression. In any of the foregoing examples, the percentage of the tumor sample composed of tumor-infiltrating immune cells is the percentage of the tumor area covered by tumor-infiltrating immune cells (e.g., anti-PD- immune cells) in a section of the tumor sample obtained from the subject. as assessed by IHC using the L1 antibody (eg, the SP142 antibody). Any 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 of suitable anti-PD-L1 antibodies can be used. In some examples, the anti-PD-L1 antibody is SP142. In another example, 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, the tumor sample obtained from the subject has less than 1% tumor cells in the tumor sample, 1% or more tumor cells in the tumor sample, 1% to less than 5% tumor cells in the tumor sample, 5% or more of the tumor cells in the tumor sample, 5% to less than 50% of the tumor cells in the tumor sample, or 50% or more of the tumor cells in the tumor sample have detectable levels of PD-L1 expression.

In some examples, the tumor samples obtained from the subject are less than 1% of the tumor samples, more than 1% of the tumor samples, 1% to less than 5% of the tumor samples, more than 5% of the tumor samples, 5 of the tumor samples % to less than 10%, or greater than 10% of tumor samples with detectable PD-L1 expression levels in tumor-infiltrating immune cells.

In some aspects, the tumor sample obtained from the subject has a detectable PD-L1 expression level in tumor-infiltrating immune cells that constitute 5%-19% (e.g., TIC 5%-19%) of the tumor sample. , eg, have a PD-L1 expression level that is PD-L1 low. In some aspects, the tumor sample obtained from the subject has a detectable PD-L1 expression level in tumor-infiltrating immune cells that constitute ≧20% (e.g., TIC≧20%) of the tumor sample, e.g., Have a PD-L1 expression level that is PD-L1 high. In some embodiments, a tumor sample determined to have a TIC of 5% or greater is comparable to a CPS of 1 or greater.

In some examples, tumor samples can be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or tumor cells according to the criteria for diagnostic assessment shown in Table 1 and/or Table 2, respectively.

In some examples, in any of the methods, uses or compositions for use described herein, the subject has a PD-L1-selected tumor (e.g., PD-L1-expressing tumor-infiltrating immune cells (ICs) The percentage of tumor area occupied is greater than or equal to 5% in tumor samples as determined by IHC using the SP 142 antibody. In some examples, a PD-L1-selected tumor is a tumor that has 5% or more of the tumor area occupied by PD-L1-expressing immune cells (ICs) as determined by an immunohistochemistry (IHC) assay. . In some examples, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3 or 28-8. In some examples, the IHC assay uses the anti-PD-L1 antibody SP142. In some examples, the IHC assay uses the anti-PD-L1 antibody SP263. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some examples, the IHC assay uses the anti-PD-L1 antibody 28-8.

In some examples, the IC has been determined to be 5% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be 2 or 3 (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC has been determined to be 1% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC has been determined to be 10% or greater (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 50% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay). In some examples, the IC has been determined to be greater than or equal to 1% and less than 30% (eg, as determined using the Ventana (SP142) PD-L1 IHC assay).

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

In some examples, in any of the methods, uses or compositions for use described herein, the subject has a PD-L1-selected tumor (e.g., PD-L1 high (e.g., SP 263 antibody) PD-L1 Tumor Proportion Score (TPS) of 50% or more in the tumor sample as determined by IHC using In some examples, the PD-L1-selected tumor is a PD-L1-highly selected tumor. In some examples, a PD-L1-selected tumor is a tumor determined to have 50% or greater TPS by an immunohistochemistry (IHC) assay, hi some examples, the IHC assay is an anti-PD-L1 antibody Use SP263, SP142, 22C3 or 28-8 In some examples, the IHC assay uses the anti-PD-L1 antibody SP263 In some examples, the IHC assay uses the anti-PD-L1 antibody SP142 In some examples, the IHC assay uses anti-PD-L1 antibody 22C3 In some examples, TPS is 50% (eg, as determined using the Ventana (SP263) PD-L1 IHC assay) In some instances, TPS has been determined to be less than 50% (eg, as determined using the Ventana (SP263) PD-L1 IHC assay). In some examples, TPS is determined to be greater than or equal to 1% (eg, as determined using the Ventana (SP263) PD-L1 IHC assay). (SP263) as determined using the PD-L1 IHC assay) has been determined to be greater than or equal to 1% and less than 50%.

In some examples, in any of the methods, uses, or compositions for use described herein, the tumor sample obtained from the individual has a detectable PD-L1 protein expression level. In some examples, the detectable PD-L1 protein expression level was determined by an IHC assay. In some examples, the IHC assay uses the anti-PD-L1 antibody SP263. In some examples, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction of 50% or greater of the tumor sample. In some examples, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction of less than 50% of the tumor sample. In some examples, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction of greater than or equal to 1% and less than 50% of the tumor sample.

In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some examples, the IHC assay is the pharmDx 22C3 IHC assay. In some examples, the PD-L1 positive tumor cell fraction is greater than or equal to 50% as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has a composite positive score (CPS) of 10 or greater in the tumor sample, eg, as determined using the anti-PD-L1 anti-2 body 2C3 as part of the pharmDx 22C3 IHC assay, or Determined to have a Tumor Proportion Score (TPS) of 1% or greater. In some embodiments, the tumor sample has 10 or more CPS or 1% or more in the tumor sample, eg, as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. It has been determined to have a TPS of less than 50%. In some embodiments, the tumor sample exhibits 20 or more CPS or 50% or more TPS in the tumor sample, eg, as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. determined to have In some embodiments, a tumor sample determined to have 1 or more CPS corresponds to a TIC of 5% or more.

In some examples, the IHC assay uses the anti-PD-L1 antibody 28-8. In some examples, the IHC assay is the pharmDx 28-8 IHC assay. In some examples, the PD-L1 positive tumor cell fraction is greater than or equal to 50% as determined by positive staining with anti-PD-L1 antibody 28-8.

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

H. Assessing TIGIT Expression Expression of TIGIT can be assessed in subjects treated according to any of the methods, uses and compositions for use described herein. Methods, uses and compositions for use can include determining the expression level of TIGIT in a biological sample (eg, tumor sample) obtained from a subject. In other examples, the level of expression of TIGIT in a biological sample (eg, tumor sample) obtained from the subject has been determined prior to or after treatment initiation. TIGIT expression can be determined using any suitable approach. Any suitable tumor sample can be used, such as formalin-fixed paraffin-embedded (FFPE) tumor samples, archived tumor samples, fresh or frozen tumor samples.

For example, the expression of TIGIT can be measured with respect to the percentage of tumor-infiltrating immune cells in a tumor sample that express a detectable expression level of TIGIT, relative to the percentage of tumor-infiltrating immune cells in a tumor sample that express a detectable expression level of TIGIT. and/or as the percentage of tumor cells in a tumor sample that express a detectable expression level of TIGIT. In any of the foregoing examples, the proportion of a tumor sample composed of tumor-infiltrating immune cells, e.g., as assessed by IHC using an anti-TIGIT antagonist antibody, is It should be understood that it may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells. Any suitable anti-TIGIT antagonist antibody can be used. In some examples, the anti-TIGIT antagonist antibody is 10A7 (WO 2009/126688 A3; US Patent No. 9,499,596).

I. Assessment of EGFR and ALK Abnormalities In some examples, in any of the methods, uses, or compositions for use described herein, the subject has epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some examples, in any of the methods, uses or compositions for use described herein, the subject has an EGFR gene mutation (e.g., a sensitizing or activating EGFR gene mutation) or an ALK gene rearrangement. No organization (eg, ALK fusion oncogene). In some examples, the subject has a US East Coast Clinical Trials Group (ECOG) Performance (PS) of 0 or 1.

Methods for detecting mutational status EGFR and ALK are well known in the art and include, but are not limited to, Frampton et al. (Nature Biotechnology. 31(11): 1023-1033, 2013) using next-generation sequencing methods such as targeted gene pull-down and sequencing methods described in Clinical samples (e.g., tumor biopsies or blood samples). (eg, circulating tumor DNA in blood)). Such next-generation sequencing methods employ the use of small samples (e.g., from small core needle biopsies, fine needle aspirates, and/or cell blocks) or fixed samples (e.g., formalin-fixed paraffin-embedded (FFPE) samples). use 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 allowing be able to. Other methods for detecting EGFR and ALK mutation status include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods. An exemplary method for detecting the mutational status of ALK is disclosed in US Pat. No. 9,651,555, which is incorporated herein by reference in its entirety. In some examples, the VENTANA® anti-ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.

In some examples 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 described in US Patent Application Publication No. 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 examples, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (eg, mutations in exon 18, exon 19, exon 20 and/or exon 21). In some examples, the sensitizing EGFR mutation is a deletion of exon 19 (del19). In another example, the sensitizing EGFR mutation is the L858R point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the G719X point mutation in exon 18, where "X" is most commonly C, A, or S. In some examples, the sensitizing EGFR mutation is the G719S point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the G719A point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the S720F point mutation in exon 18. In some examples, the sensitizing EGFR mutation is the L861Q point mutation in exon 21. In some examples, the sensitizing EGFR mutation is the L861R point mutation in exon 21. In another example, the sensitizing EGFR mutation is the T790M point mutation. In some examples, the sensitizing EGFR mutation is the E709X point mutation, where "X" is most commonly K, A, or H. In some examples, the sensitizing EGFR mutation is the S768I point mutation.

In some examples of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are well known in the art and are described in US Pat. No. 9,651,555 and Du et al. (Thoracic Cancer. 9:423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, ALK gene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways to increase cell proliferation and survival. In some instances, the ALK gene rearrangement results in the formation of a fusion oncogene, EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC , TMP4, and MSN. In some instances, the ALK gene rearrangement is an EML4 rearrangement with ALK, resulting in the formation of the fusion oncogene EML4-ALK.

IV. Exemplary Anti-TIGIT Anti-Agonist Antibodies, PD-1 Axis Binding Antagonists, and Other Agents Useful for Treating Subjects (eg, Humans) Having Cancer According to the Methods, Uses and Compositions for Use of the Invention Exemplary anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, chemotherapeutic agents, colony stimulating factors and VEGF antagonists are described herein.

A. Exemplary Anti-TIGIT Antagonist Antibodies The present invention provides anti-TIGIT antagonist antibodies useful for treating cancer in a subject (eg, human).

In some examples, the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

In certain examples, the anti-TIGIT antagonist antibody comprises at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) a HVR comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1)- (b) HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO:2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3); (d) 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 of the above HVRs Combinations of one or more, and at least about 90% sequence identity to any one of SEQ ID NOs: 1-6 (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%) , 98% or 99% identity).

In some examples, any of the anti-TIGIT antagonist antibodies include (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2) -H2; (c) HVR-H3 containing the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3); (d) HVR-L1 containing the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO:4), (e) the amino acids of WASTRES (SEQ ID NO:5) and (f) HVR-L3, which contains the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).いくつかの例では、抗ＴＩＧＩＴアンタゴニスト抗体は、ＥＶＱＬＱＱＳＧＰＧＬＶＫＰＳＱＴＬＳＬＴＣＡＩＳＧＤＳＶＳＳＮＳＡＡＷＮＷＩＲＱＳＰＳＲＧＬＥＷＬＧＫＴＹＹＲＦＫＷＹＳＤＹＡＶＳＶＫＧＲＩＴＩＮＰＤＴＳＫＮＱＦＳＬＱＬＮＳＶＴＰＥＤＴＡＶＦＹＣＴＲＥＳＴＴＹＤＬＬＡＧＰＦＤＹＷＧＱＧＴＬＶＴＶＳＳ（配列番号１７）と少なくとも９０％（例えば、少なくとも９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％又は９９％の配列同一性）を有するアミノ酸配列若しくはその配列、又はＱＶＱＬＱＱＳＧＰＧＬＶＫＰＳＱＴＬＳＬＴＣＡＩＳＧＤＳＶＳＳＮＳＡＡＷＮＷＩＲＱＳＰＳＲＧＬＥＷＬＧＫＴＹＹＲＦＫＷＹＳＤＹＡＶＳＶＫＧＲＩＴＩＮＰＤＴＳＫＮＱＦＳＬＱＬＮＳＶＴＰＥＤＴＡＶＦＹＣＴＲＥＳＴＴＹＤＬＬＡＧＰＦＤＹＷＧＱＧＴＬＶＴＶＳＳ（配列番号１８）と少なくとも９０％（例えば、少なくとも９１％、９２％、９３％、９４％、９５％、９６％、９７％ 、９８％又は９９％の配列同一性）を有するアミノ酸配列若しくはその配列を有するＶＨドメイン、及び／又はＤＩＶＭＴＱＳＰＤＳＬＡＶＳＬＧＥＲＡＴＩＮＣＫＳＳＱＴＶＬＹＳＳＮＮＫＫＹＬＡＷＹＱＱＫＰＧＱＰＰＮＬＬＩＹＷＡＳＴＲＥＳＧＶＰＤＲＦＳＧＳＧＳＧＴＤＦＴＬＴＩＳＳＬＱＡＥＤＶＡＶＹＹＣＱＱＹＹＳＴＰＦＴＦＧＰＧＴＫＶＥＩＫ配列番号１９）と少なくとも９０％の配列同一性（例えば、少なくとも９１％、９２％、９３ %, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) or an amino acid sequence having that sequence. In some examples, the anti-TIGIT antagonist antibody has at least 90% sequence identity to SEQ ID NO: 17 or a sequence thereof (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, or 99% sequence identity) and/or at least 90% sequence identity (e.g., at least 91%, 92%, 93%) with SEQ ID NO: 19 or a sequence thereof , 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some examples, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO:17 and a VL domain comprising the amino acid sequence of SEQ ID NO:19. In some examples, the anti-TIGIT antagonist antibody has at least 90% sequence identity with SEQ ID NO: 18 or a sequence thereof (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, or 99% sequence identity) and/or at least 90% sequence identity (e.g., at least 91%, 92%, 93%) with SEQ ID NO: 19 or a sequence thereof , 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some examples, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO:18 and a VL domain comprising the amino acid sequence of SEQ ID NO:19.

いくつかの例では、抗ＴＩＧＩＴアンタゴニスト抗体は、重鎖及び軽鎖配列を含み、（ａ）重鎖は、アミノ酸配列：ＥＶＱＬＱＱＳＧＰＧＬＶＫＰＳＱＴＬＳＬＴＣＡＩＳＧＤＳＶＳＳＮＳＡＡＷＮＷＩＲＱＳＰＳＲＧＬＥＷＬＧＫＴＹＹＲＦＫＷＹＳＤＹＡＶＳＶＫＧＲＩＴＩＮＰＤＴＳＫＮＱＦＳＬＱＬＮＳＶＴＰＥＤＴＡＶＦＹＣＴＲＥＳＴＴＹＤＬＬＡＧＰＦＤＹＷＧＱＧＴＬＶＴＶＳＳＡＳＴＫＧＰＳＶＦＰＬＡＰＳＳＫＳＴＳＧＧＴＡＡＬＧＣＬＶＫＤＹＦＰＥＰＶＴＶＳＷＮＳＧＡＬＴＳＧＶＨＴＦＰＡＶＬＱＳＳＧＬＹＳＬＳＳＶＶＴＶＰＳＳＳＬＧＴＱＴＹＩＣＮＶＮＨＫＰＳＮＴＫＶＤＫＫＶＥＰＫＳＣＤＫＴＨＴＣＰＰＣＰＡＰＥＬＬＧＧＰＳＶＦＬＦＰＰＫＰＫＤＴＬＭＩＳＲＴＰＥＶＴＣＶＶＶＤＶＳＨＥＤＰＥＶＫＦＮＷＹＶＤＧＶＥＶＨＮＡＫＴＫＰＲＥＥＱＹＮＳＴＹＲＶＶＳＶＬＴＶＬＨＱＤＷＬＮＧＫＥＹＫＣＫＶＳＮＫＡＬＰＡＰＩＥＫＴＩＳＫＡＫＧＱＰＲＥＰＱＶＹＴＬＰＰＳＲＥＥＭＴＫＮＱＶＳＬＴＣＬＶＫＧＦＹＰＳＤＩＡＶＥＷＥＳＮＧＱＰＥＮＮＹＫＴＴＰＰＶＬＤＳＤＧＳＦＦＬＹＳＫＬＴＶＤＫＳＲＷＱＱＧＮＶＦＳＣＳＶＭＨＥＡＬＨＮＨＹＴＱＫＳＬＳＬＳＰＧＫ（配列番号３３）を含み；（ｂ）軽鎖は、アミノ酸配列：ＤＩＶＭＴＱＳＰＤＳＬＡＶＳＬＧＥＲＡＴＩＮＣＫＳＳＱＴＶＬＹＳＳＮＮＫＫＹＬＡＷＹＱＱＫＰＧＱＰＰＮＬＬＩＹＷＡＳＴＲＥＳＧＶＰＤＲＦＳＧＳＧＳＧＴＤＦＴＬＴＩＳＳＬＱＡＥＤＶＡＶＹＹＣＱＱＹＹＳＴＰＦＴＦＧＰＧＴＫＶＥＩＫＲＴＶＡＡＰＳＶＦＩＦＰＰＳＤＥＱＬＫＳＧＴＡＳＶＶＣＬＬＮＮＦＹＰＲＥＡＫＶＱＷＫＶＤＮＡＬＱＳＧＮＳＱＥＳＶＴＥＱＤＳＫＤＳＴＹＳＬＳＳＴＬＴＬＳＫＡＤＹＥＫＨＫＶＹＡＣＥＶＴＨＱＧＬＳＳＰＶＴＫＳＦＮＲＧＥＣ（配列番号３４）を含む。

In some examples, the anti-TIGIT antagonist antibody further comprises at least one, two, three or four of the following light chain variable region framework regions (FR): FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLG ERATINC FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO:8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO:9); and/or comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO:10) FR-L4, or a combination of one or more of the above FRs, and at least about 90% sequence identity to any one of SEQ ID NOs: 7-10 (e.g., 90%, 91%, 92%, 93%, 94% , 95%, 96%, 97%, 98% or 99% identity) thereof. In some examples, for example, the antibody comprises FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO:7), FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO:8), GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO:9) and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

In some examples, the anti-TIGIT antagonist antibody further comprises 1, 2, 3, or 4 heavy chain variable region FRs: X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (where 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 WGQGTLVTVSS (SEQ ID NO: 14) ), or one or more of the above FRs, with at least about 90% sequence identity to any one of SEQ ID NOS: 11-14 (e.g., 90%, 91%, 92%, 93% %, 94%, 95%, 96%, 97%, 98% or 99% identity). The anti-TIGIT antagonist antibody can further comprise, for example, one, two, three, or four heavy chain variable region FRs: FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15): WIRQSPSRGLEWLG (sequence FR-H2 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 one of the above FRs. and at least about 90% sequence identity to any one of SEQ ID NOS: 12-15 (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%) % or 99% identity) with one or more variants thereof. In some examples, the anti-TIGIT antagonist antibody is 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); RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO:13) FR-H3 containing the sequence; and FR-H4 containing the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In another example, for example, the anti-TIGIT antagonist antibody can further comprise 1, 2, 3, or 4 heavy chain variable region FRs: FR- H1: FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14); or at least about 90% sequence identity with any one of SEQ ID NOs: 12-14 and 16 with one or more of the above FRs (e.g., 90%, 91%, 92%, 93%, 94%, 95%, A combination with one or more variants thereof having 96%, 97%, 98% or 99% identity). In some examples, the anti-TIGIT antagonist antibody comprises FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO:16), FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO:12); RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO:13) FR-H3 containing the sequence; and FR-H4 containing the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

In another aspect, anti-TIGIT antagonist antibodies are provided, wherein the antibody comprises a VH as in any example above and a VL as in any example above, wherein one or both of the variable domain sequences are post-translationally modified. include.

In some examples, any one of the anti-TIGIT antagonist antibodies described above can bind to rabbit TIGIT in addition to human TIGIT. In some examples, any one of the anti-TIGIT antagonist antibodies described above can bind to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some examples, any one of the anti-TIGIT antagonist antibodies described above can bind to human TIGIT, cynomolgus monkey TIGIT and rabbit TIGIT. In some examples, any one of the anti-TIGIT antagonist antibodies described above can bind to human TIGIT, cynomolgus TIGIT, and rabbit TIGIT, but not mouse TIGIT.

In some examples, the anti-TIGIT antagonist antibody binds human TIGIT with a K _D of about 10 nM or less and binds cynomolgus monkey TIGIT with a K _D of about 10 nM or less (eg, a K _D of about 0.1 nM to about 1 nM). and binds to cynomolgus monkey TIGIT with a K _D of about 0.5 nM to about 1 nM, for example, binds human TIGIT with a K _D of about 0.1 nM or less and binds to human TIGIT with a K _D of about 0.5 nM or less. binds to cynomolgus monkey TIGIT).

In some examples, the anti-TIGIT antagonist antibody specifically binds to TIGIT and inhibits or blocks TIGIT interaction with the poliovirus receptor (PVR) (e.g., the antagonist antibody binds TIGIT to the PVR). mediated intracellular signaling). In some examples, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or less (eg, 1 nM to about 10 nM). In some examples, an anti-TIGIT antagonist antibody specifically binds to TIGIT and inhibits or blocks TIGIT interaction with PVR without affecting PVR-CD226 interaction. In some examples, the antagonist antibody inhibits or blocks binding of cynomolgus monkey TIGIT to cynomolgus monkey PVR with an IC50 value of 50 nM or less (eg, 1 nM to about 50 nM, eg, 1 nM to about 5 nM). In some examples, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction between CD226 and TIGIT. In some examples, an anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

In some examples, the methods or uses described herein can comprise using or administering an isolated anti-TIGIT antagonist antibody that competes with any of the anti-TIGIT antagonist antibodies described above for binding to TIGIT. . For example, the method 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) SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) KSSQTVLYSSSNNKKYLA (sequence (e) HVR-L2 containing the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). be done. The methods described herein can also include administering an isolated anti-TIGIT antagonist antibody that binds to the same epitope as the anti-TIGIT antagonist antibody described above.

In some aspects, the anti-TIGIT antagonist antibody is an antibody with intact Fc-mediated effector functions (e.g., tiragolumab, vivostolimab, etiglimab, EOS084448 or TJ-T6) or enhanced effector functions (e.g., SGN-TGT). be.

In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector functions (eg, domvanalimab, BMS-986207, ASP8374, or COM902).

In some aspects, the anti-TIGIT antagonist antibody is an IgG1 class antibody, such as tiragolumab, vivostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308.

In other aspects, the anti-TIGIT antagonist antibody is an IgG4 class antibody, such as ASP8374 or COM902.

Anti-TIGIT antagonist antibodies (eg, tiragolumab) useful in the invention, including compositions containing such antibodies, are PD-1 axis binding antagonists (eg, PD-L1 binding antagonists (eg, anti-PD-L1 antagonists) antibodies (eg, atezolizumab), PD-1 binding antagonists (eg, anti-PD-1 antagonist antibodies, such as pembrolizumab) and PD-L2 binding antagonists (eg, anti-PD-L2 antagonist antibodies)).

In some embodiments, an anti-TIGIT antagonist antibody functions to inhibit TIGIT signaling. In some embodiments, an anti-TIGIT antagonist antibody inhibits binding of TIGIT to its binding partner. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2) and CD113 (PVRL3 or Nectin-3). In some embodiments, an anti-TIGIT antagonist antibody can inhibit binding between TIGIT and CD155. In some embodiments, an anti-TIGIT antagonist antibody can inhibit binding between TIGIT and CD112. In some embodiments, an anti-TIGIT antagonist antibody inhibits binding between TIGIT and CD113. In some embodiments, an anti-TIGIT antagonist antibody inhibits TIGIT-mediated cell signaling of immune cells. In some embodiments, an anti-TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (eg, FcγRs).

In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv and (Fab') ₂ fragments. In some embodiments, the anti-TIGIT antibody is a humanized antibody. In some embodiments, the anti-TIGIT antibody is a human antibody. In some embodiments, an anti-TIGIT antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

In some embodiments, the anti-TIGIT antibody is tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201), EOS884448 (EOS-448), SEA-TGT (SGN-TGT) , BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, Dombanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131, NB6253, HLX301, HLX53, SL-9258 TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti-TIGIT antibody consists of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201), EOS-448, and SEA-TGT (SGN-TGT) Selected from the group. The anti-TIGIT antibody can be tiragolumab (MTIG7192A, RG6058 or RO7092284).

Non-limiting examples of anti-TIGIT antibodies useful in the methods disclosed herein and methods of making them can be found in PCT Publication Nos. WO2018183889A1, WO2019129261A1, WO2016106302A9 , WO2018033798A1, WO2020020281A1, WO2019023504A1, WO2017152088A1, WO2016028656A1, WO2017030823A2, WO2018204405A1, WO2019152574A1 and WO2020041541A2; US 10,189,902, US 10,213,505, US 10,124,061, US 10,537 , 633 and U.S. Patent No. 10,618,958; incorporated herein by. Further non-limiting examples of anti-TIGIT antibodies useful in the methods disclosed herein and methods of making the same can be found in PCT Publication Nos. WO2018204363A1, WO2018047139A1, No. 2019175799 A2, International Publication No. 2018022946 A1, International Publication No. 2015143343 A2, International Publication No. 2018218056 A1, International Publication No. 2019232484 A1, International Publication No. 2019079777 A1, International Publication No. 2018128939 A1, International Publication No. 2017196867 A1, International Publication No. 2019154415 A1, International Publication No. 2019062832 A1, International Publication No. 2018234793 A3, International Publication No. 2018102536 A1, International Publication No. 2019137548 A1 , International Publication No. 2019129221 A1, International Publication No. 2018102746 A1, International Publication No. 2018160704 A9, International Publication No. 2020041541 A2, International Publication No. 2019094637 A9, International Publication No. 2017037707 A1, International Publication No. 2019168382 A1, International Publication No. 2006124667 A3, International Publication No. 2017021526 A1, International Publication No. 2017184619 A2, International Publication No. 2017048824 A1, International Publication No. 2019032619 A9, International Publication No. 2018157162A1, WO2020176718A1, WO2020047329A1, WO2020047329A1, WO2018220446A9; U.S. Patent No. 9,617,338, U.S. Patent No. 9 , 567,399, U.S. Patent Nos. 10,604,576 and 9,994,637; US2019/0382477, US2019/0010246, US2020/0164071, US2020/0131267, US2019 /0338032, U.S. Patent Application Publication No. 2019/0330351, U.S. Patent Application Publication No. 2019/0202917, U.S. Patent Application Publication No. 2019/ 0284269, US2018/0155422, US2020/0040082, US2019/0263909, US2018/0185480, US2019/0185480 0375843, US2017/0037133, US2019/0077869, US2019/0367579, US2020/0222503, US2020/ 0283496, CN109734806A and CN110818795A, each of which is incorporated herein by reference.

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, domvanalimab (AB154), vibostolimab (MK-7684) and SEA-TGT (SGN-TGT). Additional anti-TIGIT antibodies useful in the methods disclosed herein include AGEN 1307; AGEN 1777; antibody clones pab2197 and pab2196 (Agenus Inc.); antibody clones TBB8, TDC8, 3TB3, 5TB10, and D1Y1A (Anhui Anke Biotechnology Group Co. Ltd.), antibody clones MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB 7, MAB8, MAB9, MAB 10, MAB 11, MAB 12, MAB 13, MAB 14, MAB 15, MAB 16, MAB 17 , MAB 18, MAB19, MAB20, MAB21 (Astellas Pharma/Potenza Therapeutics), antibody clones hu1217-1-1 and hu1217-2-2 (BeiGene), antibody clones 4D4 and 19G (Brigham & Women's Hospital), antibody clone 11G11, 10D7, 15A6, 22G2, TIGIT G2a, and TIGIT G1 D265A, (including such antibodies with modified heavy chain constant regions (Bristol-Myers Squibb)); antibody clone 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 clone T-01, T- 02, T-03, T-04, T-05, T-06, T-07, T-08, T-09, and T-10 (Gensun BioPharma Inc.); antibody clones 1H6, 2B11, 3A10, 4A5 , 4A9, 4H5, 6A2, 6B7, 7F4, 8E1, 8G3, 9F4, 9G6, 10C1, 10F10, 11G4, 12B7, 12C8, 15E9, 16C11, 16D6, and 16E10 (Hefei Ruida Immunological Drugs Research Co. Institute); Antibody clones h3C5H1, h3C5H2, h3C5H3, h3C5H4, h3C5H3-1, h3C5H3-2, h3C5H3-3, h3C5L1 and h3C5L2 (IGM Biosciences Inc.); , 222H4, 327C9, 342A9, 344F2, 349H6, and 350D10 (I-Mab Biopharma); 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.); (iTeos Therapeutics); m1707, m1708, m1709, m1710, m1711, h1707, h1708, h1709, h1710, and h1711 (Jiangsu Hengrui Medicine Co., Ltd.). Ltd. ); antibody clones TIG1, TIG2, and TIG3 (JN Biosciences LLC); , K16, K17, K18, K19, K20, K21, K22, K23 Kymab TIGIT (antibody 2), and Tool TIGIT (antibody 4) (Kymab Limited); in-house anti-TIGIT with bispecific antibody 1D05/1D05 (anti-PD-L1) native variable domain and Kymab TIGIT antigen binding site (ABS) domain (bispecific 1), In-house anti-TIGIT/1D05 with Kymab TIGIT native variable domain and 1D05 ABS domain (bispecific 2), Tool anti-TIGIT/Tool anti-PD-L1 (bispecificity 3) with Toon anti-TIGIT native variable domain and Tool anti-PD-L1 ABS domain, Tool anti-PD-L1 native variable domain and Tool anti-TIGIT ABS domain Tool anti-PD-L1/Tool anti-TIGIT (bispecificity 4) (Kymab Limited); antibody clones and cloned antibodies 14D7, 26B10, Hu14D7, Hu26B10, 14A6, Hu14A6, 28H5, 31C6, Hu31C6, 25G10, MBS43, ３７Ｄ１０、１８Ｇ１０、１１Ａ１１、ｃ１８Ｇ１０、及びＬＢ１５５．１４Ａ６．Ｇ２．Ａ８（Ｍｅｒｃｋ）；エチジリマブ（ＯＭＰ－３１３Ｍ３２）（Ｍｅｒｅｏ ＢｉｏＰｈａｒｍａ）；抗体クローン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, and AS19886-Fc (Nanjing Legend Biotechnology Co. Ltd. ); antibody clones ARE clones: Ab58, Ab69, Ab75, Ab133, Ab177, Ab122, Ab86, Ab180, Ab83, Ab26, Ab20, Ab147, Ab12, Ab66, Ab176, Ab96, Ab123, Ab109, Ab149, Ab34, Ab61, Ab64 , Ab105, Ab108, Ab178, Ab166, Ab29, Ab135, Ab171, Ab194, Ab184, Ab164, Ab183, Ab158, Ab55, Ab136, Ab39, Ab159, Ab151, Ab139, Ab107, Ab36, Ab128, Ab1953, Ab128, Ab1953 , Ab165, Ab155, Ab19, Ab6, Ab187, Ab179, Ab65, Ab114, Ab102, Ab94, Ab163, Ab110, Ab80, Ab92, Ab117, Ab162, Ab121, Ab195, Ab84, Ab161, Ab198, Ab17, Ab198, Ab198, Ab198, Ab24 , Ab196, Ab51, Ab91, Ab185, Ab23, Ab7, Ab95, Ab100, Ab140, Ab145, Ab150, Ab168, Ab54, Ab77, Ab43, Ab160, Ab82, Ab189, Ab17, Ab103, Ab18, Ab130, Ab134, Ab134 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, Ab9, Ab9, Ab9, Ab50 , Ab3, Ab148, Ab124, Ab22, Ab41, Ab119, Ab157, Ab27, Ab15, Ab191, Ab190, Ab79, Ab181, Ab146, Ab167, Ab88, Ab199, Ab71, Ab85, Ab59, Ab141, Ab68, Ab463, Ab148 , Ab175, Ab156, Ab63, Ab11, Ab182, Ab89, Ab8, Ab101, A b25, Ab154, Ab21, Ab111, Ab118, Ab173, Ab38, Ab76, Ab131, Ab1, Ab67, Ab70, Ab170, Ab30, Ab93, Ab142, Ab104, Ab112, Ab35, Ab126, and Ab125 (Rigel Pharmaceuticals, ); CASC-674 (Seattle Genetics); 25B, 25C, 25D, 25E, 27, 54, 13 IgG2a defucosylation, 13 hIgG1 wild-type, and 13 LALA-PG (Seattle Genetics); JS006 (Shanghai Junshi Biosciences Ltd.); anti-TIGIT Fc antibody and bispecific Antibodies PD1×TIGIT (Xencor), antibody clones VSIG9#1 (Vsig9.01) and 258-CS1#4 (#4) (Yissum Research Development Company of The Hebrew University Of Jerusalem 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.); (E9400), and 318.77.1.10 (ZymoGenetics, Inc). is mentioned.

In some embodiments, the anti-TIGIT antibody is tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448 ), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT). ASP874 (PTZ-201) is an anti-TIGIT monoclonal antibody described in PCT Publication No. WO2018183889A1 and US Patent Application Publication No. 2020/0095324. BGB-A 1217 is an anti-TIGIT antibody described in PCT Publication No. WO2019129261 A1. BMS-986207 (ONO-4686) is an anti-TIGIT antibody described in PCT Publication No. WO2016106302A9, US Patent No. 10,189,902, and US Patent Application Publication No. 2019/0112375 be. . COM902 (CGEN-15137) is an anti-TIGIT antibody described in PCT Publication No. WO2018033798A1 and US Pat. Nos. 10,213,505 and 10,124,061. IBI939 is an anti-TIGIT antibody described in PCT Publication No. WO2020020281A1. EOS884448 (EOS-448) is an anti-TIGIT antibody described in PCT Publication No. WO2019023504A1. Domvanalimab (AB 154) is an anti-TIGIT monoclonal antibody described in PCT Publication No. WO2017152088A1 and US Pat. No. 10,537,633. Vivostolimab (MK-7684) can be found in PCT Publication Nos. WO2016028656A1, WO2017030823A2, WO2018204405A1, and/or WO2019152574A1, U.S. Patent No. 10,618, 958 and the anti-TIGIT antibody described in US2018/0371083. SEA-TGT (SGN-TGT) is an anti-TIGIT antibody as described in PCT Publication No. WO2020041541A2 and US Patent Application Publication No. 2020/0062859.

In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A, RG6058 or RO7092284. WO2003072305A8, WO2004024068A3, WO2004024072A3, WO2009126688A2, WO2015009856A2, WO2016011264A1, WO2016109546 A2, WO2017053748A2 and WO2019165434A1, and U.S. Patent Application Publication Nos. 2017/0044256, 2017/0037127, 2017/0145093, 2017/260594, 2017/0088613 , 2018/0186875, 2019/0119376, and US Pat. It is an antagonistic monoclonal antibody described in Patent No. 10047158 B2 and US Patent No. 10017572 B2.

In some embodiments, an anti-TIGIT antibody comprises at least 1, 2, 3, 4, 5, or 6 complementarity determining regions (CDRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, an anti-TIGIT antibody comprises the 6 CDRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody is tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448 ), domvanarimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) sequence of any one of the anti-TIGIT antibodies disclosed herein; A light chain comprises the light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIGIT antibody is tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448 ), domvanarimab (AB154), vivostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, an anti-TIGIT antibody comprises the heavy and light chains of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody is tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448 ), domvanarimab (AB154), vivostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, an anti-TIGIT antagonist antibody (according to any of the embodiments described herein) incorporates any of the features, alone or in combination, as described in Section C below be able to.

B. PD-1 Axis Binding Antagonists Provided herein are methods for treating cancer in a subject (eg, human) comprising administering to the subject an effective amount of a PD-1 axis binding antagonist. 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.

1. PD-L1 Binding Antagonists In some examples, a PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners. In another example, a PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1. In yet another example, the PD-L1 binding antagonist inhibits binding of PD-L1 to B7-1. In some examples, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. PD-L1 binding antagonists can be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides or small molecules. In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (eg, GS-4224, INCB 086550, MAX-10181, INCB 090244, CA-170 or ABSK 041). In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some examples, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some examples, the small molecule is a compound described in WO2015/033301 and/or WO2015/033299.

In some examples, the PD-L1 binding antagonist is an anti-PD-L1 antibody. Various anti-PD-L1 antibodies are contemplated and described herein. In any of the examples herein, the isolated anti-PD-L1 antibody is human PD-L1, eg, human PD-L1 as set forth in UniProtKB/Swiss-Prot Accession No. Q9NZQ7-1, or its Can be combined into variants. In some examples, anti-PD-L1 antibodies can inhibit binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1. In some examples, the anti-PD-L1 antibody is a monoclonal antibody. In some examples, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. In some examples, the anti-PD-L1 antibody is a humanized antibody. In some examples, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, rhodapolimab, 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 them are described in International Patent Application Publication No. 2010/077634 and US Pat. No. 8,217,149, each of which is incorporated herein by reference in its entirety.

In some examples, the anti-PD-L1 antibody (eg, atezolizumab) comprises at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR- (b) HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO:21); (c) HVR-H3 sequence is RHWPGGFDY (SEQ ID NO:22); (d) HVR -L1 sequence is RASQDVSTAVA (SEQ ID NO:23); (e) HVR-L2 sequence is SASFLYS (SEQ ID NO:24); (f) HVR-L3 sequence is QQYLYHPAT (SEQ ID NO:25).

In some examples, the anti-PD-L1 antibody is
(a) HVR-H1, HVR-H2 and HVR-H3 sequences of SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22 respectively; and (b) HVR-L1 of SEQ ID NO:23, SEQ ID NO:24 and SEQ ID NO:25 respectively; HVR-L2 and HVR-L3 sequences.

いくつかの例では、抗ＰＤ－Ｌ１抗体（例えば、アテゾリズマブ）は、重鎖及び軽鎖配列を含み：（ａ）重鎖可変（ＶＨ）領域配列は、アミノ酸配列：ＥＶＱＬＶＥＳＧＧＧＬＶＱＰＧＧＳＬＲＬＳＣＡＡＳＧＦＴＦＳＤＳＷＩＨＷＶＲＱＡＰＧＫＧＬＥＷＶＡＷＩＳＰＹＧＧＳＴＹＹＡＤＳＶＫＧＲＦＴＩＳＡＤＴＳＫＮＴＡＹＬＱＭＮＳＬＲＡＥＤＴＡＶＹＹＣＡＲＲＨＷＰＧＧＦＤＹＷＧＱＧＴＬＶＴＶＳＳ（配列番号２６）； (b) the light chain variable (VL) region sequence comprises the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 27).

いくつかの例では、抗ＰＤ－Ｌ１抗体（例えば、アテゾリズマブ）は、重鎖及び軽鎖配列を含み：（ａ）重鎖は、アミノ酸配列：ＥＶＱＬＶＥＳＧＧＧＬＶＱＰＧＧＳＬＲＬＳＣＡＡＳＧＦＴＦＳＤＳＷＩＨＷＶＲＱＡＰＧＫＧＬＥＷＶＡＷＩＳＰＹＧＧＳＴＹＹＡＤＳＶＫＧＲＦＴＩＳＡＤＴＳＫＮＴＡＹＬＱＭＮＳＬＲＡＥＤＴＡＶＹＹＣＡＲＲＨＷＰＧＧＦＤＹＷＧＱＧＴＬＶＴＶＳＳＡＳＴＫＧＰＳＶＦＰＬＡＰＳＳＫＳＴＳＧＧＴＡＡＬＧＣＬＶＫＤＹＦＰＥＰＶＴＶＳＷＮＳＧＡＬＴＳＧＶＨＴＦＰＡＶＬＱＳＳＧＬＹＳＬＳＳＶＶＴＶＰＳＳＳＬＧＴＱＴＹＩＣＮＶＮＨＫＰＳＮＴＫＶＤＫＫＶＥＰＫＳＣＤＫＴＨＴＣＰＰＣＰＡＰＥＬＬＧＧＰＳＶＦＬＦＰＰＫＰＫＤＴＬＭＩＳＲＴＰＥＶＴＣＶＶＶＤＶＳＨＥＤＰＥＶＫＦＮＷＹＶＤＧＶＥＶＨＮＡＫＴＫＰＲＥＥＱＹＡＳＴＹＲＶＶＳＶＬＴＶＬＨＱＤＷＬＮＧＫＥＹＫＣＫＶＳＮＫＡＬＰＡＰＩＥＫＴＩＳＫＡＫＧＱＰＲＥＰＱＶＹＴＬＰＰＳＲＥＥＭＴＫＮＱＶＳＬＴＣＬＶＫＧＦＹＰＳＤＩＡＶＥＷＥＳＮＧＱＰＥＮＮＹＫＴＴＰＰＶＬＤＳＤＧＳＦＦＬＹＳＫＬＴＶＤＫＳＲＷＱＱＧＮＶＦＳＣＳＶＭＨＥＡＬＨＮＨＹＴＱＫＳＬＳＬＳＰＧ（配列番号２８）を含み；（ｂ ）軽鎖は、アミノ酸配列：ＤＩＱＭＴＱＳＰＳＳＬＳＡＳＶＧＤＲＶＴＩＴＣＲＡＳＱＤＶＳＴＡＶＡＷＹＱＱＫＰＧＫＡＰＫＬＬＩＹＳＡＳＦＬＹＳＧＶＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＴＩＳＳＬＱＰＥＤＦＡＴＹＹＣＱＱＹＬＹＨＰＡＴＦＧＱＧＴＫＶＥＩＫＲＴＶＡＡＰＳＶＦＩＦＰＰＳＤＥＱＬＫＳＧＴＡＳＶＶＣＬＬＮＮＦＹＰＲＥＡＫＶＱＷＫＶＤＮＡＬＱＳＧＮＳＱＥＳＶＴＥＱＤＳＫＤＳＴＹＳＬＳＳＴＬＴＬＳＫＡＤＹＥＫＨＫＶＹＡＣＥＶＴＨＱＧＬＳＳＰＶＴＫＳＦＮＲＧＥＣ（配列番号２９）を含む。

In some examples, the anti-PD-L1 antibody has (a) at least 95% sequence identity to SEQ ID NO:26 or the sequence of SEQ ID NO:26 (e.g., at least 95%, 96%, 97%, 98%, or (b) SEQ ID NO: 27 or at least 95% sequence identity with the sequence of SEQ ID NO: 27 (e.g., at least 95%, 96%, 97%, 98% sequence identity); % or 99% sequence identity), or (c) a VH domain according to (a) and a VL domain according to (b). In one embodiment, the anti-PD-L1 antibody comprises atezolizumab comprising: (a) the heavy chain amino acid sequence of SEQ ID NO:28, and (b) the light chain amino acid sequence of SEQ ID NO:29.

In some examples, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

In some examples, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody (MedImmune, AstraZeneca) described in WO2011/066389 and US2013/034559. .

In some examples, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.

In some examples, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

In some examples, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL-1 antibody.

In some examples, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

In some examples, the anti-PDL1 antibody, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain, e.g., by removing a non-binding steric moiety, thereby It consists of a cleavable site or linker that allows antigen to be attached. In some examples, the anti-PDL-1 antibody is CX-072 (CytomX Therapeutics).

In some examples, the anti-PD-L1 antibody comprises 6 HVR sequences (eg, 3 heavy chain HVRs and 3 light chain HVRs) and/or US Patent Application Publication No. 20160108123, WO2016/000619 No., WO2012/145493, U.S. Patent No. comprising heavy and light chain variable domains from an anti-PD-L1 antibody described in WO 9,205,148, WO 2013/181634, or WO 2016/061142.

In a still further particular aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a more particular aspect, it results from "effector-less Fc mutation" or aglycosylation mutation. In yet a further example, the effectorless Fc mutation is an N297A or D265A/N297A substitution within the constant region. In a still further example, the effectorless Fc mutation is an N297A substitution within the constant region. In some instances, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to attachment of the carbohydrate moiety to the side chain of the asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences within 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-hydroxy Lysine can also be used. Removal of glycosylation sites from the antibody is conveniently accomplished by altering the amino acid sequence such that one of the tripeptide sequences described above (for N-linked glycosylation sites) is removed. This modification may be accomplished by replacement of an asparagine, serine, or threonine residue within a glycosylation site with another amino acid residue (eg, glycine, alanine, or conservative substitution).
2. PD-1 binding antagonist

In some examples, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some instances, a PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners. In some examples, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L1. In another example, the PD-1 binding antagonist inhibits binding of PD-1 to PD-L2. In yet another example, a PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. PD-1 binding antagonists can be, but are not limited to, antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides or small molecules. In some examples, the PD-1 binding antagonist is an immunoadhesin, such as an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (eg, the Fc region of an immunoglobulin sequence) immunoadhesins, including For example, in some instances the PD-1 binding antagonist is an Fc fusion protein. In some examples, 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 WO2010/027827 and WO2011/066342. In some examples, the PD-1 binding antagonist is a peptide or small molecule compound. In some examples, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). For example, WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317 and See WO2011/161699. In some examples, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

In some examples, the PD-1 binding antagonist is an anti-PD-1 antibody. Various anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the examples herein, the PD-1 antibody can bind human PD-1 or a variant thereof. In some examples, the anti-PD-1 antibody is a monoclonal antibody. In some examples, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. In some examples, the anti-PD-1 antibody is a humanized antibody. In other examples, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifanlimab, sasanlimab, penplimab, CS1003, HLX10, SCT-I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budikarimab, AMG404, CX-188, JTX-4014, 609A, LZM0219, LZM0219, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 and hAb21.

In some examples, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO® are anti-PD -1 antibody.

In some examples, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in WO2009/114335.

In some examples, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some examples, the anti-PD-1 antibody is PDR 001 (CAS Registry Number 1859072-53-9; Novartis). PDR 001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

In some examples, the anti-PD-1 antibody is REGN 2810 (Regeneron). REGN 2810 is a human anti-PD-1 antibody.

In some examples, the anti-PD-1 antibody is BGB-108 (BeiGene).

In some examples, the anti-PD-1 antibody is BGB-A 317 (BeiGene).

In some examples, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

In some examples, the anti-PD-1 antibody is STI-A 1110 (Sorrento). STI-A 1110 is a human anti-PD-1 antibody.

In some examples, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

In some examples, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some examples, the anti-PD-1 antibody is TSR-042 (also known as ANB 011; Tesaro/AnaptysBio).

In some examples, the anti-PD-1 antibody is AM 0001 (ARMO Biosciences).

In some examples, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244 C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking PD-L1 binding to PD-1.

In some examples, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388 D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

In some examples, the anti-PD-1 antibody is WO2015/112800, WO2015/112805, WO2015/112900, US20150210769, WO2016/ 089873, WO2015/035606, WO2015/085847, WO2014/206107, WO2012/145493, U.S. Patent No. 9,205,148, WO2015/ 119930, WO2015/119923, WO2016/032927, WO2014/179664, WO2016/106160, and WO2014/194302 It includes 6 HVR sequences (eg, 3 heavy chain HVRs and 3 light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain from an antibody.

In a still further specific aspect, the anti-PD-1 antibody has reduced or minimal Fc-mediated effector functions. In a still further specific aspect, minimal Fc-mediated effector function is due to "effectorless Fc mutations" or aglycosylation mutations. In a still further example, the effectorless Fc mutation is an N297A or D265A/N297A substitution within the constant region. In some instances, the isolated anti-PD-1 antibody is aglycosylated.

3. PD-L2 Binding Antagonists In some examples, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some examples, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partner. In certain aspects, the PD-L2 binding ligand partner is PD-1. PD-L2 binding antagonists can be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides or small molecules.

In some examples, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the examples herein, an anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some examples, the anti-PD-L2 antibody is a monoclonal antibody. In some examples, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. In some examples, the anti-PD-L2 antibody is a humanized antibody. In other examples, the anti-PD-L2 antibody is a human antibody. In a still further specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In a more particular aspect, it results from "effector-less Fc mutation" or aglycosylation mutation. In a still further example, the effectorless Fc mutation is an N297A or D265A/N297A substitution within the constant region. In some examples, the isolated anti-PD-L2 antibody is non-glycosylated.

PD-1 axis binding antagonists (eg, atezolizumab) useful in the invention, including compositions containing 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 of the above examples and any of the characteristics, alone or in combination, as described in Section C below. can be incorporated.

C. Forms and Properties of Antibodies 1 . Antibody Affinity In specific examples, provided herein are anti-TIGIT antagonist antibodies, PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies, or anti-PD-1 antagonist antibodies), anti-VEGF antibodies, and/or anti-IL-6R antibody) is 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (eg, 10 ⁻⁸ M or less, such as 10 ⁻ It has a dissociation constant (K _D ) of ⁸ M to 10 ⁻¹³ M, such as 10 ⁻⁹ M to 10 ⁻¹³ M).

In one example, _KD is measured by a radiolabeled antigen binding assay (RIA). In one example, RIA is performed using the antibody of interest and the Fab version of its antigen. For example, the solution binding affinity of Fabs for antigen was evaluated by equilibrating the Fabs with a minimal concentration of ( ¹²⁵ I)-labeled antigen in the presence of a titration system of unlabeled antigen and then coating the bound antigen with anti-Fab antibody. Measured by plate capture (see, eg, Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish assay conditions, MICROTITER® multiwell plates (Thermo Scientific) were treated overnight with 5 μg/mL capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate, pH 9.6. Coat and then block with 2% (w/v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). 100 pM or 26 pM of [ ¹²⁵ I]-antigen is mixed with serial dilutions of the Fab of interest in non-adsorbing plates (Nunc#269620) (see, eg, Presta et al., Cancer Res. 57:4593- 4599 (1997) for the anti-VEGF antibody Fab-12). The Fab of interest is then incubated overnight; however, incubation may be continued for longer periods (eg, about 65 hours) to reach equilibrium. The mixture is then transferred to a capture plate for incubation (eg, 1 hour) at room temperature. The solution is then removed and the plate washed 8 times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plates are dry, 150 μL/well of scintillant (MICROSCINT-20™, Packard) is added and the plates are counted for 10 minutes on a TOPCOUNT™ gamma counter (Packard). Concentrations of each Fab that yield 20% or less of maximal binding are selected for use in competitive binding assays.

According to another example, K _D is measured using the BIACORE® surface plasmon resonance assay. For example, assays using BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) can be performed at about 10 response units (RU) on immobilized antigen on a CM5 chip. at 25° C. by In one example, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) was prepared with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N- Activated with hydroxysuccinimide (NHS). Antigen was diluted with 10 mM sodium acetate, pH 4.8, to 5 μg/ml (approximately 0.2 μM) before injection at a flow rate of 5 μl/min, resulting in approximately 10 response units (RU) of coupled protein. to achieve After injection of antigen, 1M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fabs (0.78 nM to 500 nM) in PBS with 0.05% polysorbate 20 (TWEEN-20™) detergent (PBST) were added to 25 °C and inject at a flow rate of approximately 25 μL/min. A simple one-to-one Langmuir binding model (BIACORE® Evaluation Software Version 3.2) was developed by simultaneously fitting the association rate (k _on ) and dissociation rate (k _off ) to the association and dissociation sensorgrams. Calculate using The equilibrium dissociation constant (K _D ) is calculated as the ratio k _off /k _on . For example, Chen et al. , J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 10 ⁶ M- ¹ s- ¹ by the surface plasmon resonance assay described above, the on-rate can be measured using a stop-flow-equipped spectrophotometer (Aviv Instruments) with a stirred cuvette or an 8000 series SLM-AMINCO ( Fluorescence emission of 20 nM anti-antigen antibody (Fab type) in PBS (pH 7.2) at 25° C. in the presence of increasing concentrations of antigen as measured in a spectrometer such as the ThermoSpectronic™. It can be determined by using a fluorescence quenching technique that measures the increase or decrease in intensity (Excitation=295 nm, Emission=340 nm, 16 nm bandpass).
2. antibody fragment

In certain examples, the anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies) provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, and other fragments described below. Reviews of particular antibody fragments include Hudson et al. Nat. Med. 9:129-134 (2003). References to scFv fragments include, for example, Pluckthuen, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. , (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and see also US Pat. Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a discussion of Fab and F(ab') ₂ fragments that constitute salvage receptor binding epitope residues and have increased in vivo half-lives.

Diabodies are antibody fragments with two antigen-binding sites that can 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. See USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

Single domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In a particular example, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, Mass., see, eg, US Pat. No. 6,248,516 B1).

Antibody fragments can be produced by a variety of techniques including, but not limited to, proteolysis and production of intact antibodies by recombinant host cells (e.g., E. coli or phage) as described herein. .
3. Chimeric and humanized antibodies

In certain examples, the anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies) provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in US 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 a non-human variable region (eg, a variable region derived from a non-human primate such as mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, chimeric antibodies are "class-switched" antibodies in which the class or subclass has been altered from that of the parent antibody. A chimeric antibody includes an antigen-binding fragment thereof.

In certain examples, a chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce their immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, humanized antibodies comprise one or more HVRs, eg, variable domains in which the CDRs (or portions thereof) are derived from a non-human antibody and the FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally also will comprise at least a portion of a human constant region. In some instances, some FR residues in the humanized antibody are derived 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. is substituted with the corresponding residue of

Humanized antibodies and methods for their production are described, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and further in Riechmann et al. , Nature 332:323-329 (1988); Queen et al. , Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al. , Methods 36:25-34 (2005) (describing the transplantation of the specificity determining region (SDR)); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al. , Methods 36:43-60 (2005) (describing "FR shuffling"), and Osbourn et al. , Methods 36:61-68 (2005) and Klimka et al. , Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

Human framework regions that can be used for humanization include, but are not limited to: framework regions selected using the "best fit" method (e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from human antibody consensus sequences of a particular subtype of the heavy or light chain variable region (e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89). :4285 (1992); and Presta et al., J. Immunol., 151:2623 (1993)); human mature (somatic mutation) framework regions or human germline framework regions (e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); 10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

4. Human Antibodies In certain examples, the 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) provided herein are human antibodies. be. Human antibodies can be made using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies can be prepared by administering an immunogen to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically have all or part of the human immunoglobulin loci replacing the endogenous immunoglobulin loci, or existing extrachromosomally, or randomly integrated into the animal's chromosomes. contains In such transgenic mice, the endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). Also, for example, U.S. Pat. Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Pat. No. 5,770,429 describing HuMab® technology; See also US Pat. No. 7,041,870, which describes KM MOUSE® technology; and US Patent Application Publication No. 2007/0061900, which describes VelociMouse® technology. Human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining with a different human constant region.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human xenomyeloma cell lines have been described for the production of human monoclonal antibodies. (eg, Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York 7 et al.) and B198; , J. Immunol., 147:86 (1991).) Human antibodies generated via human B-cell hybridoma technology have also been described by Li et al. , Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods are described, for example, in US Pat. No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268 (2006). (describing human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 1805-1 (525-9). is also described.

Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
5. Antibodies from libraries

Anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies) of the invention screen combinatorial libraries for antibodies having the desired activity or activities. can be isolated by For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding properties. Such methods are described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001); , Nature 348:552-554; Clackson et al. , Nature 352:624-628 (1991); Marks et al. , J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al. , J. Mol. Biol. 338(2):299-310 (2004); Lee et al. , J. Mol. Biol. 340(5):1073-1093 (2004); Fellowe, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al. , J. Immunol. Methods 284(1-2):119-132 (2004).

In a particular phage display method, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR), randomly recombined in a phage library, and then used as described by Winter et al. , Ann. Rev. Immunol. , 12:433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) or Fab fragments. Libraries from immunogens provide high affinity antibodies to immunogens without the need to construct hybridomas. Alternatively, a naive repertoire can be found in Griffiths et al. , EMBO J, 12:725-734 (1993), to provide a single source of antibodies against a wide range of non-self and also self antigens without immunization. It can be cloned (eg, from humans). Finally, a naive library was created by cloning unrearranged V-gene segments from stem cells and using PCR primers containing random sequences to encode the highly variable CDR3 region, Hoogenboom and Winter, J. Am. Mol. Biol. , 227:381-388 (1992), by effecting rearrangements in vitro. Patent publications describing human antibody phage libraries include, for example: US Pat. 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies) or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein. .

6. Antibody Variants In certain examples, amino acid sequence variants of anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies) of the invention are contemplated. As described in detail herein, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) are optimized based on desired structural and functional properties. obtain. For example, it may be desirable to improve the binding affinity and/or other biological properties of an antibody. Amino acid sequence variants of the antibody may 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 sequences of the antibody. are mentioned. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, eg, antigen binding.

I. Substitutional, Insertional, and Deletional Variants In certain examples, 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) with one or more amino acid substitutions antibody) variants are provided. Sites of interest for substitutional mutagenesis include HVR and FR. Conservative substitutions are shown in Table 3 under the heading of "preferred substitutions." More substantial changes are provided in Table 3 under the heading "Exemplary Substitutions" and as 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 the desired activity, such as retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

Amino acids can be grouped according to common side chain properties.
(1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;
(2) neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;
(3) acidic: Asp, Glu;
(4) basic: His, Lys, Arg;
(5) residues affecting chain orientation: Gly, Pro;
(6) Aromatics: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (eg, a humanized or human antibody). Generally, the resulting variant(s) selected for further testing are modified (e.g. , improvement) and/or have substantially retained certain biological properties of the parent antibody. Exemplary substitutional variants are affinity matured antibodies, which can be conveniently generated using, for example, phage display-based affinity maturation techniques as described herein. Briefly, one or more HVR residues are mutated and the variant antibodies are displayed on phage and screened for a particular biological activity (eg, binding affinity).

Alterations (eg, substitutions) may be made, eg, in HVRs, to improve antibody affinity. Such alterations are made by HVR "hotspots", i.e., residues encoded by codons that are frequently mutated during the somatic maturation process (e.g., Chowdhury, Methods Mol. Biol. 207:179-196). 2008)), and/or within residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by constructing secondary libraries and reselecting from them is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some examples of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis). be introduced. A secondary library is then created. This library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves an HVR-directed approach that randomizes several HVR residues (eg, 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified using, for example, alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain instances, substitutions, insertions, or deletions may occur within one or more HVRs, so long as such modifications do not substantially reduce the ability of the antibody to bind antigen. For example, conservative modifications (eg, conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such changes can be, for example, outside the antigen contacting residues within the HVR. In the specific examples of variant VH and VL sequences described above, each HVR is either unmodified or has no more than 1, 2, or 3 amino acid substitutions.

A useful method for identifying residues or regions of an antibody that can be targeted for mutagenesis is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. . In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are used to determine whether antibody-antigen interaction is affected. Identified and replaced by a neutral or negatively charged amino acid (eg, alanine or polyalanine). Further substitutions may be introduced at amino acid positions demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of the antigen-antibody complex to identify contact points between the antibody and the antigen. Such contact residues and flanking residues may be targeted as candidates for substitution or removed. Variants may be screened to determine whether they possess the desired property.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence of one or more amino acid residues. Includes inserts. Examples of terminal insertions include antibodies with N-terminal methionyl residues. Other insertional variants of the antibody molecule include N- or C-terminal fusions of the antibody to enzymes (eg, for ADEPT) or polypeptides that increase the serum half-life of the antibody.

II. Glycosylation Variants In certain examples, the 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) of the invention are glycosylated. Modifications can be made to increase or decrease the degree. Addition or deletion of glycosylation sites to the anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention creates one or more glycosylation sites or It can be conveniently accomplished by altering the amino acid sequence so as to remove it.

Where the antibody contains an Fc region, the carbohydrate attached to it may be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides commonly attached to Asn297 of the CH2 domain of the Fc region by an N-linkage. For example, Wright et al. See TIBTECH 15:26-32 (1997). Oligosaccharides can include a variety of carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the "stem" GlcNAc of the biantennary oligosaccharide structure. In some instances, oligosaccharide modifications in the antibodies of the invention are made to generate antibody variants with improved specific properties.

In one example, a variant 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) is attached (directly or indirectly) to the Fc region Carbohydrate structures lacking fucose are provided. For example, the amount of fucose in such antibodies can be 1%-80%, 1%-65%, 5%-65% or 20%-40%. The amount of fucose is determined by MALDI-TOF mass spectrometry, for example as described in WO 2008/077546, Asn297 (e.g. complex, hybrid and high mannose structures). ) by calculating the average amount of fucose within the sugar chain at Asn297 for the sum of all sugar chain structures attached to . Asn297 refers to the asparagine residue located at about position 297 of the Fc region (EU numbering of Fc region residues); That is, it may be located at about ±3 amino acids between positions 294 and 300. Such fucosylation variants may improve the function of ADCC. See, for example, US Patent Application Publication Nos. 2003/0157108 (Presta, L.); 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: US Patent Application Publication No. 2003/0157108; WO 2000/61739; 2003/0115614; 2002/0164328; 2004/0093621; 2004/0132140; 2004/0110704; 2004/0110282; 2003/085119; 2003/084570; 2005/035586; 2005/035778; 2005/053742; 2002/031140; 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 Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially Example 11), and knockout cell lines such as the α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (eg, Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and international publication See 2003/085107).

In view of the above, in some examples, the methods of the invention include anti-TIGIT antagonist antibodies comprising non-glycosylation site mutations (e.g., anti-TIGIT antagonist antibodies disclosed herein (e.g., tiragolumab) and /or administering a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody) variant to the subject in the context of a divided dose escalating dosing regimen. In some examples, the aglycosylation site mutations reduce the effector function of the antibody.In some examples, the aglycosylation site mutations are substitution mutations.In some examples, the aglycosylation site mutations are substitution mutations. The antibodies comprise substitution mutations in the Fc region that reduce effector function, hi some examples, the substitution mutations are at amino acid residues N297, L234, L235, and/or D265 (EU numbering). In some examples, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G In some examples, the substitution mutation is at amino acid residue N297 In a preferred example, the substitution mutation is N297A.

Anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 Further provided are antagonist antibody (anti-PD-1 antagonist antibody) variants. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are, for example, WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); 0123546 (Umana et al). Antibody variants having at least one galactose residue of the oligosaccharide attached to the Fc region are also provided. 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.; )It is described in.

III. Fc Region Variants In certain examples, one or more amino acid modifications are associated with an anti-TIGIT antagonist (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab) antibody of the invention and/or PD-1 axis binding. introduced into the Fc region of an antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody), thereby creating an Fc region variant (e.g., US Patent Application Publication No. 2012 /0251531). An Fc region variant can include a human Fc region sequence (eg, a human IgG1, IgG2, IgG3, or IgG4 Fc region) with amino acid modifications (eg, substitutions) at one or more amino acid positions.

In certain instances, the present invention provides that by having some, but not all, effector functions, the half-life of antibodies in vivo is important, but certain effector functions (such as complement and ADCC) are important. Anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibody variants) are contemplated as desirable candidates for unwanted or harmful uses. Reduced/absence of CDC and/or ADCC activity. In vitro and/or in vivo cytotoxicity assays can be performed to confirm, for example, performing Fc receptor (FcR) binding assays to determine if the antibody lacks FcγR binding (thus NK cells, which are the primary cells for mediating ADCC, express Fc (RIII only), but retain FcRn binding capacity. , whereas monocytes express Fc(RI, Fc(RII, and Fc(RIII). FcR expression in hematopoietic cells has been reported by Ravetch and Kinet, Annu. 464, Table 3. Non-limiting examples of in vitro assays for assessing ADCC activity of a molecule of interest are described in US Pat. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. 5, 821, 337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987). Alternatively, non-radioactive assay methods may be used. (e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc., Mountain View, Canada) and CYTOTOX 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WY)) Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. The ADCC activity of the molecule is determined in vivo, eg, by Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998) can be evaluated in animal models. A C1q binding assay may also be performed to confirm that the antibody is incapable of binding C1q and lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO2006/029879 and WO2005/100402. CDC assays may be performed to assess complement activation (eg, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M. S. et al. Blood. 101 : 1045-1052 (2003); and Cragg, M. S. and M. J. Glennie Blood. 103:2738-2743 (2004)). Determination of FcRn binding and in vivo clearance/half-life can also be performed using methods known in the art (e.g., Petkova, SB et al. Int'l. Immunol. 18 ( 12): 1759-1769 (2006)).

Antibodies with reduced effector function include those in which one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 have been substituted (U.S. Pat. Nos. 6,737,056 and ibid.). 8,219,149). Such Fc mutations include the so-called "DANA" Fc mutations with substitutions of residues 265 and 297 to alanine at amino acid positions 265, 269, 270, 297 and 327. Fc mutations with substitutions in more than one are included (US Pat. Nos. 7,332,581 and 8,219,149).

In a particular example, the proline at position 329 of the wild-type human Fc region in the antibody is combined with proline 329 of Fc and the tryptophan residue Trp87 of FcgRIII (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). and Fc/Fc. γ. Amino acid residues large enough to disrupt the proline sandwich within the receptor interface, or substituted with glycine or arginine. In certain examples, the antibody further comprises at least one amino acid substitution. In one example, the additional amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in yet another example, the at least one additional amino acid substitution is L234A of the human IgG1 Fc region and L235A, or S228P and L235E of the human IgG4 Fc region (see, e.g., US Patent Application Publication No. 2012/0251531), and in yet another example, the at least one additional amino acid substitution is human IgG1 Fc Regions L234A and L235A and P329G.

Specific antibody variants with improved or decreased binding to FcRs are described. (See, eg, U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

In certain examples, antibody variants comprise an Fc region having one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 (EU numbering of residues) of the Fc region. .

Some examples include, for example, US Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000), changes occur within the Fc region that result in altered (i.e., either increased or decreased) C1q binding and/or complement dependent cytotoxicity (CDC). .

The neonatal Fc receptor (FcRn), which has an increased half-life and plays a role in transferring 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 US Patent Application Publication No. 2005/0014934 Al (Hinton et al.). Those antibodies comprise an Fc region having one or more substitutions therein that improve binding between the Fc region and FcRn. Such Fc variants include Fc region residues: , 413, 424 or 434, eg, with substitution of Fc region residue 434 (US Pat. No. 7,371,826).

For other examples of Fc region variants, Duncan & Winter, Nature 322:738-40 (1988); US Patent No. 5,648,260; US Patent No. 5,624,821; See also

In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or the anti-PD-L1 antagonist antibody (e.g., atezolizumab) has an Fc Includes regions (EU numbering).

In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., , atezolizumab) or anti-PD-1 antagonist antibody) comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are a first CH1 (CH1 ₁ ) domain, a first CH2 (CH2 ₁ ) domain, a first CH3 (CH3 ₁ ) domain, a second CH1 (CH1 ₂ ) domain, a second CH2 (CH2 ₂ ) domain, and a second CH3 (CH3 ₂ ) domain. In some examples, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some examples, the CH3 ₁ and CH3 ₂ domains each include a protrusion or cavity, and the protrusion or cavity within the CH3 ₁ domain can be positioned within the cavity or protrusion within the CH3 ₂ domain, respectively. In some examples, the CH3 ₁ and CH3 ₂ domains associate at the interface between the protrusion and the cavity. In some examples, the CH2 ₁ and CH2 ₂ domains each constitute a protrusion or cavity, wherein the protrusion or cavity in the CH2 ₁ domain can be positioned with the cavity or protrusion in the CH2 ₂ domain, respectively. In other examples, the CH2 ₁ and CH2 ₂ domains meet at the interface between the protrusion and the cavity. In some examples, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tiragolumab and/or an anti-PD-L1 antagonist antibody (eg, atezolizumab) is an IgG1 antibody.

IV. Cysteine Engineered Antibody Variants In certain examples, a cysteine engineered 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), e.g. It may be desirable to generate "thio MAbs" in which one or more residues are replaced with cysteine residues. In certain instances, substituted residues occur at accessible sites in the antibody. By replacing these residues with cysteines, reactive thiol groups are placed at accessible sites on the antibody, which can be used to bind other residues, such as drug moieties or linker-drug moieties, as further described herein. The moieties can be used to conjugate antibodies to make immunoconjugates. In particular examples, any one or more of the following residues are replaced with cysteines: 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 generated, for example, as described in US Pat. No. 7,521,541.

V. Antibody Derivatives In a particular example, an anti-TIGIT antagonist antibody of the invention (e.g., an anti-TIGIT antagonist antibody (e.g., tiragolumab) or a variant thereof) and/or a PD-1 axis binding antagonist antibody of the invention (e.g., anti-PD- L1 antagonist antibodies (eg, atezolizumab or variants thereof) are further modified to contain additional non-proteinaceous moieties that are known and readily available in the art. Suitable sites for antibody derivatization 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 copolymer, polyamino acid (either homopolymer or random copolymer), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide/ Ethylene oxide copolymers, polyoxyethylated polyols (eg, glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have manufacturing advantages due to its stability in water. The polymer can be of any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody may vary, and when multiple polymers are attached, they may be the same molecule or different molecules. In general, the number and/or type of polymers used for derivatization is not limiting, and the particular property or function of the antibody that is to be improved is defined under the conditions under which the antibody derivative is used therapeutically. can be determined based on considerations including whether

In another example, conjugates of antibodies and non-proteinaceous moieties are provided that can be selectively heated by exposure to radiation. In one example, the non-proteinaceous portion is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can be of any wavelength, including wavelengths that do not harm normal cells but that heat the non-protected site to a temperature at which cells proximal to the antibody-unprotected site are killed. is not limited to

Recombinant Production Methods Anti-TIGIT antagonist antibodies of the invention (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., tiragolumab and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies, e.g. , atezolizumab) or anti-PD-1 antagonist antibodies) using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567, which is incorporated herein by reference in its entirety. can be produced as

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), nucleic acids encoding the antibodies are isolated and grown in host cells. Insert into one or more vectors for further cloning and/or expression. Such nucleic acids are readily isolated using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody), may be sequenced.

Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, particularly if they do not require glycosylation or Fc effector functions. See, eg, US Pat. Nos. 5,648,237, 5,789,199, and 5,840,523 for expression of antibody fragments and polypeptides in bacteria. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254 describing the expression of antibody fragments in E. coli. See) After expression, the antibodies of the invention may be isolated in the soluble fraction from the bacterial cell paste and further purified.

In addition to prokaryotes, eukaryotes such as filamentous fungi and yeast are suitable cloning or expression hosts for antibody-encoding vectors, including strains and yeasts in which the glycosylation pathway has been "humanized." Strains are included that produce antibodies with a partially or fully human glycosylation pattern. Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al. , Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the 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 and can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. For example, US Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (trans. See PLANTIBODIES™ Technology for Producing Antibodies in Genetic Plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are the monkey kidney CV1 strain transformed with SV40 (COS-7); (1977))); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)); African Green Monkey Kidney Cells (VERO-76); Human Cervical Cancer Cells (HELA); Canine Kidney Cells (MDCK); Buffalo Rat Liver Cells (BRL 3A); Human Lung Cells (W138) human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); see, eg, 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 77:4216 (1980)), as well as Y0 , NS0, and Sp2/0. For reviews of specific mammalian host cell lines suitable for antibody production, see, eg, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003),

Immunoconjugates Anti-TIGIT antagonist antibodies disclosed herein, such as chemotherapeutic agents or drugs, growth inhibitors, toxins (e.g., protein toxins, bacterial , enzymatically active toxins of fungal, plant or animal origin, or fragments thereof), or tiragolumab and/or PD-1 axis binding antagonists conjugated to one or more cytotoxic agents such as radioisotopes (e.g. , an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) are also provided.

In some examples, the immunoconjugate is an antibody drug conjugate (ADC) and the antibody is a maytansinoid (U.S. Pat. Nos. 5,208,020, 5), including but not limited to , 416,064, and EP 0425235B1); auristatins such as monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (U.S. Pat. Nos. 5,635,483, 5, 780,588, and 7,498,298); dolastatin; calicheamicin or its derivatives (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)); (eg Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16 USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002). 45:4336-4343 (2002); and US Patent No. 6,630,579); methotrexate; vindesine; and taxanes such as ortataxel; trichothecenes; and CC1065.

In another example, the immunoconjugate is diphtheria A chain, non-binding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii protein, diancin protein, Phytolaca americana protein (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitgerin, restrictocin, phenomycin, enomycin, and trichothecene An anti-TIGIT antagonist antibody (e.g., tiragolumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) described herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to For example, atezolizumab)).

In another example, the immunoconjugate is an anti-TIGIT antagonist antibody described herein (eg, tiragolumab) and/or PD-1 described herein conjugated to a radioactive atom to form a radioactive conjugate. Axis binding antagonists (eg, anti-PD-L1 antagonist antibodies) (eg, atezolizumab). A variety of radioactive isotopes are available for the production of radioconjugates. Examples include radioactive isotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu. When a radioactive substance is used for detection, it may be a radioactive atom such as tc99m or I123 for scintigraphic studies, or nuclear magnetic resonance (NMR) imaging (aka magnetic resonance imaging, MRI). spin labels for, eg, again iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of antibodies and cytotoxic agents can be made using, for example, various bifunctional protein coupling agents: N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl- 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imide esters (dimethyladipimidate HCl, etc.), active esters (disuccinimidyl suberate, etc.) ), aldehydes (glutaraldehyde, etc.), bisazide compounds (bis(p-azidobenzoyl)hexanediamine, etc.), bis-diazonium derivatives (bis-(p-diazoniumbenzoyl)-ethylenediamine, etc.), diisocyanates (toluene 2,6-diisocyanate etc.), and diactive fluorine compounds (1,5-difluoro-2,4-dinitrobenzene etc.). For example, Vitetta et al. , Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating the radionucleotide to the antibody. See WO94/11026. The linker may be a "cleavable linker" that facilitates release of the cytotoxic drug within the cell. For example, acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers or disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); US Pat. No. 5,208,020). ) can be used.

Immunoconjugates or ADCs herein are commercially available (eg from Pierce Biotechnology, Inc., Rockford, Ill., USA), 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-( It is expressly contemplated, but not limited to, such conjugates prepared with crosslinker reagents including, but not limited to, 4-vinylsulfone)benzoate).

ADCs that do not contain anti-TIGIT antagonist antibodies or PD-1 axis binding antagonists can also be used in the methods described herein. In some examples, the ADC is enfortumab vedotin or sacituzumab govitecan.

D. Chemotherapeutic agents 1 . Platinum-Based Chemotherapeutic Agents Platinum-based chemotherapeutic agents include organic compounds containing platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Drugs include, but are not limited to carboplatin, cisplatin and oxaliplatin.

Platinum-based chemotherapeutic agents (such as cisplatin, carboplatin, oxaliplatin, starlaplatin) are widely used anti-tumor agents that cause cross-linking of DNA as monoadducts, interstrand cross-links, intrastrand cross-links, or DNA protein cross-links. is an agent. Platinum-based chemotherapeutic agents typically act on the adjacent N-7 positions of guanine, forming 1,2 intrastrand cross-links (Poklar et al. (1996). Proc. Natl. Acad. Sci. U SA 93(15):7606-11; Rudd et al.(1995).Cancer Chemother.Pharmacol.35(4):323-6). The resulting crosslinks inhibit DNA repair and/or DNA synthesis in cancer cells.

を有する。 Carboplatin is an exemplary platinum coordination compound for use in the methods described herein. The chemical name for carboplatin is platinum, diamine [l,l-cyclobutanedicarboxylato(2-)-0,0']-, (SP-4-2), and carboplatin has the following structural formula:

have

Carboplatin is a crystalline powder with a molecular formula of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of about 14 mg/mL and has a pH of 5-7 for a 1% solution. It is practically insoluble in ethanol, acetone, and dimethylacetamide. Carboplatin primarily produces interstrand DNA crosslinks and this effect is non-specific to the cell cycle.カルボプラチンは、ＰＡＲＡＰＬＡＴＩＮ（登録商標）、ＢＩＯＣＡＲＮ、ＢＬＡＳＴＯＣＡＲＢ、ＢＬＡＳＴＯＰＬＡＴＩＮ、ＣＡＲＢＯＫＥＭ、ＣＡＲＢＯＭＡＸ、ＣＡＲＢＯＰＡ、ＣＡＲＢＯＰＬＡＮ、ＣＡＲＢＯＴＥＥＮ、ＣＡＲＢＯＴＩＮＡＬ、ＣＹＴＯＣＡＲＢ、ＤＵＣＡＲＢ、ＫＡＲＰＬＡＴ、ＫＥＭＯＣＡＲＢ、ＮＡＰＲＯＰＬＡＴ、ＮＥＯＰＬＡＴＩＮ、ＮＩＳＣＡＲＢＯ、ＯＮＣＯＣＡＲＢＩＮ、ＴＥＶＡＣＡＲＢ、及びＷＯＭＡＳＴＩＮ等として市販It is

を有する。 Another exemplary platinum-based chemotherapeutic agent useful in the methods of the invention is cisplatin, which has the following structure:

have

2. Non-Platinum Chemotherapeutic Agents Non-platinum chemotherapeutic agents are another class of chemotherapeutic agents useful 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, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid or HU-331), alkylating agents (e.g., cyclophosphamide) and taxanes (e.g., paclitaxel (e.g., nanoparticles-albumin-bound (nab)-paclitaxel), docetaxel, larotaxel, cabazitaxel, mirataxel, tesetaxel, and/or Orataxel).

3. Antimetabolites Antimetabolites interfere with and inhibit (totally or partially) endogenous (normal) metabolic processes within cells (eg, cancer cells). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine and pralatrexate.

を有する。 Gemcitabine is an exemplary antimetabolite for use in the methods described herein and has the following structure:

have

を有する。 In some examples, pemetrexed can be administered as part of the methods of this invention. Pemetrexed has the following structure:

have

4. Topoisomerase II Inhibitors Inhibitors of topoisomerase II (e.g., etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, elliptin, orintricarboxylic acid, and HU-331) are also effective inhibitors of enzyme-mediated DNA cleavage. It is a widely used antitumor agent that stabilizes the topoisomerase IE DNA covalent complex (ie, the “cleavage complex”) after formation. Accumulation of such cleavage complexes induces cell death pathways.

Anthracycline is a type of topoisomerase II inhibitor extracted from Streptomyces. Examples include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pirarubicin, valrubicin, N-trifluoro-acetyldoxorubicin-14-valerate, aclacinomycin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino -doxorubicin (cyanomorpholino-DOX), 2-pyrrolinodoxorubicin (2-PDOX), 5-iminodaunomycin, mitoxantrone and aclacinomycin A (acrubicin). In some embodiments, an anthracycline is administered in combination with an alkylating agent such as doxorubicin in combination with cyclophosphamide (treatment with AC).

を有する。 Doxorubicin (Adriamycin®) is an exemplary topoisomerase II inhibitor for use in the methods described herein. It has the chemical name 10-[(3-amino-2,3,6trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10 tetrahydro-6,8,11 trihydroxy-8- (2-Hydroxyacetyl)-1-methoxy-(8S,10S)-5,12-naphthacenedione. Doxorubicin has the following structure:

have

Etoposide is an exemplary topoisomerase II inhibitor for use in the methods described herein. Etoposide is usually administered as the prodrug etoposide phosphate, whose chemical name is 4′-demethylepipophyllotoxin 9-[4,6-0-(R)- ethylidene-D-glucopyranoside], 4' (dihydrogen phosphate).

を有する。 Etoposide phosphate has the following structure:

have

Etoposide phosphate, the phosphate ester of etoposide, is a semi-synthetic derivative of podophyllotoxin that is converted to etoposide by dephosphorylation. Etoposide induces DNA strand breaks through interaction with DNA topoisomerase II and formation of free radicals, leading to cell cycle arrest (mainly the G2 phase of the cell cycle) and cell death. Etoposide is marketed as: ETOPOPHOS®, TOPOSAR®, VP-16, VEPESID®, 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.

を有し得る。 5. Taxanes Taxanes are chemotherapeutic agents that can bind to tubulin, promote microtubule assembly and stabilization, and/or prevent microtubule depolymerization. Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes include paclitaxel (ie, TAXOL®, CAS#33069-62-4), docetaxel (ie, TAXOTERE®, CAS#114977-28-5), larotaxel, cabazitaxel, mirataxel. , tesetaxel, and/or orataxel. In some embodiments, the taxane is an albumin-coated nanoparticle (eg, nano-albumin-bound (nab)-paclitaxel, ie ABRAXANE®, and/or nab-docetaxel, ABI-008). In some embodiments, the taxane is nab-paclitaxel (ABRAXANE®). In some embodiments, the taxane is formulated in a CREMAPHOR® (eg, TAXOL®) and/or a Tween, eg, polysorbate 80 (eg, TAXOTERE®). In some embodiments, the taxane is a liposome-encapsulated taxane. In some embodiments, the taxane is in the form of a prodrug and/or a conjugate form of the taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel polygomex, and/or linoleyl carbonate-paclitaxel). be. In some embodiments, paclitaxel is formulated substantially without surfactants (eg, in the absence of CREMAPHOR and/or Tween—TOCOSOL® paclitaxel, etc.).
In some examples, paclitaxel is administered as part of the methods of the invention. Paclitaxel has the following structure:

can have

In some examples, the method or use comprises administration of nanoalbumin binding (nab)-paclitaxel.

を有し得る。 6. Alkylating Agents Alkylating agents are chemotherapeutic agents that cause DNA damage. Alkylating agents included nitrogen mustards, nitrosoureas and alkyl sulfonates. Exemplary alkylating agents include cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1,4-butanediol dimethanesulfonate, (2S)-2-amino-3- {4-[bis(2-chloroethyl)amino]phenyl}propanoic acid, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2 -oxide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. In some embodiments, the alkylating agent is cyclophosphamide. Cyclophosphamide has the following structure:

can have

Those skilled in the art will appreciate that any of the chemotherapeutic agents described above can be administered in a variety of forms, including salt forms, which are contemplated as part of this invention.

E. Exemplary Colony Stimulating Factors Colony stimulating factors are proteins that stimulate cell proliferation. Colony stimulating factors include G-CSF (eg pegfilgrastim or filgrastim) and GM-CSF (eg sargramostim). In some embodiments, the colony stimulating factor is G-CSF (eg, pegfilgrastim or filgrastim). In some embodiments, the G-CSF is pegfilgrastim. In some embodiments, the G-CSF is filgrastim. In some embodiments, the colony stimulating factor is GM-CSF (eg, sargramostim). In some embodiments, GM-CSF is sargramostim.

F. Exemplary VEGF Antagonists The present invention provides VEGF antagonists useful for treating cancer in a subject (eg, human). VEGF antagonists of the invention are capable of binding VEGF, reducing VEGF expression levels, or neutralizing, blocking, inhibiting, abolishing, reducing, or interfering with VEGF biological activity. Any molecule is included. An exemplary human VEGF is shown as UniProtKB/Swiss-Prot Accession No. P15692, Gene ID (NCBI):7422.

In some examples, the VEGF antagonist is an anti-VEGF antibody. In some embodiments, the anti-VEGF antibody is bevacizumab, also known as "rhuMab VEGF" or "AVASTIN®." Bevacizumab has been described by Presta et al. (Cancer Res. 57:4593-4599, 1997). This consists of a mutated human IgG1 framework region and a murine anti-hVEGF monoclonal antibody, A., which blocks the binding of human VEGF to its receptor. and the antigen binding complementarity determining region from 4.6.1. Approximately 93% of the amino acid sequence of bevacizumab, including most of the framework regions, is derived from human IgG1 and approximately 7% of the sequence is derived from the murine antibody A4.6.1. Bevacizumab has a molecular weight of approximately 149,000 Daltons and is glycosylated. Bevacizumab and other humanized anti-VEGF antibodies are further described in U.S. Pat. No. 6,884,879, issued Feb. 26, 2005, the entire disclosure of which is expressly incorporated herein by reference. incorporated into. In some examples, the anti-VEGF antibody comprises a heavy chain variable (VH) region sequence and a light chain variable (VL) region sequence of bevacizumab.

Additional preferred antibodies include the G6 or B20 series antibodies (eg, G6-31, B20-4.1) described in PCT Application Publication No. WO2005/012359. For additional preferred antibodies see U.S. Pat. ３００４６、ＷＯ９４／１０２０２、ＥＰ０６６６８６８Ｂ１、米国特許出願公開第２００６００９３６０号、同第２００５０１８６２０８号、同第２００３０２０６８９９号、同第２００３０１９０３１７号、同第２００３０２０３４０９号、及び同第２００５０１１２１２６号、ならびにＰｏｐｋｏｖら（Ｊｏｕｒｎａｌ ｏｆ Ｉｍｍｕｎｏｌｏｇｉｃａｌ Ｍｅｔｈｏｄｓ２８８ : 149-164, 2004). Other preferred antibodies include residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104, or alternatively residues F17, Y21, Q22, Y25, D63, 183, and Antibodies that bind to functional epitopes on human VEGF including Q89 are included.

In other examples, the VEGF antagonist is an anti-VEGFR2 antibody or related molecule (e.g. ramucirumab, tanivirumab, aflibercept); an anti-VEGFR1 antibody or related molecule (e.g. ®), or ziv-aflibercept (VEGF Trap; ZALTRAP®)); bispecific VEGF antibodies (e.g., MP-0250, vanucizumab (VEGF-ANG2), or US2001/0236388); bispecific antibodies comprising a combination of two of an anti-VEGF arm, an anti-VEGFR1 arm and an anti-VEGFR2; anti-VEGFA antibodies (e.g. bevacizumab, sevacizumab) anti-VEGFB antibodies; anti-VEGFC antibodies (e.g., VGX-100), anti-VEGFD antibodies; or non-peptide small molecule VEGF antagonists (e.g., pazopanib, axitinib, vandetanib, stivarga, cabozantinib, lenvatinib, nintedanib, orantinib, teratinib, dovitinig ( dovitinig), cediranib, motesanib, sulfatinib, apatinib, foretinib, famitinib, and tivozanib).

In a further aspect, the VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) according to any of the examples above incorporates any of the features, singly or in combination, as described in Section C above. be able to.

G. Additional Therapeutic Agents Additional therapeutic agents that may be used in the present invention (e.g., used in combination with an anti-TIGIT antagonist antibody) include alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX). ®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN ( ®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as drugs in combination with the described compounds include apolizumab, acerizumab, atolizumab, bapinuzumab, vivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celolizumab Pegor, cidovucizumab, sidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erulizumab, feluvizumab, vontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, mattuzumab, mepolizumab, motavizumab 、モトビズマブ、ナタリズマブ、ニモツズマブ、ノロビズマブ、ヌマビズマブ、オクレリズマブ、オマリズマブ、パリビズマブ、パスコリズマブ、ペクフシツズマブ、ペクセリズマブ、ペクセリズマブ、ラリビズマブ、ラニビズマブ、レスリビズマブ、レスリズマブ、レスリビズマブ、ロベリズマブ、ルピズマブ、シブロツズマブ、シプリズマブ、ソンツズマブ、タカタツズマブテトラxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, tralizumab, tuktuzumab sermoreukin, tuktuzumab, umabizumab, ultoxazumab, ustekinumab, vigilizumab, and human sequences genetically engineered to recognize the interleukin-12 p40 protein and anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), a full-length IgG1λ antibody only.

Therapeutic antibodies also include antibodies that bind EGFR. Examples of antibodies that bind EGFR include: MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), Mab 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) ( See U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (WO 96/40210). Imclone Systems Inc.); the fully human EGFR-targeting antibody IMC-11F8 (Imclone); an antibody that binds the type II mutant EGFR (U.S. Pat. No. 5,212,290); U.S. Pat. , 996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO 98/50433, Abgenix/Amgen). ); EMD 55900 (Stragliotto et al., EurCancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding (EMD/Merck ); human EGFR antibody, HuMax-EGFR (GenMab); known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279 (29)). : 30375-30384 (2004)). Anti-EGFR antibodies may be conjugated to cytotoxic agents thereby generating immunoconjugates (see, eg, EP 659,439 A2, 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 such as CTLA-4, LAG3, TIM3, BTLA and/or VISTA; For example, CTLA-4 antagonists, such as anti-CTLA-4 antagonist antibodies (eg, ipilimumab (YERVOY)); agents that target co-stimulatory targets (eg, CD226, OX-40, CD28, CD27, CD137, HVEM and/or GITR); ); radiotherapy; antiangiogenic agents; apoptotic agents; and antitubulin agents.

V. Pharmaceutical Compositions, Formulations and Kits Any anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody), VEGF antagonist, chemotherapeutic agent described herein (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 a topoisomerase II inhibitor (e.g., doxorubicin))), an ADC (e.g., enfortumab vedotin or sacituzumab govitecan), and/or CSF (e.g., pegfilgrastim, filgrastim, or sargramostim) It can be used in pharmaceutical compositions and formulations. anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody), VEGF antagonist, one or more chemotherapeutic agents, ADC (eg, enfortumab vedotin or sacituzumab govitecan) and/or pharmaceutical compositions and formulations of CSF (e.g., pegfilgrastim, filgrastim, or sargramostim) in the form of lyophilized formulations or aqueous solutions having the desired purity 1, 2, 3, prepared by mixing four or more than four agents with any one or more pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) can be done. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include buffering agents such as phosphate, citric acid, and other organic acids; ascorbic acid and methionine; Antioxidants, including anti-oxidants; preservatives (e.g. octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (eg, Zn-protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein include soluble neutral active hyaluronidase glycoprotein (sHASEGP), e.g., human soluble PH such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Further included are intervening drug dispersants such as -20 hyaluronidase glycoprotein. Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Application Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases (eg, chondroitinases).

An exemplary lyophilized antibody formulation is described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006/044908, the latter formulation comprising a histidine acetate buffer.

An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20 and sucrose with a pH of 5.8. For example, atezolizumab can be provided in a 20 mL vial containing 1200 mg of atezolizumab formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg) and sucrose (821.6 mg). , the pH is 5.8. In another example, atezolizumab contains 840 mg of atezolizumab formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg) and (575.1 mg) It can be provided in 14 mL vials and has a pH of 5.8.

An exemplary tiragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine and WFI. Tiragolumab may be provided in 15 mL vials containing 10 mL of tiragolumab formulation at an approximate concentration of 60 mg/mL of tiragolumab antibody.

The formulations herein may also contain two or more active ingredients as required for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients are also available in colloidal drug delivery systems (e.g., microcapsules prepared by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively). , liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Such techniques are described in Remington's Pharmaceutical Sciences 16th edition, Osol, A.; Ed. (1980).

Sustained-release preparations may 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, eg films, or microcapsules. Formulations to be used for in vivo administration are generally sterile. Sterility can be readily accomplished, for example, by filtration through sterile filtration membranes.

The invention provides kits comprising anti-TIGIT antagonist antibodies for use in combination with PD-1 axis binding antagonists, eg, to treat a subject with cancer according to any of the methods described herein. do.

In another embodiment of the invention, a kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject with cancer according to any of the methods described herein is provided. In some examples, the kit further comprises a PD-1 axis binding antagonist. In some examples, the article of manufacture or kit further uses an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist to treat cancer (eg, cancer in a patient) or prevent cancer progression. including a package insert containing instructions for delaying

In another embodiment of the invention, a kit comprising a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody to treat a subject with cancer according to any of the methods described herein is provided. In some examples, the kit further comprises an anti-TIGIT antagonist antibody. In some examples, the article of manufacture or kit includes instructions for using the PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody (eg, tiragolumab) to treat or delay cancer progression in a patient. further including a package insert containing

In another embodiment, the kit comprises tiragolumab for use in combination with atezolizumab to treat a subject with cancer according to any of the methods described herein. In some embodiments, the kit further comprises atezolizumab. In some examples, the article of manufacture or kit further comprises a package insert containing instructions for using tiragolumab in combination with atezolizumab to treat or delay progression of cancer in a patient.

In another embodiment, the kit comprises atezolizumab for use in combination with tiragolumab to treat a subject with cancer according to any of the methods described herein. In some embodiments, the kit further comprises tiragolumab. In some examples, the article of manufacture or kit further comprises a package insert containing instructions for using atezolizumab in combination with tiragolumab to treat or delay progression of cancer in a patient.

In some examples, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container can be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloys (such as stainless steel or Hastelloy). In some instances, the container holds the formulation and a label on or associated with the container may indicate directions for use. The product or kit may further include other materials desirable from a commercial and user standpoint, such as other buffers, diluents, filters, needles, syringes, and package inserts with directions for use. In some examples, the article of manufacture further comprises one or more additional agents (eg, additional chemotherapeutic or anti-neoplastic agents). Suitable containers for one or more medicaments 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 is a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent), an ADC (e.g., enfortumab vedotin or sacituzumab govitecan) and/or CSF (eg, pegfilgrastim, filgrastim, or sargramostim).

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 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 of the methods described herein.

VI. Example

The following are examples of the method of the present invention. It is understood that various other embodiments may be practiced, given the general description above.

Example 1. Phase Ia/Ib Phase Ia/Ib Open Label Safety and Pharmacokinetics Dosing of Tiragolumab as Single Agent and in Combination with Atezolizumab Administered with and without Chemotherapy in Patients With Locally Advanced or Metastatic Tumors Escalation Study This study will investigate patients with locally advanced or metastatic tumors when administered as single agents (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib). ) to assess the safety, PK, pharmacodynamics and preliminary anti-tumor activity of tiragolumab (MTIG7192A). Table 5 outlines the specific objectives and corresponding endpoints of this study.

A. Study design This is a local progression for which no standard treatment exists, has been proven to be ineffective or intolerable, or is considered inadequate, or for which clinical trials of investigational agents are a recognized standard of care. A first-in-human, phase I, open-label study designed to evaluate the safety, tolerability, and PK of tiragolumab as a single-agent hospitalized patient with incurable, recurrent, or metastatic tumors. , a multicenter, global, dose escalation study. The trial also indicates that no standard of care exists, has been proven to be ineffective or intolerable, or is considered inappropriate, or is a recognized standard of care for clinical trials of an investigational drug; or with chemotherapy in patients with locally advanced, recurrent, or metastatic incurable tumors for whom clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are considered an acceptable treatment option; It is designed to allow evaluation of the safety, tolerability, and PK of tiragolumab when administered with atezolizumab without or with atezolizumab.

FIG. 1 is a flow chart showing Phase Ib chemotherapy expansion and Phase Ib Q4W dosing expansion. During the dose escalation phase, cohorts of approximately 3-6 patients are evaluated at each escalating dose level to determine the MTD or maximum administered dose (MAD) of tiragolumab as a single agent or in combination with atezolizumab.

In the dose expansion phase, patients are enrolled and treated below the MTD or MAD of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib). Tiragolumab as a single agent (Phase Ia) or combination of tiragolumab and atezolizumab (Phase Ib cohort without chemotherapy) by IV infusion on Day 1 of each 21-day cycle or Day 1 of each 28-day cycle (Phase Ib Q4W dose expansion) and no chemotherapy, tiragolumab is administered prior to atezolizumab. In the absence of clinically compelling evidence of unacceptable toxicity or disease progression, tiagolumab (Phase Ia) or tiragolumab in combination with ) beyond Cycle 1.

The phase Ib chemotherapy expansion cohort and the phase Ib Q4W dosing expansion cohort (Figure 1) have completed the safety run-in of three patients. All relevant safety data from the safety run-in will be fully reviewed by the IMC and investigator before enrollment continues.

In the chemotherapy expansion cohorts, tiragolumab and atezolizumab were combined with specific chemotherapy regimens in each of three cohorts: carboplatin or cisplatin and pemetrexed in cohort A, carboplatin and paclitaxel in cohort B, and carboplatin or cisplatin and etoposide in cohort C. (See Figure 1). In each cohort, treatment includes an induction phase and a maintenance phase. In the run-in phase, tiragolumab and atezolizumab in combination with chemotherapy will be administered by IV infusion for 4-6 cycles in Cohorts A and B and 4 cycles in Cohort C in 21-day cycles. The number of cycles of induction treatment for Cohorts A and B is at the investigator's discretion.

After the induction phase, patients who have not experienced disease progression or unacceptable toxicity continue treatment with maintenance therapy. During the maintenance phase, patients in Cohorts B and C continue on tiragolumab and atezolizumab alone, while patients in Cohort A continue on tiragolumab and atezolizumab along with pemetrexed. Atezolizumab is administered prior to tiragolumab in all chemotherapy expansion cohorts. If chemotherapy is administered, it is administered after atezolizumab and tiragolumab.

All patients will be closely monitored for adverse events throughout the study and for at least 90 days after the last dose of study treatment or until initiation of another systemic anticancer therapy (whichever occurs first). . Adverse events are graded according to the NCI CTCAE, version 4.0.

To characterize the PK properties, immunogenic responses, and pharmacodynamic effects of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) , blood samples are taken at various time points before and after dosing. Depending on the results of the interim PK analysis, the frequency of PK sampling may decrease later in the study.

Patients underwent tumor assessments at screening and during the study, as measured by the Standard Response Rating Criteria for Solid Tumors (RECIST) v 1.1 criteria. Even if standard RECIST v 1.1 criteria for disease progression are met in the Phase Ia or Phase Ib portion of the trial, if criteria for continued treatment are met, Patients may be allowed to continue study treatment. Patients who discontinue the Phase Ia portion of the trial, provided they meet crossover criteria and consent to biopsy of accessible lesions, will proceed to the Phase Ib portion of the trial and be treated with tiragolumab in combination with atezolizumab. can receive

Approximately 60-320 patients with locally advanced, recurrent, or metastatic incurable malignancies that have progressed after available standard therapy; or standard therapy has proven ineffective or intolerable, or Patients considered unsuitable; or enrolled in a trial expansion cohort if a clinical trial of an investigational drug is a recognized standard of care. In the Phase Ib portion of the study, patients for whom clinical trials of an investigational drug in combination with anti-PD-L1 antibodies with or without chemotherapy are considered an acceptable treatment option may be enrolled in an expansion cohort.

This expansion phase will focus on the safety, tolerability, A defined cohort of patients is included to better characterize PK variability, pharmacodynamic activity, and preliminary anti-tumor activity. Tiragolumab as a single agent (Phase Ia) or chemotherapy, as determined by the study investigator based on assessment of safety, tolerability, PK, pharmacodynamic and pooling antitumor activity data Enrollment of the expansion cohort will begin at selected dose levels below the MAD or MTD of tiragolumab (Phase Ib) in combination with atezolizumab with or without .

In the Phase Ia portion of the study, up to about 40 patients will have NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC, and CRC including CRC that is MSS or MSI-Low. A planned expansion cohort of PD-L1-selected and/or TIGIT-selected multiple tumor indications, including

In the Phase Ib portion of the trial (without chemotherapy), approximately 20-40 patients will be enrolled in each of the following planned indication-specific expansion cohorts. NSCLC: cancer immunotherapy (CIT) naïve (eg, no prior treatment with anti-PD-L1/PD-1); NSCLC: CIT-treated (eg, with prior treatment with anti-PD-L1/PD-1) GC including GEJ cancer; UBC; CRC including CRC that is MSS or MSI-Low; survival of specific tumor indications including melanoma, OC, RCC and UBC probate cohort.

In the Phase Ib chemotherapy expansion portion of the trial, approximately 20-40 patients will be enrolled in each of the following planned chemotherapy expansion cohorts (see Figure 1).
Cohort A:
- Run-in - combination with atezolizumab and tiragolumab Cisplatin or carboplatin and pemetrexed - Maintenance - combination of atezolizumab and tiragolumab Pemetrexed Cohort B:
- Induction - in combination with atezolizumab and tiragolumab Carboplatin and paclitaxel - Maintenance - atezolizumab and tiragolumab Cohort C:
- Induction phase - combination with atezolizumab and tiragolumab Cisplatin or carboplatin and etoposide - Maintenance phase - atezolizumab and tiragolumab

Table 6 shows the treatment combinations in each cohort.

B. Phase Ib Chemo Expansion Cohorts: Dosing and Administration In the run-in phase, patients in certain chemotherapy expansion cohorts will receive:
Cohort A received atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by cisplatin 75 mg/m ² IV or 6 mg/mL min IV carboplatin AUC and pemetrexed 500 mg/m ² IV on day 1 of every 21-day cycle. receive a combination. Four to six cycles of induction phase treatment are administered in the absence of disease progression or unacceptable toxicity.
Cohort B receives atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by carboplatin AUC 6 mg/mL min IV and paclitaxel 200 mg/m ² IV on day 1 of every 21-day cycle. Four to six cycles of induction phase treatment are administered in the absence of disease progression or unacceptable toxicity.
Cohort C received atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by cisplatin 75 mg/m2 IV, or carboplatin AUC 5 mg/mL min IV on day 1 of every 21-day cycle, then 1 of every 21-day cycle. Receive etoposide 100 mg/m ² IV on days-3. Four cycles of induction phase treatment are administered in the absence of disease progression or unacceptable toxicity.

After the run-in period, unacceptable toxicity, clinically plausible disease progression, and/or at the investigator's discretion after careful assessment and thorough discussion of potential risks and benefits with the patient Treatment is continued in the maintenance phase in the absence of clinical benefit. In the maintenance phase, patients in certain chemotherapy expansion cohorts receive:
Cohort A received atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by pemetrexed 500 mg/m ² IV on day 1 of every 21-day cycle; , received atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV; Cohort C received atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV on Day 1 of every 21-day cycle.

In the absence of toxicity and disease progression, individual chemotherapeutic or immunotherapeutic agents are discontinued independently.

C. Phase Ib Q4W Dosing Expansion Cohort

The objectives of the Phase IbQ4W dose expansion cohort were to better characterize the safety, tolerability, PK and preliminary efficacy data, and in combination with atezolizumab 1680 mg IV on a dosing schedule of every 4 weeks (28 days). To explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiragolumab 840 mg IV.

The Phase Ib Q4W cohort includes approximately 20-40 patients with tumors who can be selected for PD-L1 and/or TIGIT selection based on prospective testing of tumor tissue during screening or rescreening. Patients with insufficient or unavailable archive tissue may be eligible for enrollment in this cohort if the medical monitor determines so based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are considered an acceptable treatment option may be enrolled in these expansion cohorts.

D. Additional Inclusion Criteria for Patients in Each Index-Specific Expansion Cohort of Phase Ib

NSCLC cohort (CIT-naive) had histologically confirmed no prior treatment with CIT (investigational or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4 In patients with incurable advanced NSCLC, in combination with anti-PD-L1 antibody if CIT (including anti-PD-L1/PD-1 agents) is approved by local regulatory authorities for treatment of NSCLC Includes patients for whom a clinical trial of an investigational drug is considered an acceptable treatment option. Patients whose tumors have known sensitizing epidermal growth factor receptor (EGFR) mutations also experience disease progression (on or after treatment) or intolerance to treatment with EGFR tyrosine kinase inhibitor(s). Patients whose tumors have known anaplastic lymphoma kinase (ALK) rearrangements also have disease progression (during or after treatment) or intolerance to treatment with ALK tyrosine kinase inhibitor(s). Patients whose tumors have known ROS1 rearrangements must also not experience disease progression (during or after treatment) or intolerance to treatment with ROS1 tyrosine kinase inhibitor(s). patients whose tumors have a known BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib;

The NSCLC cohort (CIT treatment) included patients with histologically confirmed incurable advanced NSCLC previously treated with CIT (investigational or approved) containing anti-PD-L1/PD-1. included. Patients with known sensitizing EGFR mutations whose tumors must also experience disease progression (during or after treatment) or intolerance to treatment with EGFR tyrosine kinase inhibitor(s); Patients with ALK rearrangements must also experience disease progression (during or after treatment) or intolerance to treatment with ALK tyrosine kinase inhibitor(s); tumor has known ROS1 rearrangement Patients must also experience disease progression (during or after treatment) or intolerance to treatment with ROS1 tyrosine kinase inhibitor(s); during or after treatment), or intolerance to treatment with dabrafenib in combination with trametinib; patients must have prior anti-PD-L1/PD-1, CIT monotherapy and/or have documented disease progression on concomitant therapy (investigational or approved).

Best documented response of PR or CR confirmed by investigator assessment by RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy or combination therapy At least about 10 experienced patients may be enrolled. At least the best documented effect of Investigator-rated SD by RECIST v1.1 experienced at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy About 10 patients can be enrolled. Investigator-assessed best documented response to progressive disease (PD) by RECIST v1.1 while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy At any time, at least about 10 patients who have experienced Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy must be the most recent systemic anti-cancer therapy administered prior to enrollment in this expansion cohort. Patients who discontinued prior anti-PD-L1/PD-1 monotherapy and/or combination therapy primarily due to toxicity or intolerance are not eligible for enrollment in this expansion cohort.

The TNBC cohort has histologically confirmed incurable advanced estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, and human EGFR2 (HER2)-negative adenocarcinoma (triple-negative) of the breast Patients included. Triple-negative status must be documented as defined by the American Society of Clinical Oncology-American Society of Pathologists (ASCO-CAP) guidelines: less than 1% of tumor cell nuclei are immunoreactive for ER and less than 1% of tumor cell nuclei immunoreactive for the progesterone receptor and HER2 testing demonstrating IHC1+, IHC0, or negative in situ hybridization (ISH). patients with adenocarcinoma of the colon or rectum are included. 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 adenocarcinoma who are not amenable to curative therapy. Ruediger Siewert et al., as adenocarcinoma of the distal esophagus with the tumor center located within 1-5 cm above the anatomical esophagogastric junction. (2000) are eligible for the study with type 1 GEJ tumors. Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with a medical monitor. Patients with known HER2-positive tumors must also have experienced disease progression (during or after treatment) or intolerance to treatment with HER2-targeting antibody/HER2 inhibitor(s); HER2-positive is defined as either IHC3+ or IHC2+/ISH+ (ISH positivity is defined as a HER2:CEP17 ratio of 2 or greater) assessed by local laboratory testing for primary tumor or metastatic disease. Patients who have not undergone HER2 testing due to insufficient or unavailable tissue (eg, archival and/or biopsy) and therefore whose tumor HER2 status is unknown may still be eligible.

The HNSCC cohort included histologically confirmed inoperable, locally advanced or metastatic, recurrent or persistent squamous cell carcinoma of the head and neck (oral, oropharyngeal, Included are patients with hypopharynx, or larynx. HNSCC patients of any other primary anatomical location in the head and neck, HNSCC patients of unknown primary, or patients with tumors of non-squamous tissue are not eligible. Nasopharyngeal HNSCC patients may be eligible. The HPV status of HNSCC must be known.

The UBC cohort includes patients with histologically confirmed, incurable, advanced transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, bladder, and urethra). Patients with mixed histology should have a predominant transitional cell pattern.

The melanoma cohort includes patients with histologically confirmed incurable advanced metastatic melanoma. Investigational drug in combination with anti-PD-L1 antibody if CIT (including anti-PD-L1/PD-1 and/or anti-CTLA-4 agents) is approved by the local regulatory agency for the treatment of melanoma Patients with melanoma for whom clinical trials are considered an acceptable treatment option. Patients whose tumors have known BRAFV 600 mutations must also have experienced disease progression (during or after treatment) or intolerance to BRAF and/or MEK inhibitors. Enrollment will be managed so that approximately 20% or less of the patients in this cohort are those with ocular (uveal) melanoma.

The OC cohort includes patients with histologically confirmed incurable advanced epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Borderline ovarian epithelial neoplasms (eg, low-grade tumors, atypical proliferative tumors) are excluded.

The RCC cohort includes patients with histologically confirmed incurable advanced RCC with a clear cell histology component and/or a sarcomatoid histology component. If CITs (including anti-PD-L1/PD-1 agents) are approved by local regulatory authorities for the treatment of RCC, clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are an acceptable treatment option. Patients with considered RCC.

E. Dosing and Administration

In the Phase Ib portion of the study, the dose of atezolizumab administered in combination with tiragolumab is 1200 mg IV every 3 weeks, except for the Phase Ib Q4W dose cohort, which receives atezolizumab 1680 mg IVQ4W. This dose is fixed and independent of body weight. In all Phase Ib cohorts without chemotherapy, atezolizumab will be administered after tiragolumab infusion and a subsequent observation period. Atezolizumab is administered prior to tiragolumab in the Phase Ib chemotherapy expansion cohort.

The initial dose of atezolizumab is delivered over 60 (±10) minutes. If the first infusion is tolerated without infusion-related adverse events, the second infusion may be delivered over 30 (±10) minutes. If a 30 minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (±10) minutes. In Cycle 1, administration of atezolizumab is followed by a 90 minute observation period. All subsequent atezolizumab infusions may be followed by a 30 minute observation period. Patients who have previously received atezolizumab in another clinical trial can receive the initial dose at the fastest rate previously tolerated.

Chemotherapy in the Phase Ib Expansion Cohort Chemotherapy will be administered after atezolizumab and tiragolumab infusions followed by an observation period. During the induction phase, chemotherapy cycles count toward the prespecified number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once during the 21-day cycle. Cycles in which no chemotherapy component is administered are not counted in the total number of induction chemotherapy cycles.

Patients receive chemotherapeutic antiemetics and IV hydration according to local standard of care and manufacturer's instructions. However, due to the immunomodulatory effects of steroids, premedication with steroids should be minimized as clinically practicable.

Cohort A—Atezolizumab + Tiragolumab + Carboplatin/Cisplatin + Pemetrexed On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order.

Induction: atezolizumab > tiragolumab > pemetrexed > carboplatin or cisplatin After 4-6 cycles of the induction phase, patients begin maintenance therapy with the following dosing sequence.

Maintenance: atezolizumab > tiragolumab > pemetrexed

Table 8 lists recommended infusion times for treatment administration of pemetrexed and carboplatin or cisplatin during the induction phase and for pemetrexed during the maintenance phase.

Cohort B—Atezolizumab + Tiragolumab + Carboplatin + Paclitaxel On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:

In-licensing; atezolizumab > tiragolumab > paclitaxel > carboplatin

Table 8 lists the recommended premedications for the induction treatment of Cohort B patients. Table 9 lists recommended infusion times for treatment administration of paclitaxel and carboplatin during the induction phase.

Cohort C—Atezolizumab + Tiragolumab + Carboplatin or Cisplatin + Etoposide On Day 1 of each 21 cycle, all eligible patients will receive study drug infusions in the following order.

Induction: atezolizumab > tiragolumab > cisplatin or carboplatin > etoposide After the induction phase, patients will begin maintenance therapy with the following dosing sequence.

Maintenance: atezolizumab > tiragolumab

Table 10 lists recommended infusion times for treatment administration of carboplatin or cisplatin and etoposide during the induction phase.

Cisplatin Guidelines for administration of cisplatin in different cohorts are shown in Table 11.

Carboplatin Guidelines for administration of cisplatin in different cohorts are shown in Table 12.

式中：ＣｒＣｌ＝ｍＬ／分単位のクレアチニンクリアランス
年齢＝年単位の患者の年齢
体重＝ｋｇ単位の患者の体重
Ｓｃｒ＝血清クレアチニン（ｍｇ／ｄＬ） For the purposes of this study, GFR is considered equivalent to calculated creatinine clearance (CrCl). CrCl is calculated by institutional guidelines or by the method of Cockcroft and Gault (1976) using the following formula.

Where: CrCl = creatinine clearance in mL/min Age = patient age in years Weight = patient weight in kg Scr = serum creatinine (mg/dL)

For patients with abnormally low serum creatinine levels, a minimum creatinine level of 0.8 mg/dL is used to estimate GFR or limit estimated GFR at 125 mL/min.

When a patient's GFR is estimated based on serum creatinine measurements by isotope dilution mass spectrometry, the U.S. FDA recommends that physicians use carboplatin for desired exposure (AUC) to avoid potential toxicity from overdose. It is recommended that consideration be given to capping the dose of Based on the Calvert formula described in the carboplatin label, the maximum dose can be calculated as follows.

Maximum Carboplatin Dose (mg) = Target AUC (mg-min/mL) x (GFR + 25 mL/min).

Maximum dose is based on GFR estimates capped at 150 mL/min for patients with normal renal function. Higher estimated GFR values should not be used.

For target AUC=6, the maximum dose is 6×150=900 mg.

For target AUC=5, the maximum dose is 5×150=750 mg.

For target AUC=4, the maximum dose is 4×150=600 mg.

Guidelines for administration of pemetrexed in Pemetrexed Cohort A are shown in Table 13.

The pre-dosing dose administered is according to the prescribing information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with long half-lives for at least 5 days before, on the day of, and for at least 2 days after administration of pemetrexed.

Guidelines for paclitaxel dosing for paclitaxel Cohort B are shown in Table 14.

Patients of Asian race/ethnicity have a lower starting dose of paclitaxel at 175 mg/m2 IV over 3 hours. A lower starting dose of paclitaxel is associated with a higher overall incidence of hematologic toxicity in patients from Asian countries compared with patients from non-Asian countries, as observed during the internal safety review of lung cancer clinical trials. based on As used in this study, Asian race/ethnicity refers to a pan-ethnic/racial group that includes diverse populations residing in or having ancestral origins in East Asia, Southeast Asia, or South Asia. The applicability of such terms in a particular patient is at the discretion of the treating investigator and should be based on the patient's clinical characteristics and country of origin.

Etoposide Guidelines for administration of etoposide in Cohort C are shown in Table 15.

Example 2. Phase Ib/II, open-label, randomized study of chemotherapy in combination with atezolizumab and tiragolumab Efficacy, safety and pharmacokinetics of atezolizumab and chemotherapy (nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine) are evaluated. This study evaluates the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in patients with metastatic PDAC.

A. Study Design Patients in Cohort 1 are randomly assigned to a control group (chemotherapy) or an experimental group consisting of chemotherapy in combination with atezolizumab and tiragolumab. Enrollment within the experimental group is conducted in two phases, a preliminary phase followed by an expansion phase. Approximately 20 patients will be enrolled during the preliminary phase. Randomization will be discontinued to allow safety evaluation in a minimum of 6 patients. Safety assessments included at least 6 patients who received at least one dose of treatment (i.e., one dose of each agent for a given combination) and completed safety follow-up assessments during at least one complete treatment cycle. Based on safety data from human patients. If the combination is determined to be sufficiently safe, enrollment will resume in that group. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients may be enrolled in that group during the expansion phase. Additional patients can be enrolled to ensure balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers, to allow for further subgroup analyses.

Patients were randomly assigned to treatment groups, and the randomization rate was determined by the number of experimental groups open for enrollment (e.g., whether groups were added pending analysis of results from the preliminary phase, or There is a stipulation that the chance of being assigned to the control group is 35% or less, depending on when enrollment in the group is discontinued).

The end of the study is defined as the date the last patient completed the last visit (LPLV), including a survival follow-up visit conducted by phone or in the clinic. The total length of the trial, from initial patient screening to study termination, is approximately 3-5 years.

Table 16 shows the activity schedule.

On treatment days, all assessments must be performed prior to dosing unless otherwise specified.

^a If a visit is excluded due to a holiday, vacation, or other circumstances, the visit may occur outside of the designated window if the medical monitor agrees.

^bIt is recommended to start treatment within 7 days after randomization.

^cPatients return to the clinic for a treatment discontinuation visit within 30 days after the last dose of study treatment. A visit with confirmed disease progression may be used as a treatment discontinuation visit. The patient then undergoes follow-up evaluations.

^dVital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure, pulse oximetry, and temperature while the patient is seated. Record new or worsening clinically significant abnormalities on the Adverse Events eCRF. For the first infusion of atezolizumab, vital signs should be measured within 60 minutes prior to infusion and, if clinically indicated, every 15 (±5) minutes during infusion and every 30 (±10) minutes after infusion. must. For subsequent infusions, vital signs will be measured within 60 minutes prior to infusion and 30 (±10) during and after infusion if clinically indicated or if symptoms occurred during the previous infusion Vital signs must be measured within minutes. For the first infusion of tiragolumab, vital signs must be measured within 60 minutes prior to infusion, 15 (±5) during infusion, and every 30 (±10) minutes after infusion. For subsequent infusions of tiragolumab, vital signs were measured within 60 minutes prior to infusion and, if clinically indicated or symptoms occurred during the previous infusion, during and 15 (± 15) post-infusion 10) Vital signs must be measured within minutes.

^e A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, as well as the cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, genitourinary, and nervous systems. be Record new or worsening clinically significant abnormalities on the Adverse Events eCRF.

^f Perform limited symptom-directed testing at designated time points and at other time points as clinically indicated. Record new or worsening clinically significant abnormalities on the Adverse Events eCRF.

^gPatients are recommended to rest in supine position for at least 10 minutes prior to ECG recording.

^hHematology includes WBC counts, RBC counts, hemoglobin, hematocrit, platelet counts, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

ⁱ Laboratory tests must occur within 96 hours prior to Day 1 of Cycle 1 and within 24 hours prior to designated subsequent visits during the Treatment Period.

If the ^training laboratory assessments were performed within 96 hours prior to Cycle 1 Day 1, they do not need to be repeated.

^k Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the area), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, Included are albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.

^l TSH, free T3 (or total T3 for sites where free T3 has not been performed) and free T4 are assessed at screening and on day 1 of cycle 1 and every 3 cycles thereafter (i.e., cycles 4, 7 , 10, etc.).

^mPatients with positive quantitative HBV DNA at screening (must be <500 IU/mL per eligibility criteria) at treatment discontinuation (±7 days) and at 3, 6, 9, and 12 months after treatment discontinuation (±14 days at each time point), receive an additional HBV DNA test on Day 1 of every third cycle (ie, cycles 3, 6, 9, etc.). Study treatments and procedures can proceed while HBV DNA is being processed, but results must be reviewed by the investigator as soon as they become available. If HBV DNA increases below 500 IU/mL, a medical monitor should be consulted prior to continuation of study treatment, and consultation with a hepatologist or gastroenterologist specializing in hepatitis B is recommended.

ⁿ All women of childbearing potential will have a urine or serum pregnancy test performed at designated visits during treatment and 3 and 6 months after the last dose of study treatment. If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.

^o Includes pH, specific gravity, glucose, protein, ketones, and blood; dipsticks are allowed.

^P- autoantibody assays include antinuclear antibodies, anti-double-stranded DNA, circulating antineutrophil cytoplasmic antibodies, and perinuclear antineutrophil cytoplasmic antibodies.

^{qAutoantibody} assays should be repeated for patients who develop signs or symptoms suggestive of an autoimmune disease (eg, lupus erythematosus).

^r Not applicable to establishments not licensed for RBR sampling. Performed only on patients from participating centers who provided written informed consent to participate.

^sPatients will undergo tumor biopsy sample collection at the time of Investigator-determined unacceptable toxicity or loss of clinical benefit, if deemed clinically feasible by the Investigator. A biopsy must be performed within 40 days after determination of unacceptable toxicity or loss of clinical benefit or before the next anticancer therapy, whichever comes first. In addition, patients enrolled in the expansion phase will be treated 4 days after initiation of treatment unless an in-treatment tissue sample has already been obtained from a minimum of 15 patients treated with the same CIT combination and determined to be evaluable. Tumor biopsy samples will be collected weekly (±7 days) (if considered clinically feasible).

^tPatients who consented to a voluntary biopsy had a tumor biopsy sample collected 4 weeks (± 7 days) after initiation of treatment and if clinically feasible (biopsy already under treatment). (not applicable to patients enrolled in an expansion phase who are currently enrolled) and may undergo additional in-treatment biopsies at other time points at the discretion of the Investigator.

^uPatients will be followed until radiographic disease progression by RECIST v 1.1 at baseline and every 6 weeks for the first 48 weeks after starting treatment, except for patients continuing treatment after radiographic disease progression ( ± 1 week), then every 12 weeks (± 2 weeks) regardless of dose delay, and such patients will undergo tumor assessments every 6 weeks ( ± 1 week) to undergo tumor assessment. Therefore, tumor assessment should continue on schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new non-protocol-specified anticancer therapy. not.

^vAll measurable and/or evaluable lesions identified at baseline must be reassessed at each subsequent tumor assessment according to the tumor assessment schedule described above (see appendix "t"). The same radiographic procedure used to assess disease sites at screening should be used for subsequent tumor assessment (eg, same contrast protocol for CT scan).

^wAny drugs (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal remedies, or therapy, dietary supplements).

^x All adverse events reported after initiation of study treatment, 30 days after last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever comes first, 135 days after last dose of study treatment Serious adverse events and adverse events of particular interest continue to be reported until the start of a new systemic anticancer therapy, whichever occurs first. After this period, all deaths, regardless of cause, must be reported. The investigator will track each adverse event until the event resolves to ≥ baseline grade, until the event is rated stable by the investigator, until the patient fails follow-up, or until the patient gives consent. You must follow up until you withdraw. Every effort should be made to follow up all serious adverse events considered related to study treatment or study-related procedures until final results can be reported.

^y Atezolizumab is administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle. The initial dose of atezolizumab is delivered over 60 (±15) minutes. Subsequent infusions will last for 30 (±10) minutes if the previous infusion was tolerated without infusion-related adverse events, or 60 (±15) minutes if the patient experienced an infusion-related adverse event on the previous infusion. delivered over

^zTreatment is continued until unacceptable toxicity or loss of clinical benefit as determined by the Investigator.

^aa A fixed dose of 420 mg is administered by IV infusion on days 1 and 15 of each 28-day cycle. The initial dose of tiragolumab is delivered over 60 (±10) minutes. Subsequent infusions will last for 30 (±10) minutes if the previous infusion was tolerated without infusion-related adverse events, or 60 (±10) minutes if the patient experienced an infusion-related adverse event on the previous infusion. delivered over On Day 1 of Cycle 1, tiragolumab is administered 60 minutes after completion of atezolizumab infusion. The interval between subsequent infusions is 30 minutes if the previous atezolizumab infusion was tolerated without IRR, or 60 minutes if the patient experienced IRR on the previous atezolizumab infusion.

^bb On days 1, 8 and 15, patients received nab-paclitaxel 125 mg/ ^m2 administered by IV infusion over 30 (±5) minutes followed by IV infusion over 30 (±5) minutes. Receive 1000 mg/m ² administered gemcitabine. On Day 1 of Cycle 1, nab-paclitaxel is administered 60 minutes after the end of tiragolumab infusion to allow observation after tiragolumab administration. The interval between subsequent infusions is 30 minutes if the previous tiragolumab infusion was tolerated without IRR, or 60 minutes if the patient experienced an IRR on the previous tiragolumab infusion.

After cessation of ^cc treatment, survival follow-up and information on new anticancer therapies (including targeted therapies and immunotherapies) will be provided approximately every 3 months until death (unless patient withdraws consent or study ends) , phone calls, patient medical records, and/or clinic visits. If a patient requests withdrawal from follow-up, this request must be documented in the source document and signed by the investigator. If a patient is withdrawn from the study, study staff can only obtain information on survival status using public sources (eg, county records).

Assessment and Monitoring All patients were closely monitored for adverse events throughout the study, and adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE). v4.0)). Patients undergo tumor assessments every 6 weeks (starting on Day 1 of Cycle 1) for the first 48 weeks and every 6 or 12 weeks thereafter. Responses will be assessed by the investigator using RECIST v1.1. Responses per modified RECIST v 1.1 to immune-based therapeutics (iRECIST) are determined programmatically based on investigator-assessed individual lesion data. If clinical activity is demonstrated in an experimental arm, tumor assessment scans of that arm may be submitted for evaluation by an independent review center.

A baseline tumor tissue sample is collected from all patients, eg, by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, tumor tissue storage may be submitted after obtaining Medical Monitor approval, provided that the tissue was obtained within 3 months prior to enrollment, Provided that the patient had not received any anticancer therapy from the time of biopsy. Patients who discontinue Stage 1 due to unacceptable toxicity, disease progression by RECIST v 1.1, or loss of clinical benefit as determined by the Investigator if deemed clinically feasible by the Investigator of tumor tissue. For patients enrolled in the experimental arm during the expansion phase, unless an in-treatment tissue sample was already collected and determined to be evaluable from a minimum of 15 patients treated with the same CIT combination, In-treatment tumor tissue samples will be collected 4 weeks after initiation of Stage 1 treatment (if clinically feasible). These samples are utilized for biomarker testing (see rationale for biomarker assessment).

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are collected at various time points before and during study treatment administration (Table 17). Based on review of real-time safety data and available PK data, treatment regimens can be modified.

Laboratory, Biomarkers, and Other Biological Samples Exploratory biomarker studies include genes or gene signatures associated with tumor immunobiology, PD-L1, cytokines associated with T cell activation, T cell receptors including, but not limited to, analysis of repertoire, carcinoembryonic antigen, or density, localization and activation state of immune cells and their subsets, DNA or RNA extraction, analysis of somatic mutations, and NGS ( WES) may be included.

Samples for the following clinical tests will be sent to the testing facility's local laboratory for analysis:
Hematology: WBC counts, RBC counts, hemoglobin, hematocrit, platelet counts, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)
Chemistry panel (serum or plasma): CPK, bicarbonate or carbon dioxide (if considered standard of care for that 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 tests: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 is not performed), and free thyroxine (also known as T4)
Ferritin and γ-glutamyltransferase HIV serology unless permitted according to local regulations HAV serology: HAV IgM
• HBV serology: HBsAg, total HBcAb, and (if HBsAg test negative and total HBcAb test positive) HBV DNA.
If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has HBV infection.
• HCV serology: HCV antibody and (if HCV antibody test positive) HCV RNA.
If a patient tests positive for HCV antibodies at screening, an active HCV RNA test should also be performed to determine the presence or absence of 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 if clinically indicated)
• Pregnancy Testing All women of childbearing potential undergo a serum pregnancy test for stage 1 screening. Serum pregnancy tests were performed at subsequent designated visits. If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
Females must be postmenopausal, have not reached a postmenopausal state (>12 consecutive months of amenorrhea with no identified cause other than menopause), and be surgically infertile (removal of the ovaries and/or uterus). ) is considered to be of possible gestation.
・Urinalysis (pH, specific gravity, glucose, protein, ketones, blood)
A dipstick urine test is possible. However, patients with a dipstick urine test at screening of 2+ or higher protein must undergo a 24-hour urine collection for protein if the bevacizumab-containing arm is open for enrollment.

Samples for the following laboratory tests are sent to a central laboratory or local laboratory at the test site for analysis.
・Soluble CD25

The following samples are sent to one or several central laboratories or sponsors for analysis.
Serum samples for analysis of autoantibodies: antinuclear antibodies, anti-double-stranded DNA, circulating antineutrophil cytoplasmic antibodies, and perinuclear antineutrophil cytoplasmic antibodies For PK analysis using validated assays Plasma or serum samples for immunogenicity analysis using validated assays Plasma, serum and peripheral blood mononuclear cell (PBMC) samples for biomarker exploratory testing PD- Tumor Tissue Samples Collected at Baseline for Determination of L1 Expression and Research Studies for Biomarkers Baseline tumor tissue samples from primary or metastatic lesions are obtained from all patients, preferably by biopsy performed at study enrollment. Collected. If a biopsy is not considered feasible by the Investigator, tumor tissue storage may be submitted after obtaining medical monitor approval, provided that the tissue was performed within 3 months prior to enrollment. Obtained from a biopsy, provided that the patient has not received any anticancer therapy since the time of biopsy.
A representative FFPE tumor specimen in paraffin block (preferred) or at least 16 slides containing unstained freshly cut serial sections must be submitted along with the relevant pathology report. If only 10-15 slides are available, the patient may still be eligible for the study after obtaining medical monitor approval.
Tumor tissue must be of good quality based on total tumor content and viable tumor content. Samples must contain a minimum of 50 viable tumor cells preserving cellular context and histology, regardless of stylus gauge or collection method. Excision, core needle biopsy (at least 3 cores embedded in a single paraffin block, 18-gauge needle or larger [16-gauge needle preferred]), or excisional, incisional, punch, or forceps biopsy Samples taken by Fine-needle aspirations (defined as samples that do not preserve tissue architecture and yield cell suspensions and/or smears), brushings, cell pellets from pleural effusions, and lavage fluid samples are not permitted. Tumor tissue from demineralized bone metastases is not permitted.
The remaining tumor tissue archive blocks will be returned to the site on demand or 18 months after the final closure of the study database, whichever occurs first.
Patients enrolled in the exploratory arm during the expansion phase: Tumor tissue samples collected 4 weeks (± 7 days) after the start of treatment (if deemed clinically feasible by the investigator) for exploratory biomarker studies Same If an in-treatment tissue sample has already been collected from a minimum of 15 patients treated with the CIT combination and determined to be evaluable, the sample will not be collected.
Samples collected by excision, core needle biopsy (at least three cores are preferred), or excision, incision, punch or forceps biopsy are preferred.
- Unacceptable toxicity, disease progression according to RECIST v1.1, or clinical benefit as determined by the investigator if deemed clinically feasible by the investigator for research studies on biomarkers Tumor tissue sample collected at time of loss of biopsy within 40 days after determination of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to next anticancer therapy, whichever comes first must go to Samples collected by excision, core needle biopsy (at least three cores are preferred), or excision, incision, punch or forceps biopsy are preferred.

Atezolizumab Dose and Schedule Atezolizumab is administered at a fixed dose of 840 mg (Q2W) every 2 weeks (840 mg on days 1 and 15 of each 28-day cycle).

Tiragolumab Dose and Schedule Tiragolumab will be administered at a fixed dose of 420 mg Q2W (420 mg on days 1 and 15 of each 28-day cycle). The mean concentration after the 420 mg Q2W dose is expected to be equivalent to the mean concentration of 600 mg every 3 weeks (Q3W). A fixed tiragolumab dose of 600 mg IV Q3W was selected based on available pharmacokinetic (PK), efficacy, and safety data from the GO30103 study in which patients received single-agent tiragolumab or tiragolumab plus atezolizumab. . The MTD was not reached and no DLTs were observed with tiragolumab monotherapy at doses of 2-1200 mg Q3W or tiragolumab in combination with atezolizumab 1200 mg Q3W. In addition, development of anti-drug antibodies (ADA) to tiragolumab was observed in 3 of 145 evaluable patients receiving tiragolumab (doses of 2-600 mg Q3W) in combination with atezolizumab. Complete occupancy of peripheral TIGIT receptors on CD4 ⁺ , CD8 ⁺ , and NK cells was observed starting with the 30 mg Q3W dose of tiragolumab and remained sustained at all higher doses. When administered in combination with atezolizumab 1200 mg Q3W, anti-tumor activity (partial radiological response) was observed at tiragolumab doses of 30-600 mg Q3W.
Dosage and Administration

Patients will be screened by the investigator after integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as pain secondary to disease). Receive treatment as outlined until determined unacceptable toxicity or loss of clinical benefit.

Participants will receive an IV infusion of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle according to the instructions outlined in Table 18.

Participants will receive an IV infusion of tiragolumab 420 mg on days 1 and 15 of each 28-day cycle according to the instructions outlined in Table 19. On Day 1 of Cycle 1, tiragolumab is administered 60 minutes after completion of atezolizumab infusion. The interval between subsequent infusions was 30 minutes if the previous atezolizumab infusion was given without premedication and was tolerated without an infusion-related reaction (IRR), or if the patient experienced an IRR on the previous atezolizumab infusion. 60 minutes.

Participants received an IV infusion of nab-paclitaxel 125 mg/ ^m2 on days 1, 8, and 15 of each 28-day cycle, administered by IV infusion over 30 (±5) minutes, followed by gemcitabine 1000 mg/m2. ^m2 is administered by IV infusion over 30 (±10) minutes. On Day 1 of Cycle 1, nab-paclitaxel is administered 60 minutes after the end of the tiragolumab infusion. The interval between subsequent infusions is 30 minutes if the previous tiragolumab infusion was tolerated without IRR, or 60 minutes if the patient experienced an IRR on the previous tiragolumab infusion.

Dose Modifications There were no dose modifications of atezolizumab or tiragolumab in this study. To manage drug-related toxicity, doses of nab-paclitaxel up to 25 mg/m ² (1 dose level) and gemcitabine up to 200 mg/m ² (1 dose level) were increased as outlined in Table 20. ) can be reduced.

If a further dose reduction is indicated for nab-paclitaxel and/or gemcitabine after two dose reductions, the drug (or both drugs, if applicable) will be discontinued, but the patient may be given another dose at the investigator's discretion. Study treatment can be continued. After dose reduction, the dose may be escalated during subsequent administrations at the discretion of the investigator.

Concomitant Therapy Concomitant therapy includes any drug used by the patient (e.g., prescription drug, over-the-counter drug, vaccines, herbal or homeopathic remedies, dietary supplements).

Patients are allowed to use the following therapies during the study:
colony-stimulating factors ( CSF), such as granulocyte colony stimulating factor (G-CSF), and erythropoiesis stimulating agents (ESA).
There is limited evidence to support the use of the long-acting (PEGylated) form of G-CSF in patients receiving weekly chemotherapy (ie nab-paclitaxel). Therefore, investigators should consider prioritizing conventional formulations of G-CSF.
● Oral contraceptives ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable dose warfarin or low molecular weight heparin)
Inactivated influenza vaccination Megestrol acetate administered as an appetite stimulant after initiation of study treatment Mineralcorticoids (eg fludrocortisone)
Inhaled corticosteroids given for chronic obstructive pulmonary disease or asthma Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency Gonadotropin-releasing hormone agonists or antagonists for prostate cancer hormonal therapy using palliative radiation therapy (e.g. treatment of known bone metastases or symptomatic relief of pain) as outlined below:
Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with nab-paclitaxel and gemcitabine should be withheld during palliative radiotherapy. Treatment with atezolizumab and tiragolumab may be continued during palliative radiotherapy.
● Radiation therapy to the brain as outlined below:
Patients with stable extracranial tumor burden or responding to study treatment who are subsequently found to have ≤3 brain metastases will receive radiation therapy to the brain if all of the following criteria are met: (either stereotactic radiosurgery or whole-brain radiotherapy).
- Patient has no evidence of progression or bleeding after completion of CNS-directed therapy.
- Patient has no ongoing need for corticosteroids as treatment for CNS disease.
Patients requiring corticosteroid therapy more than 7 days after completion of radiation therapy must discontinue study treatment.
- Anticonvulsant therapy is administered at stable doses as needed.
Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent atezolizumab and tiragolumab infusions at the investigator's discretion.

In general, investigators should manage patient care using clinically indicated supportive care according to local standard practice. Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine) or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and _β2- adrenergic must be administered by a sexual agonist).

Inclusion Criteria Patients meet the following criteria:
● Age 18 or older at the time of signature ● ECOG performance status 0 or 1
- Histologically or cytologically confirmed metastatic PDAC
A definitive diagnosis of metastatic PDAC is made by evaluating histopathological data within the context of clinical and radiological data.
Patients with endocrine or acinar pancreatic carcinoma are not eligible for the study.
No prior systemic treatment for PDAC Investigator-determined life expectancy ≥3 months Availability of representative tumor specimens suitable for determination of PD-L1 and/or further biomarker status by central laboratory Base Line tumor tissue samples are preferably collected from all patients by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, tumor tissue storage may be submitted after obtaining medical monitor approval, provided that the tissue was performed within 3 months prior to enrollment. Obtained from a biopsy, provided that the patient has not received any anticancer therapy since the time of biopsy.
Formalin-fixed, paraffin-embedded tumor specimens in paraffin blocks (preferred) or at least 16 slides containing unstained freshly cut serial sections must be submitted with relevant pathology reports prior to study enrollment. If only 10-15 slides are available, the patient may still be eligible for the study after obtaining medical monitor approval.
- Signed informed consent form - Ability to comply with study protocol, as determined by investigator - Measurable disease (at least 1 target lesion) per RECIST v 1.1
Previously irradiated lesions can be considered measurable disease only if progressive disease is clearly documented at the site after irradiation.
- Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:
- ANC ≥ 1.5 x 10 ⁹ /L (1500/μL) without granulocyte colony stimulating factor support within 14 days prior to screening test test
- WBC count ≧2.5×10 ⁹ /L (2500/μL)
- Lymphocyte count ≧0.5×10 ⁹ /L (500/μL)
- Platelet count ≥ 100 x 10 ⁹ /L (100,000/μL) without transfusion within 7 days prior to screening laboratory test
- hemoglobin ≥ 90 g/L (9.0 g/dL)
Patients may be transfused to meet this criteria after review with a medical monitor.
- AST, ALT and ALP ≤2.5 times the upper limit of normal (ULN) except for:
Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
- Serum bilirubin ≤ 1.5 x ULN, with the following exceptions:
Patients with known Gilbert's disease: Serum bilirubin level < 3 x ULN
- Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)
- Serum albumin ≥25 g/L (2.5 g/dL)
- For patients not receiving anticoagulant therapy: INR or aPTT ≤ 1.5 x ULN
• Patients receiving therapeutic anticoagulants: stable anticoagulant regimen • Tumors accessible for biopsy • For women of childbearing potential: abstinence (abstinence from heterosexual intercourse) or contraceptive measures and agree to refrain from donating eggs For men: maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and refrain from donating sperm you agree to

Safety Measures are taken to ensure the safety of patients participating in this study, including the use of strict inclusion and exclusion criteria and close monitoring of patients during the study. Administration of the study treatment will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions. Adverse events will be reported as described.

Verbal adverse event terms are mapped to the Medical Dictionary for Regulatory Activities thesaurus terms and adverse event severity is graded according to NCI CTCAE v 4.0.

Safety will be assessed through a summary of adverse events, changes in laboratory results, changes in vital signs and ECG, and exposure to study drug. Exposure to combination treatment and length of safety follow-up are summarized by treatment group within each phase.

Treatment-emergent adverse events occurring after treatment initiation will be summarized. For each patient, the maximum reported severity of each adverse event will be used in the summary by severity grade. List all n treatment emergent adverse events, serious adverse events, adverse events leading to study treatment discontinuation, grade 3 adverse events, deaths, and causes of death, mapped terms, appropriate synonym levels, and summarized by NCI CTCAE severity grade. Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data are displayed by time with grades identified as appropriate. In addition, baseline and post-baseline maximum severity grades will be summarized using shift tables for selected laboratory tests. Summarize changes in vital signs and ECG.

Atezolizumab is associated with the following risks: IRR and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barre syndrome, myasthenia syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis and myositis. Immune-mediated reactions can involve any organ system and can lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome (considered potential risks of atezolizumab).

The following are the most common adverse events observed with nab-paclitaxel in PDAC patients: neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, fever, vomiting, anorexia. , rash, and dehydration. The following adverse events have also been observed: myelosuppression (mainly neutropenia, anemia, thrombocytopenia), cranial nerve palsy, hypersensitivity reactions, pneumonitis, myalgia, arthralgia, cardiotoxicity (myocardial injury, heart failure). , angina pectoris, tachycardia, ventricular arrhythmias), cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, injection site reactions/extravasation, hepatotoxicity (drug-induced liver injury), Acute renal failure, hemolytic uremic syndrome, and drug-induced lupus erythematosus.

The most common adverse events observed with gemcitabine were nausea/vomiting, anemia, hepatic transaminates, neutropenia, increased ALP, proteinuria, pyrexia, hematuria, rash, thrombocytopenia, dyspnea and Peripheral edema.

IRR is a risk identified for tiragolumab. Although clinical evaluation of tiragolumab is limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is expected to enhance T cell and NK cell proliferation, survival, and function. Therefore, tiragolumab may increase the risk of autoimmune inflammation (also described as immune-mediated adverse events). Furthermore, due to the intact Fc effector function of tiragolumab, antibody-dependent cellular cytotoxicity (ADCC)-mediated lymphopenia is a theoretical risk.

Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, hypersensitivity reactions, target-mediated cytokine release, and/or acute ADA-associated IRR can occur. Clinical signs and symptoms of such reactions may include hypothermia, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia and fever. IRR has been reported in patients treated with tiragolumab alone or in combination with atezolizumab. Most events were mild to moderate and manageable.

To minimize the risk of IRR and sequelae, the initial dose of tiragolumab is administered over 60 minutes followed by a 60 minute observation period. Subsequent injections and observation times can be shortened if the preceding injections are well tolerated. All tiragolumab infusions are administered in an appropriate medical setting.

Non-clinical models suggest a role for disruption of TIGIT signaling in autoimmunity. In a knockout model (TIGIT-/-), loss of TIGIT signaling resulted in exacerbation of hyperproliferative T-cell responses and experimental autoimmune encephalitis (EAE). TIGIT-/- and wild-type B6 mice were immunized with suboptimal doses of myelin oligodendrocyte glycoprotein peptides to induce EAE. In contrast to wild-type B6 mice, the majority of TIGIT-/- mice developed severe EAE (Joller et al. 2011).

Clinical experience with therapeutics intended to enhance anti-tumor T cell responses has demonstrated that the development of autoimmune inflammatory conditions is a common risk and thus could be considered a potential risk for tiragolumab. . Such immune-mediated adverse events have been described for virtually all organ systems, including but not limited to colitis, hepatitis, pneumonitis, endocrine insufficiency, ocular toxicity, pancreatic toxicity, neurotoxicity, myocarditis, Nephritis, myositis and rash are included.

Patients with a history of autoimmune disease are excluded from this study. In addition, patients with a history of severe immune-mediated adverse events related to prior immunotherapy or adverse events that did not resolve to baseline after discontinuation of prior immunotherapy are excluded from the study.

In this study, certain immune-mediated adverse events are considered adverse events of special interest and captured accordingly.

Given the IgG1 backbone of tiragolumab with intact Fc effector function, ADCC-mediated reduction in lymphocyte counts is a potential risk. However, in repeated-dose toxicity studies in cynomolgus monkeys, there was no tiragolumab-related decrease in global lymphocyte counts.

A transient decrease in lymphocyte counts without clinical sequelae has been observed in patients treated with tiragolumab, alone or in combination with atezolizumab, in a phase I trial in solid tumors (GO 30103 study) . Because of this potential risk of tiragolumab inducing lymphopenia, patients with lymphocyte counts <0.5×10 ⁹ /L (500/μL) are excluded from the study. Complete blood counts are monitored throughout the study.

The following adverse events are potential overlapping toxicities associated with the combination of atezolizumab, nab-paclitaxel, gemcitabine, and tiragolumab: hemophagocytic lymphohistiocytosis, immune-mediated toxicities including macrophage activation syndrome, gastrointestinal Toxicity, hematotoxicity, and skin toxicity.

On Day 1 of each cycle, patients had an ANC of ≥1.5 x 10 ⁹ /L (1500/μL) and an ANC of 100 x 10 ⁹ /L (100,000) to receive treatment with nab-paclitaxel and gemcitabine. /μL) or higher.
Treatment interruption for toxicity

Atezolizumab and/or tiragolumab may be temporarily discontinued in patients experiencing toxicity considered related to study treatment. When corticosteroids are initiated for the treatment of toxicity, corticosteroids must be tapered to no more than 10 mg/day oral prednisone or equivalent over 1 month before drug can be restarted. If atezolizumab or tiragolumab is held for more than 12 weeks, patients will be discontinued from the drug. However, drug may be withheld for more than 12 weeks to allow patients to taper corticosteroids before resuming treatment. Atezolizumab or tiragolumab may be held for more than 12 weeks and then resumed if the medical monitor believes the patient is likely to experience clinical benefit.

Based on the available characterization of mechanism of action, tiragolumab may cause similar but independent adverse events to atezolizumab. Tiragolumab may also exacerbate the frequency or severity of atezolizumab-related adverse events or have toxicities that do not overlap with atezolizumab. Because these scenarios may be indistinguishable from each other in clinical practice, immune-mediated adverse events should generally be attributed to both agents, and drug interruption or treatment discontinuation in response to immune-mediated adverse Must apply to both atezolizumab.

Nab-paclitaxel and/or gemcitabine treatment may be temporarily discontinued in patients experiencing toxicity considered related to study treatment. If nab-paclitaxel or gemcitabine are withheld for more than 56 days due to toxicity, patients must discontinue both chemotherapy agents. However, nab-paclitaxel or gemcitabine can be held for more than 56 days and then resumed if the medical monitor believes that the patient is likely to experience clinical benefit.

If atezolizumab is discontinued, tiragolumab should also be discontinued, but nab-paclitaxel and gemcitabine may be continued if the patient is likely to benefit clinically, as determined by the investigator. When discontinuing nab-paclitaxel, gemcitabine, or tiragolumab, other drugs may be continued if the patient is likely to benefit clinically, as determined by the investigator.
statistics

Final study analysis is based on patient data collected through study discontinuation. Unless otherwise stated, efficacy analyzes were based on the efficacy evaluable population defined as all patients who received at least one dose of each drug on their assigned treatment regimen; Based on a safety evaluable population defined as all patients who received any amount of study treatment.

Data are described and summarized as warranted by sample size. Continuous variables are summarized using mean, standard deviation, median and range. Categorical variables are summarized by the use of counts and percentages. If the sample size is small, use lists instead of tables.

This test was not designed to account for explicit power and Type I errors for hypothesis testing. Instead, this study is designed to obtain preliminary efficacy, safety, and PK data for immunotherapy-based treatment combinations when administered to patients with metastatic PDAC.

Table 21 shows the estimated difference in ORR between the experimental and control groups, assuming asymptotic normality, with 90% confidence intervals with a sample size of 15 patients each in the preliminary phase.

Table 22 shows the estimated difference in ORR between the experimental and control groups with 90% confidence intervals, assuming asymptotic normality, combined sample size of 40 patients each in the pre- and expansion phases. ing.

Objectives and Endpoints A summary of the objectives and corresponding endpoints of this study is provided in Table 23.

Overall response at one time point will be assessed by the investigator using RECIST v 1.1. Overall response by iRECIST is not captured in the eCRF, but is calculated programmatically based on individual investigator-assessed lesion data recorded in the eCRF.

Efficacy analysis The primary efficacy endpoint is objective response. ORR, the proportion of patients with a complete or partial response, is calculated for each group with 90% confidence intervals (Clopper-Pearson method). Differences in ORR between experimental and control groups are calculated with 90% confidence intervals. Confidence intervals are estimated by the asymptotic droplet normality method, depending on the sample size.

Secondary efficacy endpoints are PFS, OS, OS at a specified time point (e.g., 6 months), duration of response (DOR); Determined by the Investigator. DOR is derived for efficacy evaluable patients with complete or partial response. For patients with no documented disease progression or death during the study phase, PFS and DOR will be censored on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day known to be alive.

The Kaplan-Meier method is used to estimate median PFS, OS, and DOR, and 90% confidence intervals are constructed by using the Brookmeyer and Crowley method. The OS rates at specific time points are estimated using the Kaplan-Meier method and 90% confidence intervals are calculated based on Greenwood's estimate of the variance. Disease-control rate, proportion of patients with stable disease, partial response, or complete response over 12 weeks is calculated for each treatment group, and 90% confidence intervals are estimated by use of the Clopper-Pearson exact method. .

Exploratory efficacy endpoints were investigator-determined objective response, PFS, DOR, and disease control according to iRECIST, the change from baseline in CA19-9 at subsequent time points during both phases. DOR is derived for efficacy evaluable patients with complete or partial response. The change in CA19-9 from baseline over time is summarized. In addition, the proportion of patients with a maximal reduction of ≥50% from baseline in CA19-9 or other thresholds can be calculated for each treatment group, with 90% confidence intervals using the Clopper-Pearson exact method. estimated by

Pharmacokinetic Analysis Sparse samples for potential PK analysis of atezolizumab (patients who received atezolizumab at least 1 dose) and the indicated drug administered in combination with atezolizumab (patients who received at least 1 dose of drug) can be collected. Serum or plasma concentrations of various study drugs were reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range) by treatment group and, where appropriate and data permitted, by cycle and day. , geometric mean, and geometric mean coefficient of variation). Individual and median serum or plasma concentrations of various study drugs can be plotted by treatment group and cycle and day. PK data for formulations can be compared to available historical data from internal and previous published studies. Atezolizumab concentration data can be pooled 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 Analysis Immunogenicity may be assessed for atezolizumab and other test treatments as appropriate (see group specific appendix for details). Immunogenicity analysis included all patients who had at least one anti-drug antibody (ADA) assessment. Patients are grouped according to the treatment received or assigned treatment if they had not received treatment prior to study discontinuation.

For atezolizumab, baseline (baseline prevalence) and post-baseline (post-baseline incidence) number and proportion of ADA-positive and ADA-negative patients will be summarized by treatment group. When determining post-baseline incidence, if a patient is ADA-negative or has missing data at baseline but develops an ADA response after study drug exposure (treatment-induced ADA response), or ADA positive if the patient is ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response) is considered to be If the patient is ADA-negative or has missing data at baseline and all post-baseline samples are negative, or if the patient is ADA-positive at baseline but the titer of the baseline sample is higher than Patients are considered ADA-negative if they have no post-baseline sample with a titer at least 0.60 titer units greater (treatment is unaffected).

For other test treatments that test for ADA, ADA positivity is determined according to standard methods established for previous testing of these drugs. Relationships between ADA status and safety, efficacy, PK, and biomarker endpoints can be analyzed and reported by descriptive statistics.

Example 3. A phase Ib, open-label, multicenter study of the safety, efficacy, and pharmacokinetics of atezolizumab and tiragolumab in combination with chemotherapy in patients with triple-negative breast cancer. A phase Ib, open-label, multicenter study designed to evaluate the safety, efficacy and pharmacokinetics of tiragolumab in combination with atezolizumab and chemotherapy is described. This trial will consist of the following cohorts:
Cohort A will enroll patients with unresectable, locally advanced, or metastatic programmed death ligand 1 (PD-L1)-positive TNBC (primary metastatic TNBC) who have not received prior systemic therapy for metastatic breast cancer . Patients receive tiragolumab in combination with atezolizumab and nab-paclitaxel.

A. STUDY DESIGN This Phase Ib, multicenter, open-label, multicenter global study will evaluate patients with unresectable, locally advanced or metastatic PD-L1-positive TNBC who have received no prior systemic treatment for metastatic breast cancer (Cohort A, It is designed to investigate the safety and tolerability, preliminary efficacy, and pharmacokinetics of tiragolumab in combination with atezolizumab and nab-paclitaxel in metastatic TNBC). PD-L1 positivity is assessed using the SP142 PD-L1 IHC assay. FIG. 2 shows the study design for Cohort A.

Eligible patients (ie, PD-L1 positive patients) received tiragolumab (840 mg) and atezolizumab (1680 mg) by IV infusion on day 1 of every 28-day cycle, plus nab-paclitaxel (100 mg/m2). Patients are enrolled to be dosed by IV infusion on days 1, 8, and 15 of every 28-day cycle.

In the absence of disease progression or unacceptable toxicity, nab-paclitaxel is administered to target for at least 6 cycles, but not maximally.

Tumor tissue may optionally be collected on Day 1 of Cycle 2 prior to dosing in order to assess the mechanism of action and possible resistance mechanisms of the drug combination in the tumor microenvironment.

To examine mechanisms of resistance to drug combinations in the tumor microenvironment, all patients will undergo disease progression as assessed by the investigator according to RECIST v1.1 (prior to initiation of new anticancer treatment). undergo mandatory tumor biopsy collection (if clinically feasible) at first evidence of

Patients undergo tumor assessments at baseline and every 8 weeks (±7 days) after Day 1 of Cycle 1 for the first 48 weeks, regardless of any delay in treatment. After completion of the 48-week tumor assessment, the tumor assessment will be based on treatment delay, withdrawal of consent, death, or study termination (whichever occurs first) until disease progression as determined by the Investigator according to RECIST v1.1. Regardless, it is required every 12 weeks (±7 days).

Study treatment will be discontinued upon disease progression as determined by the investigator according to RECIST v 1.1. For definite evidence of progression (e.g., very small or equivocal new lesions or lymph nodes; cystic changes or necrosis in pre-existing lesions), follow the investigator-assessed RECIST v1.1 for the next scheduled Treatment may be continued until evaluation is completed. If progression is confirmed at the next scheduled assessment, the date of progression should be the earlier date when progression was suspected.

B. Dosing and Administration The treatment regimen is summarized in FIG.

On the day of the scheduled infusion of atezolizumab, tiragolumab and chemotherapy, chemotherapy is administered after infusion of atezolizumab and tiragolumab.

After atezolizumab infusion (1680 mg), the patient receives 840 mg of tiragolumab.

Administration of atezolizumab, tiragolumab, and chemotherapy will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Refer to the Investigational Product Control Procedures for detailed instructions regarding formulation, storage, and administration.
Tiragolumab and atezolizumab

Patients in Cohort A received a fixed dose of atezolizumab of 1680 mg administered by IV infusion Q4W on Day 1 of each 28-day cycle, followed by 840 mg administered by IV infusion Q4W on Day 1 of each 28-day cycle. fixed dose of tiragolumab. The doses of tiragolumab and atezolizumab are fixed and independent of body weight. Tiragolumab and atezolizumab infusions (including the observation period) will be administered according to the instructions outlined in Table 24.

Nab-paclitaxel Nab-paclitaxel will be administered according to local prescribing information. The starting dose level of nab-paclitaxel in this study was 100 mg/m ² administered intravenously over 30 minutes to patients on days 1, 8, and 15 of each 28-day cycle (3 weeks on/1 weekly off schedule). Nab-paclitaxel should be administered after atezolizumab and tiragolumab. Nab-paclitaxel is administered alone on days 8 and 15 of each cycle. Doses of nab-paclitaxel should not be administered more frequently than every 7 days.

Sites must follow the institution's standard of care for determining nab-paclitaxel doses for patients who are obese and for dose adjustments in the event of patient weight change. The injection site must be closely monitored for possible infiltration during drug administration.

In the absence of disease progression or unacceptable toxicity, nab-paclitaxel is administered to target for at least 6 cycles, but not maximally.

See topical prescribing information for additional details regarding the preparation and administration of nab-paclitaxel.

Dose change

There were no dose modifications of atezolizumab or tiragolumab in this study. See Table 25 for administration of nab-paclitaxel (ie dose modification and treatment interruption rules).

C. Concomitant Therapy Concomitant therapy is any medication used by the patient (e.g., prescription, over-the-counter, vaccines, herbal or homeopathic remedies, dietary supplements).

Allowed Treatments Patients will be allowed to use the following treatments during the study:
● Oral contraceptives with an annual failure rate of less than 1% ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable-dose warfarin or low molecular weight heparin)
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
o Corticosteroids given for chronic obstructive pulmonary disease or asthma o Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency o Bisphosphonates for the prevention of skeletal events o For the following: Palliative radiotherapy outlined (e.g. treatment of known bone metastases or symptomatic relief of pain):
Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with tiragolumab and atezolizumab may be continued during palliative radiotherapy. Treatment with nab-paclitaxel must be discontinued according to institutional standard of care.
Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent atezolizumab and tiragolumab infusions at the investigator's discretion.

Treatments requiring caution Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines must be considered If alternatives are not feasible, corticosteroids and TNF-α inhibitors Systemic administration of agents can be at the discretion of the investigator.

Systemic corticosteroids are recommended at the investigator's discretion for treatment of specific adverse events when associated with atezolizumab therapy.

Prohibited Therapies The use of the following concomitant therapies is prohibited as described below:
Any health authority-approved or experimental combination therapy for the treatment of cancer (including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy). Concomitant therapy for various periods prior to initiation of study treatment, depending on drug, and during study treatment until disease progression is documented and patient discontinues study treatment, excluding palliative radiation therapy, regardless of • Study treatment within 28 days prior to initiation of study treatment and during study treatment • Live attenuated vaccine (e.g., FLUMIST®) within 4 weeks prior to initiation of study treatment, during atezolizumab treatment and 5 months after the last dose of study treatment ))
Due to the potential increased risk of autoimmune symptoms when administered in combination with atezolizumab and tiragolumab, no drug elimination half-lives (either within 4 weeks or 5 during study treatment) or longer), systemic immunostimulants (including but not limited to interferon and IL-2)
Systemic immunosuppressants (including but not limited to azathioprine, methotrexate, and thalidomide) during study treatment (as these agents may potentially alter the efficacy and safety of atezolizumab and tiragolumab)
• Plinabulin, a new molecule being tested for the reduction of chemotherapy-induced neutropenia, has not been accepted as an alternative to G-CSF/GMCSF.

D. Inclusion Criteria Patients must meet the following general criteria for study entry:
● Signed informed consent form ● Females and males ≥18 years of age at the time of signing the informed consent form ● Ability to comply with the study protocol ● ECOG performance status 0 or 1
Adequate hematologic and end-organ function, defined as the following laboratory results obtained within 14 days prior to the start of study treatment (Day 1 of Cycle 1) - Prior to Day 1 of Cycle 12 ANC ≧1.5×109/L (1500/μL) without G-CSF support within weeks
- Lymphocyte count ≥0.5 X 109/L (≥500/μL)
- Platelet count ≥100 X 109/L (≥100,000/μL) without transfusion within 2 weeks prior to Cycle 1 Day 1
- Hemoglobin ≧90 g/L (≧9 g/dL).
Patients can receive blood transfusions or erythropoietic procedures to meet this criterion - AST, ALT, ALP ≤ 2.5X upper limit of normal (ULN)
- serum bilirubin ≤ 1.5 XULN, with the following exceptions:
Known Gilbert's disease patients with serum bilirubin levels < 3XULN can be enrolled.
- INR and aPTT ≤ 1.5XULN
This applies only to patients not receiving therapeutic anticoagulant therapy, and patients receiving therapeutic anticoagulant therapy should be on stable doses.
- Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula)
- serum albumin ≥25 g/L (≥2.5 g/dL)
A negative HIV test at screening A negative hepatitis B surface antigen (HBsAg) test at screening A positive hepatitis B surface antibody (HBsAb) test at screening or negative HBsAb at screening with any of the following:
- total hepatitis B core antibody (HBcAb) negative - positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA
<500 IU/mL
HBV DNA testing is performed only for patients with negative HBsAg, negative HBsAb, and positive total HBcAb tests.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening.
HCV RNA testing is performed only for patients who test positive for HCV antibodies.
For women of childbearing potential: Consent to abstinence (abstinence from heterosexual intercourse) or use of contraceptive methods, and consent to abstain from donating eggs, as defined below:
Women should be treated during treatment and for at least 5 months after the last dose of atezolizumab, 90 days after the last dose of tiragolumab, 1 month after the last dose of nab-paclitaxel, 6 months after the last dose of carboplatin or doxorubicin, or For 12 months after the last dose of Famide, whichever is later, must maintain abstinence or use a contraceptive method that results in a failure rate of <1% per year. Females should refrain from donating eggs during this same period.
Females are post-menopausal, have not reached a post-menopausal state (>12 consecutive months of amenorrhea, no other cause identified), and are surgically infertile (removal of ovaries and/or uterus). ) is considered to be of possible gestation.
Examples of methods of contraception with an annual failure rate of <1% include combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation, progestogens associated with inhibition of ovulation when used consistently and correctly. hormonal contraception alone, bilateral fallopian tube obstruction, male infertility; intrauterine devices; intrauterine hormone releasing systems; and sexual abstinence.
The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle.
Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.
Women who wish to become pregnant after discontinuing study treatment should seek advice on oocyte storage prior to initiation of study treatment due to possible irreversible infertility resulting from chemotherapy treatment. .
For men: agreeing to maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and to abstain from donating sperm, as defined below:
For female partners of childbearing potential or pregnant, either during the treatment period and for 90 days after the last dose of tiragolumab or 6 months after the last dose of nab-paclitaxel, carboplatin, doxorubicin, or cyclophosphamide Later, men must maintain abstinence or use additional methods of contraception in conjunction with condoms that result in failure rates of <1% per year. Men must stop donating sperm during the same period.
The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle.
Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.
Men who wish to have children after initiation of study treatment should seek advice on sperm storage prior to initiation of study treatment due to the potential for irreversible infertility resulting from treatment with chemotherapy.
• Females who are not postmenopausal (≥12 months of non-treatment-induced amenorrhea) or who have undergone surgical sterilization must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other testing procedures

Patients in Cohort A must meet the following cancer-specific criteria for study entry:
- Life expectancy ≥12 weeks - Metastatic or locally advanced unresectable histologically documented TNBC (absence of HER2, ER and progesterone receptor (PgR) expression as determined by local examination)
HER2-negative is defined as either of the following (Wolff et al. 2018) by local laboratory assessment:
In situ hybridization (ISH) unamplified (HER2 to CEP 17 ratio <2.0 or single probe average HER2 gene copy number <4 signals/cell), or IHC 0 or IHC 1+.
ER and PgR negative is defined as <1% of cells expressing hormone receptors as determined by IHC analysis.
- Only patients with metastatic TNBC tumors that are centrally tested and found to be PD-L1 positive will be enrolled

Tumor specimens from recurrent metastatic or locally advanced disease (if applicable) should be submitted, if clinically feasible.

Representative FFPE tumor specimens in paraffin blocks (preferred) or at least 20 unstained slides (either archival specimens or fresh pretreated tissue from recurrent disease)

Tumor tissue must be of good quality based on total tumor content and viable tumor content and assessed for PD-L1 expression as determined using the Ventana (SP142) PD-L1 IHC assay prior to enrollment. Positivity is defined as ≥1% of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells of any intensity as determined by a central laboratory. Patients whose tumor tissue was not evaluable for PD-L1 expression were not eligible.

If multiple tumor specimens are submitted, if at least one specimen is evaluable and positive for PD-L1 expression (whether the tissue is from archival specimens or from recurrent disease); Patients may be eligible.

Acceptable samples include core needle biopsies (minimum of 3 cores) for deep tumor tissue, or excision, incision, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspirations, brushings, cell pellets from pleural effusions, bone metastases, and lavage fluid samples are not permitted. Tumor tissue from bone metastases cannot be assessed for PD-L1 expression and is therefore unacceptable.
- No prior chemotherapy or targeted systemic therapy for inoperable, locally advanced, or metastatic TNBC

Prior radiation therapy for metastatic disease is permissible. There is no minimum washout period required for radiation therapy. Patients must recover from the effects of radiation.

Prior chemotherapy (including taxanes) and/or CIT (anti-PD-L1 agents or anti-PD-1 agents only) in neoadjuvant or adjuvant therapy acceptable if therapy was completed ≥12 months prior to initiation of study treatment be done.
- Investigator-assessed measurable disease according to RECIST v1.1

Previously irradiated lesions can be considered measurable disease only if there is clearly documented disease progression at the site after irradiation.

E. Exclusion Criteria Patients meeting any of the following criteria will be excluded from the study:
Pregnancy during study treatment, within 90 days after tiragolumab treatment, within 5 months after atezolizumab treatment, within 6 months after nab-paclitaxel, carboplatin or doxorubicin treatment, or within 12 months after cyclophosphamide treatment (whichever is longer) or breastfeeding, or intending to become pregnant

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
- Evidence of significant uncontrolled comorbidities that could affect interpretation of results, including protocol compliance or significant liver disease (e.g., cirrhosis, uncontrolled grand paroxysmal disorder, or superior vena cava syndrome) • Significant cardiovascular disease within 3 months prior to initiation of study treatment, eg New York heart disease (class II or greater), myocardial infarction, unstable arrhythmia or unstable angina Pectoris with known LVEF <53% are excluded.
Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.
- Severe infection within 4 weeks prior to initiation of study treatment (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia)
Oral or IV antibiotic treatment within 2 weeks prior to study treatment initiation Patients receiving routine antibiotic prophylaxis (e.g., to prevent exacerbation of chronic obstructive pulmonary disease or for tooth extraction) are eligible is.
Anticipation of need for major surgical procedure within 28 days prior to initiation of study procedure, or non-diagnostic procedure during study Placement of central venous access catheter(s) (e.g., ports, etc.) It is not considered a surgical procedure and is therefore acceptable.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, or fusion proteins.
Known hypersensitivity or allergy to CHO cell-produced biologics or any component of tiragolumab or atezolizumab formulations Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Active autoimmune disease including, but not limited to, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; or Their History Patients with a history of autoimmune-mediated hypothyroidism on stable doses of thyroid replacement hormone are eligible for this trial.
Patients with type 1 diabetes controlled on a stable insulin dosing regimen are eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin symptoms only (e.g., no psoriatic arthritis) are allowed if they meet the following conditions:
- Rash must cover <10% body surface area - Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UV within the last 12 months No occurrence of acute exacerbation of underlying symptoms requiring A-irradiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids - Administration of another immunostimulatory anticancer agent Caution should be exercised when considering atezolizumab in patients who have previously experienced severe or life-threatening cutaneous adverse reactions while being treated Prior allogeneic stem cell or solid organ transplantation Thoracic at screening History or activity of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (ie, bronchiolitis obliterans, subclinical organizing pneumonia) on computed tomography (CT) scan Evidence of pneumonitis A history of radiation pneumonitis (fibrosis) in the radiation field is acceptable.
Positive EBV viral capsid antigen (VCA) IgM test at screening EBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for suspected active or chronic active infection. must.
Patients with a positive EBV PCR test are excluded.
● Active tuberculosis (TB)
- Receiving a live-attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipating need for such a live-attenuated vaccine during the study Patients will receive treatment within 28 days prior to initiation of study treatment Must agree not to receive a live attenuated vaccine (eg, FLUMIST®) during or within 5 months after the last dose of study treatment.
- Pretreatment with CD137 agonists or immune checkpoint blockade therapy, including anti-CTLA-4, excluding anti-PD-1 or anti-PD-L1 therapeutic antibodies - Within 4 weeks prior to initiation of study treatment or 5 drug elimination halves of drug Treatment with systemic immunostimulating agents (including but not limited to interferon or IL-2) within the period (whichever is longer) Systemic immunosuppressive agents (including but not limited to,
Prednisone, dexamethasone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) or investigational systemic immunosuppressants expected to require acute low-dose systemic immunosuppressants (e.g., for nausea) of dexamethasone) may be enrolled in the study.
Patients with a history of allergic reactions to IV contrast agents requiring steroid pretreatment should undergo baseline and subsequent tumor assessments performed using magnetic resonance imaging (MRI).
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency is permissible. be.
Patients in Cohort A who meet any of the following cancer-specific exclusion criteria are excluded from study participation:
- FFPE tumor tissues that are PD-L1 negative as measured by the SP142 PD-L1 IHC assay, with FFPE tumors defined as ≥1% of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells of any intensity Tissues - Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression with clinically stable disease >2 weeks prior to initiation of study treatment. Spinal cord compression with no evidence of having known central nervous system (CNS) disease, provided all of the following criteria are met, except for treated asymptomatic CNS metastases:
- Only supratentorial and cerebellar metastases were allowed (ie no midbrain, pons, medulla oblongata or spinal cord metastases)
- No ongoing need for corticosteroids as treatment for CNS disease - No stereotactic radiation within 7 days or whole brain radiation within 14 days prior to initiation of study treatment - Completion of CNS-directed therapy and No evidence of interim progression between screening radiographs Note: Patients with new asymptomatic CNS metastases detected on screening must have undergone radiotherapy and/or surgery for CNS metastases . After treatment, these patients may be eligible without the need for additional brain scans prior to enrollment if all other criteria are met.
• Leptomeningeal disease • Uncontrolled pleural effusion, pericardial effusion, or ascites Patients with indwelling catheters (eg, PLEURX®) are permitted.
• Uncontrolled tumor-related pain Patients requiring narcotic analgesics must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (eg bone metastases or metastases causing nerve impingement) must be treated prior to enrollment. Patients must recover from the effects of radiation. There is no minimum recovery period required.
Asymptomatic metastatic lesions (epidural metastases not currently associated with spinal cord compression) whose further growth may cause dysfunction or intractable pain should be treated with locoregional therapy prior to enrollment, if appropriate. must be considered;
Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy, especially Patients receiving bisphosphonate therapy to prevent skeletal events and with no history of clinically significant hypercalcemia are eligible.
- Malignancies other than TNBC within 5 years prior to initiation of study treatment, but with negligible risk of metastasis or death (e.g., >90% 5-year OS) and treatment with expected curative outcome known hypersensitivity to nab-paclitaxel or any of its excipients disease

F. Analysis A safety analysis will be performed in all patients.

Efficacy analyzes will use the ITT approach for Cohorts A and B, and any enrolled patient will be included in the analysis regardless of whether the patient is receiving their assigned study drug. Analysis based on subsets of the ITT population can also be performed.

Hypothesis tests are two-sided unless otherwise indicated.

Sample Size The purpose of Cohort A is to estimate the effect of tiragolumab in combination with atezolizumab and nab-paclitaxel on the primary efficacy endpoint defined as objective response. Compared to historical data, the proportion of responses is considered either promising or unpromising for further development. There are no formal hypothesis tests. Statistics are presented as two-sided 90% CI. When recommending continuation or cessation of development, the overall data, including the results of secondary efficacy endpoints, including but not limited to PFS, OS, and subgroup analyses, will be considered.

The primary efficacy analysis is an estimate of the true proportion of patients expected to have a CR or PR (ie, ORR). Data from completed and ongoing trials in similar disease settings can be used as historical controls for comparison. Currently available data show a historically confirmed response rate of approximately 53% (TECENTRIQ® US Package Insert) in locally advanced, unresectable or metastatic PD-L1-positive TNBC there is

A sample size of 40 patients was used, assuming an observed response rate of 67.5%, point estimates and lower bounds for a two-sided 90% CI to exclude clinically irrelevant response probabilities of less than 53%. is considered sufficient to provide adequate accuracy of Specifically, if at least 27 out of 40 patients achieve a response, it can be concluded that the response rate is greater than 53%. Updated estimates of the proportion of patients expected to achieve a response are expected to be available from ongoing trials by the time of efficacy analysis and will be used as baseline data.

Table 26 lists the two-sided 90% Clopper-Pearson exact CIs for the true probability of achieving a response for a range of observed proportions based on a sample of 40 patients. The observed point estimates of ORR under various thresholds and the probabilities of detecting positive and negative signals based on the underlying true ORR are shown in Tables 27 and 28.

Safety analysis Safety assessments should include the incidence, nature and severity of adverse events, protocol-specified vital signs, laboratory abnormalities, and other factors considered important to the safety evaluation of the study. Includes protocol-specified studies. Adverse events are graded according to NCI CTCAE v5.0.

Safety is measured by the ADA and assessed by treatment group presented adverse events, changes in laboratory test results, changes in vital signs, study treatment exposure and immunogenicity summaries.

Verbal descriptions of adverse events are mapped to MedDRA terminology.

A treatment-emergent event (defined as an event occurring at or after the first dose of study treatment), regardless of relationship to study drug as assessed by the Investigator, is a MedDRA term, an appropriate MedDRA level, and summarized by the NCI CTCAE v5.0 grade. For each patient, if multiple occurrences of the same adverse event occur, the maximum severity reported will be used for summaries.

The following treatment-emergent adverse events will be summarized separately: adverse events leading to discontinuation of study drug, adverse events leading to dose reduction or interruption, grade ≥3 adverse events, grade 5 adverse events, serious Adverse Events and Adverse Events of Special Interest.

Summarize all deaths and causes of death.

Relevant laboratory values are summarized by time point and NCI CTCAE Grade 3 and Grade 4 values are identified as appropriate. Changes in NCI CTCAE grades will be summarized by treatment group.
Analysis of exposure, adverse events, laboratory and vital signs data

Safety is assessed through a summary of exposure to study treatment, adverse events, changes in laboratory results, and changes in vital signs and ECG.

Study treatment exposure (eg, duration of treatment, total dose received, and number of cycles and dose modifications) will be summarized by descriptive statistics.

All verbatim adverse event terms are mapped to MedDRA thesaurus terms and adverse event severity is graded according to the NCI CTCAE v5.0. All adverse events occurring at or after the first dose of study treatment (i.e., treatment-emergent adverse events), serious adverse events, adverse events leading to death, adverse events of special interest, and study treatment Adverse events leading to discontinuation of study will be summarized by mapped terms, appropriate synonym levels, and severity. For events of varying severity, the highest grade is used for summaries. Summarize deaths and causes of death.

Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data are displayed by time with grades identified as appropriate. In addition, baseline and post-baseline maximum severity grades will be summarized using shift tables for selected laboratory tests. Summarize changes in vital signs and ECG.

Efficacy Analysis Primary Efficacy Objectives The primary efficacy objective for Cohort A is to assess the efficacy of tiragolumab in combination with atezolizumab and nab-paclitaxel based on the following endpoints.
ORR, defined as the proportion of patients with an investigator-determined CR or PR using RECIST v1.1

Confirmation of PR or CR is required. Patients who do not meet this criteria, including those who do not have a post-baseline tumor assessment, are considered non-responders. ORR is defined as the proportion of patients with an objective response.

The earliest observation of efficacy data will be made after all patients have had at least two tumor assessments.

Secondary Efficacy Objectives The secondary efficacy objectives for Cohort A are to obtain preliminary data on the efficacy of tiragolumab in combination with atezolizumab and nab-paclitaxel based on the following endpoints.
- PFS, defined as the time from enrollment to the first occurrence of disease progression or death from any cause as determined by the investigator according to RECIST v 1.1 (whichever occurs first)

Data for patients who have never experienced disease progression or who have died are censored on the date of the last known survival and progression-free prior to or at the clinical cut-off date for each analysis. be done. Patients with no post-baseline information will be censored on the day of enrollment.
DOR: defined as the time from the first occurrence of documented objective response to disease progression or death from any cause (whichever occurs first) as determined by the investigator according to RECIST v1.1

Data for patients who have never experienced disease progression or died are censored at the date of the last tumor assessment. If no tumor assessment is performed after the date of first occurrence of CR or PR, DOR will be censored at the date of first occurrence of CR or PR.
- OS, defined as the time from enrollment to death from any cause

Patients not reported dead at the time of analysis are censored on the date they were last known alive. Patients with no information after baseline will be censored on the day of enrollment.

Pharmacokinetic Analysis Samples are collected for PK analysis and exposures in this study are compared to those obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab and plasma concentrations of nab-paclitaxel, carboplatin, doxorubicin and cyclophosphamide, where appropriate and data permitting, are reported as individual values by treatment arm and cycle and summarized (mean , standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Median individual and serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be pooled with data from other studies using established population PK models to derive data-assured PK parameters such as clearance, volume of distribution and AUC. . Potential correlations between relevant PK parameters and dose, safety, efficacy or biomarker outcomes can be examined.

Immunogenicity Analysis The immunogenicity analysis includes patients with any ADA assessment and groups the patients according to the treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients during treatment and follow-up are summarized by treatment group.

Relationships between ADA status and safety, efficacy and PK endpoints can be analyzed and reported using descriptive statistics.

Biomarker Analysis Although no formal statistical analysis of the exploratory biomarkers has been performed, the data can be analyzed in the context of this study and together with data from other studies.

Example 4. A Phase Ia/Ib, Open-label, Dose Escalation Study of the Safety and Pharmacokinetics of Tiragolumab in Combination with Atezolizumab and/or Other Anticancer Therapy as a Single Agent in Patients With Locally Advanced or Metastatic Tumors This example describes a first-in-human, Phase I, open-label, multicenter, global, dose escalation study designed to evaluate:
(Phase Ia) Local progression for which no standard treatment exists, has been proven to be ineffective or intolerable, or is considered inappropriate, or clinical trials of investigational agents are the recognized standard of care Safety, tolerability, and PK of tiragolumab as single-agent hospitalized patients with incurable, recurrent, or metastatic tumors; proven to be absent or considered inappropriate, clinical trials of investigational drugs are recognized standard of care, or clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are acceptable Safety, tolerability, and PK of tiragolumab when administered in combination with standard of care therapy in patients with locally advanced, recurrent, or metastatic incurable tumors that are considered viable treatment options.

A. test plan

This first-in-human, Phase I, open-label, multicenter, global, dose escalation study demonstrated that no standard of care exists, has proven to be ineffective or intolerable, or is considered inappropriate. or Investigational Clinical Trials to assess the safety, tolerability, and PK of tiragolumab as single-agent hospitalized patients with locally advanced, recurrent, or metastatic incurable tumors, a recognized standard of care is designed to This will be assessed in the Phase Ia portion of the trial.

The trial also indicates that no standard of care exists, has been proven to be ineffective or intolerable, or is considered inappropriate, or is a recognized standard of care for clinical trials of an investigational drug; or in combination with standard treatment therapy in patients with locally advanced, recurrent, or metastatic incurable tumors for whom a clinical trial of an investigational drug in combination with an anti-PD-L1 antibody is considered an acceptable treatment option It is designed to allow assessment of the safety, tolerability, and PK of tiragolumab when administered. It is being tested in multiple cohorts in the Phase Ib portion of the trial.
Phase Ib: Tiragolumab and Atezolizumab Dose Escalation Cohort (Figure 4)
Phase Ib: Tiragolumab and Atezolizumab Indication-Specific Expansion Cohort (Figure 4)
- Phase Ib: Serial biopsy cohort of tiragolumab and atezolizumab (Figure 4)
Phase 1b: Tiragolumab and Atezolizumab every 4 weeks (Q4W) dosing expansion cohort (Figure 4)
Phase Ib: Tiragolumab and Atezolizumab in Combination with Chemotherapy Expansion Cohort (Cohorts AD; Figure 5)
Phase Ib: Tiragolumab in combination with non-chemotherapy expansion cohorts (cohorts NC 1 and NC 2; Figure 6)

The Phase Ib portion of the study was activated after the DLT evaluation of single-agent tiragolumab at at least two dose levels was completed and all relevant single-agent safety data had been fully reviewed by the investigator and the IMC. being considered. If deemed appropriate, the Phase Ib portion will begin at dose levels equal to or lower than the initial tiragolumab dose level using the same dose escalation scheme and comprehensive safety monitoring plan as for the Phase Ia portion. Additionally, patients progressing in the Phase Ia portion of the trial using single agent tiragolumab may be given the option of crossing over to the Phase Ib portion of the trial.

Both the Phase Ia and Phase Ib portions of the study consist of a screening period, a treatment period, and a post-treatment follow-up period. Patients are enrolled in two phases, a dose escalation phase and a dose expansion phase, see Figures 3 and 4 for Phases Ia and Ib, respectively. Figure 4 further shows the serial biopsy and Q4W cohorts, Figure 5 shows the Phase Ib chemotherapy expansion cohort, and Figure 6 shows the Phase Ib no-chemo expansion cohort. During the dose escalation phase, cohorts of approximately 3-6 patients are evaluated at each escalating dose level to determine the MTD or maximum administered dose (MAD) of tiragolumab as a single agent or in combination with atezolizumab. To obtain additional safety and pharmacodynamic data to more fully inform dose selection for the expansion cohort, additional patients will be enrolled to not exceed the relevant MTD based on the dose escalation criteria described below. Cohorts may be backfilled at dose levels as indicated. For purposes of dose escalation decisions, these patients will not be included as part of the DLT evaluable population.

In the dose expansion phase, patients are enrolled and treated at or below the MTD or MAD of tiragolumab, either as a single agent (Phase Ia) or in combination with atezolizumab and/or other anticancer therapies (Phase Ib).

Tiragolumab as a single agent (Phase Ia), or a combination of tiragolumab and atezolizumab, a combination of tiragolumab and atezolizumab and bevacizumab, or a combination of tiragolumab and pembrolizumab (Phase Ib cohort without chemotherapy) each for 21 days Administered by IV infusion on Day 1 of the cycle or Day 1 of each 28-day cycle (Phase Ib Q4W dosing expansion). In the chemotherapy-free Phase Ib cohort, tiragolumab is administered prior to atezolizumab, bevacizumab, or pembrolizumab. Atezolizumab and/or other anticancer therapy beyond Cycle 1, based on investigator's favorable assessment of benefit and risk, in the absence of clinically compelling evidence of unacceptable toxicity or disease progression treatment with either tiragolumab (Phase Ia) or tiragolumab (Phase Ib expansion cohort) in combination with

The Phase Ib chemotherapy and no-chemo expansion cohorts and the Phase Ib Q4W dosing expansion cohort complete a safety run-in of 3 patients. All relevant safety data from the safety run-in will be reviewed thoroughly by the IMC and investigator before enrollment continues.

Tiragolumab and atezolizumab were included in specific chemotherapy regimens in each of four chemotherapy expansion cohorts: 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. is combined with In cohorts A, B and C, treatment consisted of an induction phase and a maintenance phase. In the run-in phase, tiragolumab and atezolizumab in combination with chemotherapy will be administered by IV infusion for 4-6 cycles in Cohorts A and B and 4 cycles in Cohort C in 21-day cycles. The number of cycles of induction treatment for Cohorts A and B is at the investigator's discretion.

After the induction phase, patients who have not experienced disease progression or unacceptable toxicity continue treatment with maintenance therapy. During the maintenance phase, patients in Cohorts B and C continue on tiragolumab and atezolizumab alone, while patients in Cohort A continue on tiragolumab and atezolizumab along with pemetrexed.

In the maintenance phase, Cohort A continues with atezolizumab, tiragolumab and pemetrexed in 21-day cycles. In Cohort B, patients enrolled under Protocol GO30103 Version 4 will continue the 21-day cycle with atezolizumab and tiragolumab. In Cohort B, patients enrolled on protocol GO30103 Version 5 or later will begin a 28-day cycle with atezolizumab and tiragolumab. Cohort C will begin a 28-day cycle with atezolizumab and tiragolumab.

In Cohort D, patients receive treatment with tiragolumab, atezolizumab, and capecitabine until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients receive capecitabine at a dose of 1250 mg/m ² orally twice daily (BID) on days 1-14 of each 21-day cycle. On Day 1 of Cycle 1, the first dose of capecitabine is administered at the clinic prior to atezolizumab and tiragolumab infusions. The combination of tiragolumab and atezolizumab will be administered by IV infusion in 21-day cycles.

Atezolizumab is administered prior to tiragolumab in all chemotherapy expansion cohorts.

All patients will be closely monitored for adverse events throughout the study. Adverse events are graded according to the NCI CTCAE, version 4.0.

To characterize the PK properties, immunogenic responses, and pharmacodynamic effects of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) , blood samples are taken at various time points before and after dosing. Depending on the results of the interim PK analysis, the frequency of PK sampling may decrease later in the study.

Patients will undergo tumor assessments at screening and during the study, as measured by the Standard Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 criteria.

Even if standard RECIST v 1.1 criteria for disease progression are met in the Phase Ia or Phase Ib portion of the trial, if criteria for continued treatment are met, Patients may be allowed to continue study treatment (Figure 7). Patients who discontinue the Phase Ia portion of the trial, provided they meet crossover criteria and consent to biopsy of accessible lesions, will proceed to the Phase Ib portion of the trial and be treated with tiragolumab in combination with atezolizumab. (Fig. 8).

Patients who permanently discontinue tiragolumab (Phase Ia) or tiragolumab and atezolizumab, tiragolumab and atezolizumab with chemotherapy, tiragolumab and atezolizumab with bevacizumab, or tiragolumab and pembrolizumab (Phase Ib) will receive the last dose of study treatment They will return to the clinic for a treatment discontinuation visit within the next 30 days. Further monitoring and recording of adverse events of special interest will occur for up to 90 days after the last dose of study treatment, regardless of initiation of another systemic anticancer therapy. Monitoring and recording of all other adverse events will occur for up to 90 days following the last dose of study treatment or initiation of another systemic anti-cancer therapy, whichever occurs first. All patients in this study were followed up for survival and subsequent anticancer treatment information approximately every 3 months until death, loss of follow-up, or termination of the study, unless the patient requested withdrawal from follow-up. be done.

The IMC will periodically evaluate cumulative safety data from all patients treated in this study. Safety summary data will be evaluated by the IMC after completion of DLT assessments for the first two dose cohorts of the Phase Ia (single-agent tiragolumab) portion of the study. The IMC will review the safety data to determine whether to continue enrollment without changing the Phase Ia protocol, to review the safety data from the safety run-in cohort and to review the Phase Ib Chemistry Whether to continue enrollment in therapy expansion cohorts, non-chemotherapy expansion cohorts and Q4W treatment expansion cohorts, whether to modify safety monitoring and/or eligibility, address emerging safety issues recommend whether to initiate enrollment in the phase 1b portion of the study with tiragolumab in combination with atezolizumab to recommend whether to add an additional safety review for do. If there are no safety concerns preventing it, the Phase Ia portion of the trial will continue to ramp up while the safety analysis is ongoing.

To further reduce the risk of potential unanticipated adverse events, the IMC will also periodically review safety data from patients enrolled in the expansion cohorts of the Phase Ia and Phase Ib portions of the study. Specifically, to ensure patient safety while undergoing study treatment, make study conduct recommendations based on emerging study safety data. An interim analysis of IMC waste will also be performed in the Phase Ia and Phase Ib expansion cohorts. In addition, medical monitors can request additional safety reports and call ad hoc meetings of the IMC at any time during the study to review ongoing safety data for a balance of risks and benefits. can be done.

During the dose escalation phase, at least 3 patients will be treated at each tiragolumab dose level according to the dose escalation rules described below to determine the MTD or MAD of tiragolumab alone or in combination with atezolizumab. Enrollment of the first 3 patients in each new dose escalation cohort testing a new dose level of tiragolumab in Phase Ia or Phase Ib will be subject to ≥7 days of treatment on Day 1, Day 1 of their respective Cycle 1 It is staggered so that it is administered at intervals. All patients will be closely monitored for adverse events during the DLT evaluation period defined as 21 days (Days 1-21 of Cycle 1).

Dose escalation patients who do not complete the DLT assessment window for reasons other than DLT are considered non-evaluable for dose escalation decisions and MTD assessment and may be replaced by additional patients at that same dose level. DLT-naive patients receiving supportive care during the DLT assessment window (not including supportive care as described below) that disrupt the assessment of DLT may be replaced at the discretion of the medical monitor. Patients with any component of study treatment held during the DLT assessment window for reasons other than DLT such that administration of the next planned dose is delayed for more than 7 days will be subject to dose escalation decisions and MTD or MAD Considered non-evaluable for assessment and may be replaced by additional patients at that same dose level.

Patients treated in the Phase Ia portion of the trial who develop disease progression on tiragolumab alone will receive treatment in the Phase Ib portion of the trial (Figure 8), provided certain eligibility criteria for crossover are met may be eligible for

Definition of Dose-Limiting Toxicities In both the Phase Ia and Phase Ib portions of the study, if any one of the following events occurs during the DLT assessment window and is assessed by the Investigator to be related to study treatment: , DLT.
• Grade ≥3 non-hematologic, non-hepatic adverse events, with the following exceptions.
- Grade ≤ 3 nausea, vomiting or diarrhea that resolves to Grade ≤ 2 on standard therapy for 3 days - Grade 3 fatigue that resolves to Grade ≤ 2 in ≤ 3 days - Grade 3 fever (≤ 24 at >40°C) time and definition)
- Adverse event of Grade 3 tumor flare (defined as localized pain, rash, or rash localized to the site of known or suspected tumor) becoming Grade ≤2 within ≤7 days;
- Grade 3 laboratory abnormalities that are asymptomatic and considered by the investigator to be clinically insignificant - Grade 3 rash that becomes Grade ≤ 2 within ≤ 7 days with treatment equivalent to prednisone ≤ 10 mg/day ;
- Grade 3 joint pain that can be adequately managed with supportive care or resolves to Grade ≤ 2 within 7 days - Grade 3 autoimmune thyroiditis or endocrine therapy not requiring initiation of systemic corticosteroids other endocrine abnormalities (except replacement steroids for adrenal insufficiency) that can be managed by
o Grade ≥4 neutropenia (absolute neutrophil count (ANC) <500/μL) lasting >7 days
- Grade ≥3 febrile neutropenia - Grade ≥4 anemia - Grade ≥4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically significant bleeding;
• Grade ≥3 elevations in serum liver transaminase (ALT or AST) lasting >7 days Patients with grade 1 ALT or AST elevations at baseline as a result of liver metastases >3-fold X baseline persisting >7 days Only grade ≧3 elevations were considered DLTs.
Grade ≥3 serum total bilirubin elevation ALT or AST >3X upper limit of normal (ULN) and total bilirubin >2XULN

Dose Escalation Rule Enrollment will first begin in the Phase Ia portion of the study. The starting dose of tiragolumab is 2 mg administered IV every 21 days. The dose of tiragolumab increases ≤4-fold between successive dose levels, and the approximate dose levels proposed for the evaluation of tiragolumab are 2 mg, 8 mg, 30 mg, 100 mg, 400 mg, and 1200 mg. Maximum dose increments between successive dose levels can be decreased. Additional intermediate dose levels of tiragolumab can be evaluated based on emerging preclinical efficacy, clinical safety, and/or clinical PK data.

In addition to any DLT, other available relevant demographic, adverse event, laboratory, dosing, PK (if available) and pharmacodynamic (if available) data should be included in dose escalation decisions. Dose escalation decisions will be made by the medical monitor in consultation with the investigator and a committee consisting of, but not limited to, safety scientists, statisticians, PK scientists and/or clinical trial managers. will be

Dose escalation is performed according to the rules listed below.
• A minimum of 3 patients will be enrolled at each dose level (cohort).
- If none of the first 3 DLT-evaluable patients experience a DLT during the DLT assessment window, then enrollment of the next cohort at the escalating dose level determined as above can proceed .
- If 1 of the first 3 DLT-evaluable patients in a given cohort experiences a DLT, at least 3 additional patients at the same dose level (e.g., expand the cohort to 6 patients) ). If less than ⅓ of evaluable patients experience DLT (eg, <2 patients out of 6), dose escalation will continue and enrollment of the next cohort at the increased dose level may proceed.
• DLT per dose level in a cohort If DLT is observed in at least ⅓ of evaluable patients (eg, ≧2 patients out of 6), MTD is exceeded and dose escalation is stopped. Prior cohorts will be expanded to a minimum of 6 patients unless 6 patients have already been evaluated at that level. However, 6 patients may be evaluated at the intermediate dose level if the dose level above the MTD is ≧2-fold higher than the preceding dose level.
• If the MTD is exceeded at any dose level, the highest dose at which less than one-third of DLT-evaluable patients (ie, <2 out of 6 patients) experience DLT is declared the MTD.
• If the MTD is not exceeded at any dose level, the highest dose administered in this study will be considered the MAD.
Any dose level shown not to exceed the MTD is justified based on the investigator's assessment of non-DLT adverse events, including events occurring after Cycle 1 and events observed in the expansion cohort If so, it can be enlarged.

Based on review of available preliminary real-time safety data and available preliminary PK data (collected from either Phase Ia and/or Phase Ib studies), Phase Ia and/or Dose escalation in Phase Ib may be stopped or limited as needed.

After completing the DLT assessment for the first two dose cohorts in the Phase Ia portion of the study, safety data were reviewed by the investigator and the IMC to recommend whether to activate the Phase Ib portion of the study. be. If it is deemed appropriate to activate Phase Ib, then enrollment can proceed simultaneously in both parts of the trial. The starting dose of tiragolumab in combination with atezolizumab is 2 mg, with atezolizumab administered at a fixed dose of 1200 mg IV, both drugs administered every 21 days. The dose of tiragolumab in the Phase Ib portion of the study will never exceed the highest dose shown not to exceed the MTD in the Phase Ia portion of the study. Lower doses of tiragolumab may be considered in combination with atezolizumab if the combination MTD is exceeded in Cohort 1 of the Phase Ib portion of the study.

To obtain additional safety and pharmacodynamic data to more fully inform dose selection for the expansion cohort, additional patients were included in studies that were shown not to exceed the MTD or MAD based on the above dose escalation criteria. can be enrolled at dose levels for the Phase Ia portion and/or Phase Ib portion of For purposes of dose escalation decisions, these patients will not be considered part of the DLT evaluable population. These patients must have safely accessible tumors and consent to biopsy. Patients with tumors expressing PD-L1 and/or TIGIT based on prospective studies of tumor tissue during screening or pre-screening will be enrolled to inform the pharmacodynamic assessment. In addition, up to about 12 additional patients at the selected dose in the Phase Ia or Phase Ib study at or below the MTD or MAD to provide additional safety data before initiating the dose expansion phase level can be registered.

For the Phase Ia portion of the trial only, patients who developed radiographic progression and/or no longer receiving clinical benefit from single-agent tiragolumab had tumors that were safely available and consented to biopsy. , may be eligible to receive treatment in the Phase Ib portion of the trial if they meet the designated criteria for crossover.

Expansion Phase for Phase Ia and Phase Ib Patients with locally advanced, recurrent, or metastatic incurable malignancies that have progressed after available standard therapy; Patients who are proven or considered unsuitable; or enrolled in a study expansion cohort if the clinical trial of the investigational drug is a recognized standard of care. For the Phase Ib portion of the study only, patients for whom clinical trials of an investigational drug in combination with anti-PD-L1/PD-1 antibodies with or without chemotherapy or anti-VEGF antibodies are considered an acceptable treatment option were expanded. be enrolled in a cohort.

This expansion phase will explore the safety, tolerability and efficacy of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab, atezolizumab plus chemotherapy, atezolizumab plus bevacizumab or penprolizumab (Phase Ib) in certain cancer settings. A defined cohort of patients to better characterize sex, PK variability, pharmacodynamic activity, and preliminary anti-tumor activity. Enrollment in the expansion cohort is based on assessment of safety, tolerability, PK, pharmacodynamics, and pooling anti-tumor activity data, with tiragolumab (Phase Ia) or atezolizumab as single agents, atezolizumab plus chemotherapy, Atezolizumab plus bevacizumab or tiragolumab in combination with pembrolizumab (Phase Ib) will be initiated at a selected dose level below the MAD or MTD.

In the Phase Ia portion of the study, up to about 40 patients will have NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC, and CRC including CRC that is MSS or MSI-Low. A planned expansion cohort of PD-L1-selected and/or TIGIT-selected multiple tumor indications, including

In the Phase Ib portion of the trial (no chemotherapy), approximately 20-40 patients may be enrolled in multiple tumor indications, including each of the following planned indication-specific expansion cohorts:
NSCLC: cancer immunotherapy (CIT) naïve (eg, no prior treatment with anti-PD-L1/PD-1)
- NSCLC: CIT treatment (eg, including prior treatment with anti-PD-L1/PD-1)
●RCC
● TNBC
●Melanoma ●HNSCC
●OC
● GC including GEJ cancer
●UBC
● CRC including CRC that is MSS or MSI-Low
- Biopsy cohorts for specific tumor indications including melanoma, OC, RCC and UBC

In the Phase Ib chemotherapy expansion portion of the trial, approximately 20-40 patients may be enrolled in each of the following planned chemotherapy expansion cohorts (see Figure 5):
● Cohort A:
- Run-in - Atezolizumab and tiragolumab in combination with cisplatin or carboplatin and pemetrexed - Maintenance - Atezolizumab and tiragolumab in combination with pemetrexed Cohort B
- Induction phase - Atezolizumab and tiragolumab in combination with carboplatin and paclitaxel - Maintenance phase - Atezolizumab and tiragolumab Cohort C:
- Induction phase - Atezolizumab and tiragolumab in combination with cisplatin or carboplatin and etoposide - Maintenance phase - Atezolizumab and tiragolumab Cohort D:
- Atezolizumab and tiragolumab in combination with capecitabine

Approximately 20-40 patients may be enrolled in the planned cohort (see Figure 4) in the Phase Ib Q4W dose expansion portion of the study.

In the Phase Ib non-chemo expansion portion of the trial, approximately 20-40 patients may be enrolled in each of the following planned non-chemo expansion cohorts (see Figure 6).
- Cohort NC 1:
- Atezolizumab with pyragolumab and bevacizumab Cohort NC 2:
- tiragolumab and pembrolizumab

Only CIT-naive patients for whom clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are considered an acceptable treatment option will be considered eligible for enrollment in the relevant expansion cohort for the Phase Ib portion of the trial. Otherwise, patients will be assigned to an available expansion slot in the Phase Ia or Phase Ib portion of the study at the discretion of the Investigator.

Given that the safety profile of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab (Phase Ib) may not be fully characterized after evaluation of patients in the dose escalation phase, Not all potential adverse events or their likelihood of occurrence may be known at the time of enrollment in the expansion cohort. All available safety data are continually evaluated to assess tolerability of the dose levels tested. To further reduce the risk of potential unanticipated adverse events, the IMC will periodically review safety data from all patients enrolled in the expansion cohorts of the Phase Ia and Phase Ib portions of the study. Review and make recommendations for conducting studies relevant to patient safety. If the frequency of Grade 3 or Grade 4 toxicity or other unacceptable toxicity observed in the expansion phase cohort suggests that the MTD was exceeded at that dose level in Phase Ia or Phase Ib, then at that dose level accumulation is stopped. Reinstatement of enrollment in the expansion phase at a lower dose level is then considered. In addition, accumulating safety, tolerability, PK or pharmacodynamic data will allow dose levels in the expansion cohort to be preliminary for tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab (Phase Ib). Enrollment of new patients into the cohort at a different dose level is considered if suboptimal assessment of anti-tumor activity is suggested. Dose levels tested in Phase Ia or Phase Ib expansion phases will never exceed the highest dose level shown not to exceed the MTD in Phase Ia or Phase Ib dose escalation phases, respectively.

In the Phase Ib Chemo Expansion Cohort, Phase Ib Q4W Dose Expansion Cohort, and Phase Ib Non-Chemo Expansion Cohort, the first 3 patients in each cohort completed a full cycle of study treatment during the safety run-in. Later, the IMC also monitors initial safety (see Figure 7). The IMC will review all safety data for the first 3 patients in that cohort to determine if the study treatment was tolerable and to allow patients to continue dosing. There is an acceptable assessment of risk by the IMC and Investigator of the If study treatment is considered tolerable in the safety run-in in each cohort, enrollment can continue at the same dose of tiragolumab in each cohort until interim analysis for safety. This occurs after approximately 20 patients have been enrolled, including those in the safety run-in.

The IMC will also monitor efficacy in the expansion cohorts of the Phase Ia and Phase Ib portions of the trial by conducting an interim analysis after approximately 20 patients in each cohort have completed initial tumor assessments. If anti-tumor activity and/or clinical benefit per investigator is not detected in its expansion cohort, enrollment may be terminated as determined by the IMC in consultation with the study investigator. If anti-tumor activity and/or clinical benefit per investigator is detected in patients in its expansion cohort, the IMC may allow approximately 40 patients to remain enrolled. There is no increase in sample size for expansion cohorts beyond 40 evaluable patients. Patients who consent to serial biopsies but do not have evaluable samples may be replaced as part of the maximum of 40 evaluable patients enrolled in each expansion cohort.
Phase Ia expansion cohort

The objective of the Phase Ia expansion cohort is to better characterize the safety, tolerability, PK, and preliminary efficacy data and to To explore potential tumor biomarkers of pharmacodynamic activity in patients with This cohort consists of approximately 20-40 patients with PD-L1-selected and/or TIGIT-selected tumors. Enrollment is initially limited to patients with the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC, and CRC including MSS and MSI-Low. Enrollment may be expanded and/or modified to include other indications if anti-tumor activity and/or clinical benefit by the investigator is observed in patients with other tumor types in this study.

Up to about half of the patients enrolled in this cohort in Phase Ia had safely accessible tumor lesions and had pre- and intra-procedural biopsies (core needle, punch, forceps, or excision/incision). I have to agree. Additional patients can be enrolled to ensure that approximately half of the patients in this cohort have evaluable serial biopsies with adequate viable tumor content.

Patients who developed radiological progression and/or no longer receiving clinical benefit from single-agent tiragolumab in this Phase Ia expansion cohort must have a safely accessible tumor and consent to biopsy. , may be eligible for crossover and receive treatment in the Phase Ib portion of the study (FIG. 8) if they meet the specified criteria for crossover.
Phase Ib indication-specific expansion cohort

The aim of the Phase Ib indication-specific expansion cohort is to better characterize the safety, tolerability, PK and preliminary efficacy data and its MTD or MAD in combination with atezolizumab equal to or less than To explore potential tumor biomarkers of pharmacodynamic activity in patients with specific cancer types treated with tiragolumab at dose levels of . Each indication-specific expansion cohort is initially PD-L1-selected and/or TIGIT-selected based on prospective testing of tumor tissue during screening or prescreening and includes multiple tumor indications, including the following tumor types: Up to approximately 20 patients with tumors will be enrolled.
NSCLC: CIT-naive These patients had no prior CIT (investigational or approved) including anti-PD-L1/PD-1 and/or anti-CTLA-4 and had no anti-PD-L1 antibodies may be enrolled only if a clinical trial of an investigational drug in combination with is considered an acceptable treatment option.
• NSCLC: With CIT treatment These patients have received prior CIT (investigational or approved) including anti-PD-L1/PD-1.
● TNBC
● RCC
●CRC
● Including gastric cancer (GC) and gastroesophageal junction (GEJ) cancer ● HNSCC
●UBC
●Melanoma ●OC

After enrollment of 20 patients, the IMC will determine whether there is evidence of anti-tumor activity and/or clinical benefit assessed by the investigator to continue enrollment in approximately 40 patients A meeting will be held to conduct an interim analysis for

Up to about half of the patients enrolled in each of these indication-specific expansion cohorts in Phase Ib had safely accessible tumor lesions and were punch, forceps, or excisional/incisional biopsy). Additional patients can be enrolled to ensure that approximately half of the patients in this cohort have evaluable serial biopsies with adequate viable tumor content.

Phase Ib Serial Biopsy Expansion Cohort The purpose of the Phase Ib serial biopsy expansion cohort is to investigate potential tumor biomarkers of pharmacodynamic activity and treatment with tiragolumab at dose levels below the MTD or MAD in combination with atezolizumab. To better characterize safety, tolerability, PK, and preliminary efficacy data in patients with specific cancer types that have been identified. The cohort consists of approximately 20-40 patients with tumors who are 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 ●RCC
●OC
●UBC

Patients enrolled in this serial biopsy expansion cohort must have safely accessible tumor lesions, as they will be required to undergo two tumor biopsies: 1) Pretreatment biopsies: all; After eligibility criteria (excluding the requirement of available archived tissue) are met, at baseline prior to administration of study drug, and 2) an in-treatment biopsy: approximately 2 weeks after the first dose of tiragolumab in combination with atezolizumab ( Days 15-21 of Cycle 1 or during). RECIST target lesions are not subject to biopsy.

Tissue biopsy methods may include core needle, punch, forceps, or excisional/incisional biopsy. Patients who provide the required fresh biopsy must also submit an archival tumor specimen, if available.

In this serial biopsy cohort, a recent archival specimen can be used in lieu of a fresh baseline biopsy under the following circumstances:
• The sample meets the sample criteria (eg number of cores or punch size).
• Specimens were collected within 3 months of proposed cycle 1, day 1, or within intervals approved by the medical monitor.
• Specimens were collected after most recent systemic therapy and/or any radiotherapy administered to relevant anatomic regions.
• The specimen is from the same lesion or organ as the proposed site for biopsy during the procedure.

Patients whose baseline biopsy was found to be non-evaluable (i.e., due to insufficient material or lack of tumor cells in the sample) were still receiving study treatment and had an in-treatment biopsy. is considered. Such patients, as well as those for whom an intraprocedural biopsy is found to be non-evaluable, or for any patient with a biopsy that does not have adequate viable tumor content, should be considered for serial biopsy evaluation. May be replaced for purposes. Additional optional biopsies may be collected at the investigator's discretion and with patient consent, preferably upon radiographic response or progression.

Optional Biopsies in the Expansion Cohort Patients enrolled in the expansion cohort may undergo an optional biopsy (e.g., core needle, punch) to investigate pharmacodynamic changes related to the activity of tiragolumab alone or in combination with atezolizumab. , forceps, or excisional/incisional biopsy) to be considered. Enrollment in each expansion cohort will be managed so that up to about half of the incident patients have safely accessible tumor lesions and consent to undergo any of these biopsies. Recommended biopsy time points under this scenario are the same as above: baseline after all eligibility criteria (except the requirement for available archived tissue) are met, and approximately from the first dose of tiragolumab. After 2 weeks (Days 15-21 of Cycle 1 or during).

If the baseline sample is not evaluable and no recent archival specimen is available for comparison, no intraprocedural biopsy is required. Patients with non-evaluable baseline or on-treatment biopsies (ie, biopsies with insufficient viable tumor content) may be replaced for serial biopsy evaluation purposes.

Patients who provide any baseline biopsy will also submit an archival tumor specimen, if available.

Phase Ib Chemotherapy Expansion Cohort The purpose of the Phase Ib Chemotherapy Expansion Cohort is to better characterize the safety, tolerability, pharmacokinetics and preliminary efficacy data for tiragolumab in combination with atezolizumab and chemotherapy. To explore potential tumor biomarkers of pharmacodynamic activity in treated patients.

Each cohort consists of approximately 20-40 patients with tumors who may be PD-L1-selected and/or TIGIT-selected based on prospective testing of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archived tissue may be eligible for enrollment in this cohort if the medical monitor determines so based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational drugs in combination with anti-PD-L1 antibodies with chemotherapy are considered an acceptable treatment option may be enrolled in these expansion cohorts. The number of patients with a particular tumor type (eg, NSCLC, SCLC, TNBC) or with a particular treatment history (eg, CIT naive) may be limited in each study cohort.

The treatment combinations in each cohort are shown in Table 29.

Each cohort has an initial safety run-in of 3 patients (see Figure 5). After the first 3 patients in a cohort have completed 21 days of study treatment (i.e., Days 1-21 of Cycle 1), the IMC will review all safety data for that cohort to ensure that study treatment is There is an acceptable assessment of risk by the IMC and investigator to determine if tolerability and allow patients to continue on atezolizumab and tiragolumab and chemotherapy. Patients who do not complete the first 21 days of treatment for reasons other than treatment-related toxicity may be replaced by additional patients at the same dose level. After a minimum of 3 patients have been enrolled and have completed 21 days of study treatment, if study treatment is considered acceptable in the cohort safety run-in by the IMC, it will continue until a total of approximately 20 patients have been enrolled. You can continue to enroll in the cohort. The IMC will review the efficacy data of approximately the first 20 patients in each cohort to assess safety and efficacy. Enrollment in the cohort may continue up to a total of approximately 40 patients if the IMC determines that there is a favorable benefit risk.

If the 600 mg dose of tiragolumab is not tolerated during the safety run-in in any cohort, a safety run-in with a lower dose of tiragolumab can be initiated for 3 or more patients enrolled in that cohort. . Safety data for this low dose group will be evaluated after the first 3 patients in the cohort have completed 21 days of study treatment (Days 1-21 of Cycle 1). Approximately 3 additional patients in the safety run-in will then be enrolled to further assess the safety and tolerability of tiragolumab at this lower dose. Only the tiragolumab dose can be decreased; the atezolizumab dose remains unchanged. Chemotherapy dose adjustments, if necessary, follow the guidelines: If study treatment at this low dose is tolerated, a total of approximately 20 patients, including those in the low-dose safety run-in, will be included in each cohort. Enrollment will continue at lower doses until enrolled in . The IMC will review data from 20 patients in each cohort to assess safety and efficacy. If the IMC determines there is a favorable benefit-risk, enrollment in that cohort may continue at lower doses, up to a total of approximately 40 patients.

The 600 mg dose of tiragolumab was well tolerated during the safety run-in, and new clinical PK data (e.g. PK data differing from chemotherapy) and/or pharmacodynamic data (e.g. receptor occupancy) supported higher doses. of tiragolumab will be used, initiate a safety run-in with the higher dose of tiragolumab for the next 3 patients enrolled in each cohort. This higher dose did not exceed the maximum rated dose of 1200 mg every 3 weeks for MTG7192A in both the Phase Ia and Ib portions of the study, which was observed at the dose level of 1200 mg every 3 weeks. No maximum concentration (C _max ) greater than was observed. If study treatment at this high dose of tiragolumab is allowed, a minimum of 6 patients will be enrolled and will continue to be enrolled in the high dose safety run-in until they have completed 21 days of study treatment. If study treatment at this higher dose is deemed tolerable in the safety run-in by the IMC, continue enrollment at this higher dose of tiragolumab until a total of approximately 20 patients are enrolled in each cohort. can be done. The IMC will review data from the first 20 patients in each cohort to assess safety and efficacy. If the IMC determines there is a favorable benefit-risk profile, enrollment in that cohort may continue at higher doses up to a total of approximately 40 patients.

Phase Ib Chemotherapy Expansion Cohort: Dosing and Administration Patients in Cohorts A, B and C may receive treatment in two phases: induction and maintenance. In the induction phase, patients in certain chemotherapy expansion cohorts receive:
Cohort A received atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by pemetrexed 500 mg/m ² IV, followed by cisplatin 75 mg/m ² IV, or carboplatin AUC of 6 mg/mL fraction IV on day 1 of a 21-day cycle. receive. Four to six cycles of induction-phase treatment are administered in the absence of disease progression or unacceptable toxicity.
• Cohort B will receive atezolizumab 1200 mg IV, followed by tiragolumab 600 mg IV, followed by paclitaxel 200 mg/m ² IV, followed by carboplatin AUC of 6 mg/mL min IV on day 1 of a 21-day cycle. Four to six cycles of induction treatment are administered in the absence of disease progression or unacceptable toxicity.
Cohort C received atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV followed by cisplatin 75 mg/m ² IV or carboplatin AUC of 5 mg/mL min IV on day 1 of a 21-day cycle followed by etoposide 100 mg/m ² IV on days 1-3 of a 21-day cycle. Four cycles of induction phase treatment are administered in the absence of disease progression or unacceptable toxicity.

For Cohorts A and C, the choice of cisplatin or carboplatin is an investigator's decision, although the number of patients receiving a particular platinum-based chemotherapy agent may be limited. For Cohorts A and B, the number of cycles (4-6) administered in the run-in phase is at the investigator's discretion.

After the run-in period, unacceptable toxicity, clinically plausible disease progression, and/or at the investigator's discretion after careful assessment and thorough discussion of potential risks and benefits with the patient Treatment may be continued in the maintenance phase in the absence of clinical benefit.

In the maintenance phase, study treatment will continue every Q3W for Cohort A, Cohort B and Cohort D enrolled in Protocol Version 4 or cohorts enrolled in Protocol Version 5 or later. Continue every Q4W for B and Cohort C.

In the maintenance phase, patients in certain chemotherapy expansion cohorts receive:
• Cohort A will receive atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV followed by pemetrexed 500 mg/m ² IV on day 1 of every -21 day cycle.
• Cohort B will receive atezolizumab 1680 mg IV followed by tiragolumab 840 mg IV on Day 1 of every -28 day cycle. If patients are enrolled in GO 30103 version 4, patients in Cohort B will continue to receive atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV on Day 1 of the -21 day cycle.
• Cohort C will receive atezolizumab 1680 mg IV followed by tiragolumab 840 mg IV on Day 1 of every -28 day cycle.

Patients in Cohort D receive treatment with capecitabine, atezolizumab, and tiragolumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients receive a dose of 1250 mg/m ² BID of capecitabine orally on days 1-14 of each 21-day cycle. On Day 1 of Cycle 1, the first dose of capecitabine is administered at the clinic prior to atezolizumab and tiragolumab infusions. The combination of atezolizumab and tiragolumab is administered by IV infusion in 21-day cycles.

Individual chemotherapeutic or immunotherapeutic agents can be discontinued independently in the absence of toxicity and disease progression or loss of clinical benefit. However, treatment with atezolizumab alone or tiragolumab alone (with or without chemotherapy) has no contraindications and can only be considered after discussion with a medical monitor.

Phase Ib Q4W Dose Expansion Cohort The objectives of the Phase Ib Q4W dose expansion cohort are to better characterize safety, tolerability, PK and preliminary efficacy data, and every 4 weeks (28 days; Q4W). To explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiragolumab 840 mg IV in combination with atezolizumab 1680 mg IV on a dosing schedule of .

The Phase Ib Q4W cohort will consist of approximately 20-40 patients with tumors who may be PD-L1-selected and/or TIGIT-selected based on prospective testing of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archived tissue may be eligible for enrollment in this cohort if the medical monitor determines so based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are considered an acceptable treatment option may be enrolled in these expansion cohorts. The number of patients with a particular tumor type (eg, NSCLC, SCLC) or with a particular treatment history (eg, CIT-naive) may be limited in each study cohort.

This cohort has an initial safety run-in of 3 patients (see Figure 4). After the first three patients in a cohort have completed 28 days of study treatment (i.e., Days 1-28 of Cycle 1), the IMC will review all safety data for that cohort to ensure that study treatment is Determined if tolerable, there is an acceptable assessment of risk by the IMC and investigator to allow the patient to continue on tiragolumab with atezolizumab. Patients who do not complete the first 28 days of treatment for reasons other than treatment-related toxicity may be replaced by additional patients at the same dose level. After a minimum of 3 patients have been enrolled and have completed 28 days of study treatment, if study treatment is considered acceptable in the cohort safety run-in by the IMC, it will continue until a total of approximately 20 patients have been enrolled. You can continue to enroll in the cohort. The IMC will review the efficacy data of approximately the first 20 patients in each cohort to assess safety and efficacy. Enrollment in the cohort may continue up to a total of approximately 40 patients if the IMC determines that there is a favorable benefit risk.

If the 840 mg dose of tiragolumab is not tolerated during the safety run-in in any cohort, a safety run-in with a lower dose of tiragolumab can be initiated for 3 or more patients enrolled in that cohort. . Safety data for this low dose group will be evaluated after the first 3 patients in the cohort have completed 28 days of study treatment (Days 1-28 of Cycle 1). Approximately three additional patients will be enrolled in the safety run-in to further evaluate the safety and tolerability of tiragolumab at this lower dose. Only the tiragolumab dose can be decreased; the atezolizumab dose remains unchanged. If study treatment at this lower dose is tolerated, enrollment will continue at the lower dose until a total of approximately 20 patients are enrolled in each cohort, including patients in the low-dose safety run-in. The IMC will review data from 20 patients in each cohort to assess safety and efficacy. If the IMC determines there is a favorable benefit-risk, enrollment in that cohort may continue at lower doses, up to a total of approximately 40 patients.

If the 840 mg dose of tiragolumab is well tolerated during the safety run-in and new clinical PK and/or pharmacodynamic data (e.g., receptor occupancy) suggest higher doses of tiragolumab are used , to initiate a safety run-in at the higher dose of tiragolumab for the next 3 patients enrolled in each cohort. This higher dose did not exceed the maximum rated dose of 1200 mg for MTG7192A in both the Phase Ia and Ib portions of the study, and did not exceed the maximum dose level observed at the 1200 mg every 3 weeks dose level. Concentration (C _max was not observed. If study treatment at this high dose of tiragolumab is allowed, safety at the high dose will continue until a minimum of 6 patients are enrolled and complete 28 days of study treatment. Continue enrollment in run-in: If study treatment at this high dose is deemed tolerable in the safety run-in by the IMC, continue at this high dose until a total of approximately 20 patients are enrolled in each cohort. of tiragolumab can continue.The IMC will review data from the first 20 patients in each cohort to assess safety and efficacy.The IMC will determine favorable benefit-risk If so, enrollment in that cohort will continue at the higher doses to a total of approximately 40 patients.
Phase Ib non-chemotherapy expansion cohort

The objective of the Phase Ib non-chemotherapy expansion cohort was to better characterize the safety, tolerability, and preliminary efficacy data, patients treated with tiragolumab and atezolizumab with bevacizumab, and tiragolumab in combination with pembrolizumab To explore potential tumor biomarkers of pharmacodynamic activity in .

Each cohort consists of approximately 20-40 patients with tumors who may be PD-L1-selected and/or TIGIT-selected based on prospective testing of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archived tissue may be eligible for enrollment in this cohort if the medical monitor determines so based on discussion with the investigator. Patients with tumor types for which, at the investigator's discretion, a clinical trial of an investigational drug in combination with anti-PD-L1/PD-1 with or without bevacizumab would be considered an acceptable treatment option are included in these expansion cohorts. can be registered. The number of patients with a particular tumor type (eg HCC, melanoma) or with a particular treatment history (eg CIT naive) may be limited in each study cohort.

The treatment combinations in each cohort are shown in Table 30.

Each cohort has an initial safety run-in of approximately 3 patients (Figure 6). After the first 3 patients in a cohort have completed 3 weeks (21 days) of study treatment (i.e., Days 1-21 of Cycle 1), the IMC will review all safety data for that cohort. to determine if the study treatment was tolerable, with an acceptable assessment of risk by the IMC and investigator, and if patients were treated with bevacizumab (cohort NC 1) or tiragolumab and Tiragolumab and atezolizumab can be continued. Patients who do not complete the first 3 weeks of treatment for reasons other than treatment-related toxicity may be replaced by additional patients at the same dose level. After a minimum of 3 patients have been enrolled and have completed 3 weeks of study treatment, if study treatment is deemed acceptable in the cohort safety run-in by the IMC, it will continue until a total of approximately 20 patients have been enrolled. You can continue to enroll in the cohort. The IMC will review the efficacy data of approximately the first 20 patients in each cohort to assess safety and efficacy. Enrollment in the cohort may continue up to a total of approximately 40 patients if the IMC determines that there is a favorable benefit risk.

If the 600 mg dose of tiragolumab is not tolerated during the safety run-in in any cohort, a safety run-in with a lower dose of tiragolumab can be initiated for approximately 3 patients enrolled in that cohort. . Safety data for this low dose group will be evaluated after the first 3 patients in the cohort have completed 3 weeks of study treatment (Days 1-21 of Cycle 1). Approximately 3 additional patients in the safety run-in will then be enrolled to further assess the safety and tolerability of tiragolumab at this lower dose. Only the dose of tiragolumab can be reduced; the dose of pembrolizumab or atezolizumab with bevacizumab remains unchanged. If study treatment at this lower dose is tolerated, enrollment will continue at the lower dose until a total of approximately 20 patients are enrolled in each cohort, including patients in the low-dose safety run-in. The IMC will review data from 20 patients in each cohort to assess safety and efficacy. If the IMC determines there is a favorable benefit-risk, enrollment in that cohort may continue at lower doses, up to a total of approximately 40 patients.

If the 600 mg dose of tiragolumab is well tolerated during the safety run-in, initiate a safety run-in with the higher dose of tiragolumab for approximately the next 3 patients enrolled in each cohort be able to. This higher dose did not exceed 1200 mg every 3 weeks, which was the maximum rated dose of tiragolumab in both the Phase Ia and Ib portions of the study, and the maximum concentration observed ( _Cmax ). is no greater than that observed at the 1200 mg every 3 weeks dose level. If study treatment at this high dose of tiragolumab is allowed, a minimum of 6 patients will be enrolled and will continue to be enrolled in the high dose safety run-in until they have completed 3 weeks of study treatment. If study treatment at this higher dose is deemed tolerable in the safety run-in by the IMC, continue enrollment at this higher dose of tiragolumab until a total of approximately 20 patients are enrolled in each cohort. can be done. The IMC will review data from the first 20 patients in each cohort to assess safety and efficacy. If the IMC determines there is a favorable benefit-risk profile, enrollment in that cohort may continue at higher doses up to a total of approximately 40 patients.

Dose Reductions of Tiragolumab and Atezolizumab and Other Non-Chemotherapeutic Agents In general, there were no dose reductions of tiragolumab in this study. However, available cumulative safety data suggest that dose levels of tiragolumab initially selected as single agent (Phase Ia) or in combination with atezolizumab (Phase Ib) exceed the MTD or MAD. If so, accumulation at that dose level can be stopped and, if applicable, further dose escalation is stopped.

In this situation, individual patients have the option of dose reduction to a new dose level of tiragolumab if the following criteria are met:
• The patient's initially assigned dose is equal to (or greater than) the dose level that is closed for further enrollment.
• The overall benefit/risk balance favors continued treatment in Phase Ia or Phase Ib, in the investigator's opinion.

For atezolizumab, there is no intra-patient dose reduction; atezolizumab must be administered at a fixed dose of 1200 mg every 21 days or 1680 mg every 28 days (Q4W dosing expansion cohort).

There will be no intra-patient dose reductions for bevacizumab; bevacizumab will be administered at a fixed dose of 15 mg/kg every 3 weeks.

For pembrolizumab, there will be no intra-patient dose reduction; pembrolizumab will be administered at a fixed dose of 200 mg every 3 weeks.

Treatment after disease progression After standard RECIST v 1.1 criteria for progressive disease have been met at the discretion of the Investigator after discussion with the medical monitor, patients will enter Phase Ia or Phase Ib of the study. Partial study treatment can be continued provided the patient meets the following criteria (see Figure 7):
Absence of symptoms and signs of definite disease progression (including worsening laboratory values, e.g., new or worsening hypercalcemia) Decreased US East Coast Cancer Clinical Trials Group (ECOG) performance status No tumor progression in critical anatomic sites that cannot be readily controlled and stabilized by protocol-approved medical intervention prior to repeat dosing It includes the CNS, central airways, great blood vessels, and other organs or tissues where dysfunction secondary to tumor progression is expected to acutely lead to severe and/or irreversible disability or death.

Patients must give consent to authorize discussion with the treating investigator of the benefit-risk balance of continuing study treatment beyond radiological progression.

If subsequent tumor assessment in Phase Ia or Phase Ib confirms radiological disease progression, the patient continues to meet the above criteria and clinical benefit as evidenced by at least one of the following: continued study treatment may be considered at the Investigator's discretion after discussion with the Medical Monitor.
- Tumor reduction (at least 30% reduction in diameter from baseline) of one or more evaluable lesions
Investigator-assessed improvement in one or more symptoms or signs attributed to the underlying cancer (e.g., decreased need for narcotics for pain, decreased dyspnea associated with pleural effusion, weight gain)

In the Phase Ia portion of the trial alone, patients treated with single-agent tiragolumab who developed progressive disease and/or no longer elicited clinical benefit were treated with safe access to the patient, as outlined above. Patients with tiragolumab in combination with atezolizumab may be eligible for treatment in the phase Ib portion of the trial if they have tumors of moderate size, consent to biopsy, and meet designated criteria for crossover.

In chemotherapy expansion cohorts A, B, C and D, treatment after disease progression must include immunotherapy (atezolizumab and/or tiragolumab) with or without chemotherapy and cannot be chemotherapy alone. .

Crossover from single agent tiragolumab treatment at progression to combination of tiragolumab and atezolizumab Developing progressive disease and/or no longer gaining clinical benefit with tiragolumab as single agent in the Phase Ia portion of the study Treated patients may be eligible to receive treatment with tiragolumab in combination with atezolizumab in the Phase Ib portion of the study (see Figure 8) if the following conditions are met.
• Patients must have radiographically documented disease progression, including CT scans of the chest, abdomen, and pelvis in the Phase Ia portion of the study.
- Patients must not have experienced toxicity requiring discontinuation of tiragolumab treatment and have experienced toxicity during the last dose of study treatment that would prevent treatment with the combination of tiragolumab and atezolizumab in a Phase Ib trial. must not.
• Patients must meet all inclusion and exclusion criteria.
• Any tiragolumab-related adverse event must resolve to Grade 1 ≤ or Baseline Grade on or before Day 1 of treatment in the Phase Ib portion of the study. After careful assessment and discussion of the benefit-risk balance with the patient by the Investigator(s), exceptions may be granted with the approval of the Medical Monitor.
Treatment with tiragolumab and atezolizumab after progression on single-agent tiragolumab should be determined after careful assessment and discussion of the benefit-risk balance with the patient by the investigator(s) and by the medical monitor. shall be deemed acceptable with approval from

Patients with safely accessible disease site(s) require a tumor biopsy. This biopsy can be performed at any time prior to administration of tiragolumab and atezolizumab in the Phase Ib trial. An optional in-treatment biopsy may also be collected on or during Cycle 1 Days 15-21 after administration of tiragolumab and atezolizumab. RECIST target lesions are not biopsied.

The dose and schedule of crossover treatment with tiragolumab in combination with atezolizumab in the Phase Ib trial requires medical monitor approval. Generally, patients enrolled in the Phase Ib portion of the trial receive tiragolumab at the highest dose previously shown not to exceed its MTD in combination with atezolizumab (Figure 7). Therefore, the dose level of tiragolumab evaluated in the Phase Ib trial may differ from the dose level evaluated in the same patient in the Phase Ia trial. Patients undergoing a change in dose and/or schedule of tiragolumab as a single agent in a Phase Ia trial should be treated with a Phase Ib study as long as the dose of tiragolumab has not previously been shown to exceed the MTD of tiragolumab with atezolizumab. Continue administration of tiragolumab at the same dose and/or schedule in phases.

Patients crossing over from the Phase Ia portion of the study to the Phase Ib portion of the study will be treated as follows.
• Ratings obtained at the Study Treatment Discontinuation Visit in Phase Ia can be used as screening endpoints for concomitant treatments in the Phase Ib portion of the study. To re-establish baseline pretreatment clinical and disease status, the following rescreening assessments must be repeated within 2 weeks of Day 1 of treatment on the combination regimen (targeted physical examination, ECOG status, hematology and serum chemistry laboratory tests, clotting panel, amylase, lipase, thyroid function test, and urinalysis).
There is no clinical suspicion of positive test results for hepatitis B, hepatitis C, HIV, cytomegalovirus (CMV), and EBV because they were last performed during screening of the Phase Ia trial As long as it doesn't need to be repeated.
- Radiation oncology assessment, including CT scans of the chest, abdomen, and pelvis, as this assessment will be the new baseline scan for patients entering the Phase Ib trial, unless it has also been previously performed to document disease progression. , within 6 weeks prior to commencing combination treatment in a Phase Ib study.
Patients had secondary disease progression compared to tumor assessment documenting progressive disease, clinical deterioration, intolerance to concomitant treatment, and/or loss of clinical benefit from concomitant treatment at initial study treatment Until event, treated with a combination of tiragolumab and atezolizumab in a Phase Ib trial. As previously described, patients may continue study treatment after standard RECIST v1.1 criteria for progressive disease have been met after discussion with the medical monitor in a Phase Ib study at the discretion of the investigator. provided that it can and meets all the specified criteria.
• Evaluate crossover patients for safety and efficacy.

Clinical and exploratory data from tumor biopsies obtained prior to crossover treatment from Phase Ia to Phase Ib will be monitored continuously.

Cross-enrollment from the Phase Ia portion to Phase Ib trials may be restricted or suspended at any time. Reasons for this may include safety, inadequate patient enrollment, and/or incomplete data recording.

A. Study Treatment Dosing and Administration Administration of tiragolumab (Phase Ia) as a single agent or in combination with atezolizumab (Phase Ib) should be provided with critical care facilities, critical care units and medical emergencies to monitor and respond to. conducted in an environment accessible to staff trained to

For treatments in the Phase Ib portion of the study (the chemotherapy-free cohort), tiragolumab is administered prior to atezolizumab, with an observation period in between, on the scheduled study treatment infusion days.

For treatment in the Phase Ib chemotherapy expansion cohort, atezolizumab will be administered prior to tiragolumab with an observation period on the scheduled day of study treatment infusion. Chemotherapy is administered after atezolizumab and tiragolumab, with an intervening observation period for tiragolumab.

For treatment in the Phase Ib non-chemotherapy expansion cohort, on the day of scheduled study treatment infusion, tiragolumab was administered prior to atezolizumab (cohort NC 1) or pembrolizumab (cohort NC 2) with bevacizumab and observed. A period intervenes. Bevacizumab is administered after tiragolumab and atezolizumab with an observation period for bevacizumab.

Please refer to the respective Investigator's brochure and GO 30103 Investigational Product Management Protocol for details on dosage preparation and dosing instructions for tiragolumab, atezolizumab, or bevacizumab.

See package inserts or SmPC for detailed dosage preparation and dosing instructions for cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine, etoposide, and pembrolizumab.

Tiragolumab in Phase Ia and Phase Ib Approximate dose levels of tiragolumab evaluated in the Phase Ia and Ib portions of this study are 2 mg, 8 mg, 30 mg, 100 mg administered every 3 weeks by IV infusion , 400 mg, and 1200 mg. Other dose levels that do not exceed the Phase Ia or Phase Ib MTD, or new dosing schedules for Phase Ia and/or Phase Ib tiragolumab, are subject to new nonclinical efficacy, It can be evaluated based on clinical safety and clinical PK data. Evaluation of dose levels above 1200 mg of tiragolumab will require a protocol amendment with a supporting rationale. For Phase Ib chemotherapy and non-chemotherapy expansion cohorts, tiragolumab 600 mg is the initial dose given every 3 weeks by IV infusion. For Phase Ib chemotherapy Cohort B and Cohort C with Q4W maintenance, the tiragolumab dose is changed to 840 mg at maintenance. For the Phase Ib Q4W dose cohort, 840 mg of tiragolumab is the initial dose administered Q4W by IV infusion. Dosage is independent of body weight.

The 840 mg Q4W dosing regimen is supported by the results of PK modeling and simulation and exposure-safety analysis. Mean concentrations following the 840 mg Q4W dosing regimen are comparable to those of the 600 mg every 3 weeks dosing regimen evaluated in studies GO30103 and GO40290. The Cmax for the 840 mg Q4W dosing regimen was 28% higher at steady state compared to the Cmax for the 600 mg every 3 weeks dosing regimen, but within the highest dose exposure observed in the clinic (in study GO30103 1200 mg every 3 weeks). Preliminary exposure-safety relationship of tiragolumab based on data from study GO 30103 (tiragolumab doses of 2-1200 mg every 3 weeks administered as monotherapy or in combination with 1200 mg atezolizumab every 3 weeks) Analyzes suggest that tiragolumab exhibits a flat exposure-safety relationship. In summary, given that exposures are within the observed effective exposure range and that tiragolumab appears to have a flat exposure-safety relationship, the 840 mg 4W dosing regimen is comparable to the 600 mg every 3 weeks dosing regimen. They have equivalent safety and efficacy.

The initial dose of tiragolumab in Phase Ia of the study will be delivered over 90 (±10) minutes (although infusion may be slowed or interrupted in patients experiencing infusion-related symptoms) followed by 240 minutes of observation. do. The initial dose of tiragolumab in Phase Ib of the study is delivered over 60 (±10) minutes, followed by a 60 minute observation period. If the first infusion is tolerated without infusion-related adverse events, a second infusion of Phase Ia may be delivered over 60 (±10) minutes followed by a 60 minute observation period; A second infusion of is delivered over 30 (±10) minutes, followed by a 30 minute observation period. If the 60-minute infusion of Phase Ia is well tolerated, the third infusion of Phase Ia can be delivered over 30 (±10) minutes, followed by a 30-minute observation period. If the third infusion in Phase Ia or the second infusion in Phase Ib is well tolerated, all subsequent infusions in Phase Ia or Phase Ib will be delivered over 30 (±10) minutes followed by a 30 minute observation period. Patients previously receiving single-agent tiragolumab in Phase Ia and currently receiving tiragolumab in combination with atezolizumab in Phase Ib will receive the first dose in Phase Ib at the fastest rate previously tolerated. can receive

There will be no dose reductions of tiragolumab in this study (Phase Ia or Phase Ib) unless specified. Guidelines for modifying the dose of tiragolumab and interrupting or discontinuing treatment are provided. Guidance is provided regarding study drug administration in the context of managing specific adverse events.

Adverse events related to overdose or misadministration of study drug will be recorded.

Atezolizumab in Phase Ib The dose of atezolizumab administered in combination with tiragolumab in the Phase Ib portion of this study is 1200 mg IV every 3 weeks. For Phase Ib chemotherapy Cohort B and Cohort C with Q4W maintenance, the atezolizumab dose is changed to 1680 mg at maintenance. The Phase Ib Q4W dosing cohort will receive atezolizumab 1680 mg IV Q4W. This dose is fixed and independent of body weight.

In all Phase Ib cohorts without chemotherapy, atezolizumab will be administered after tiragolumab infusion and a subsequent observation period. Atezolizumab is administered prior to tiragolumab in the Phase Ib chemotherapy expansion cohort.

The initial dose of atezolizumab is delivered over 60 (±10) minutes. If the first infusion is tolerated without infusion-related adverse events, the second infusion may be delivered over 30 (±10) minutes. If a 30 minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (±10) minutes. In Cycle 1, administration of atezolizumab is followed by a 60 minute observation period. All subsequent atezolizumab infusions may be followed by a 30 minute observation period. Patients who have previously received atezolizumab in another clinical trial can receive the initial dose at the fastest rate previously tolerated.

There were no dose reductions of atezolizumab in this trial. Guidelines are provided for modifying dosage and interrupting or discontinuing treatment. Guidance is provided regarding study drug administration in the context of managing specific adverse events.

Adverse events related to overdose or misadministration of study drug will be recorded.

Non-Chemotherapy Cohorts in Phase Ib Expansion Cohort NC1: Tiragolumab and Atezolizumab with Bevacizumab 31 are treated. It is recommended that treatment be initiated within 7 days after enrollment; however, the first dose of study treatment should not occur within 7 days after core biopsy or other surgical procedure.

Cohort NC2: Tiragolumab and Pembrolizumab Patients in the tiragolumab and pembrolizumab cohorts will receive treatment outlined in Table 32 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after pooled assessment. It is recommended that treatment be initiated within 7 days after enrollment; however, the first dose of study treatment should not occur within 7 days after core biopsy or other surgical procedure.

Phase Ib Non-Chemotherapy Expansion Cohort: Dosing and Administration Patients in cohort NC1 receive tiragolumab 600 mg IV followed by atezolizumab 1200 mg IV followed by bevacizumab 15 mg/kg IV on Day 1 of every 3-week cycle. Treatment is continued until unacceptable toxicity or loss of clinical benefit as determined by the Investigator.

Patients in Cohort NC 2 will receive tiragolumab 600 mg IV followed by pembrolizumab 200 mg IV on Day 1 of every 3-week cycle Treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

In the event of toxicity and loss of clinical benefit, individual immunotherapeutic agents can be discontinued independently. However, treatment with pembrolizumab or bevacizumab or atezolizumab or tiragolumab alone has no contraindications and can only be considered after discussion with a medical monitor.

Bevacizumab in Phase Ib Expansion Cohort Bevacizumab will be administered by IV infusion at a fixed dose of 15 mg/kg on Day 1 of each 21-day cycle. Administration of bevacizumab is performed in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions. Guidelines are provided for dosage modification and treatment interruption or discontinuation for toxicity.

No premedication is allowed before the first bevacizumab infusion. If a patient has experienced IRR with previous drug infusions, premedication with antihistamines, antipyretics, and/or analgesics can be administered at the investigator's discretion. Vital signs (pulse rate, respiratory rate, blood pressure, temperature) are measured within 60 minutes prior to infusion. The initial dose of bevacizumab is delivered over 90 (±10) minutes. If the first infusion is tolerated without infusion-related adverse events, the second infusion may be delivered over 60 (±10) minutes. If a 60 minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (±10) minutes. In Cycle 1, administration of bevacizumab is followed by a 60 minute observation period. All subsequent infusions of bevacizumab may be followed by a 30 minute observation period. Patients who have previously received bevacizumab can receive the initial dose at the fastest rate previously tolerated. Patients are informed of the possible delay in symptoms after infusion and instructed to contact the study physician if they develop such symptoms. Instructions regarding biometric measurements are provided.

Pembrolizumab in the Phase Ib Expansion Cohort In the Phase Ib non-chemotherapy expansion cohort of this study, the dose of pembrolizumab administered in combination with tiragolumab is 200 mg IV every 3 weeks. This dose is fixed and independent of body weight.

Refer to the pembrolizumab prescribing information for guidance on dosing, storage, administration, and instructions for interrupting or discontinuing treatment of pembrolizumab.

Chemotherapy in Phase Ib Expansion Cohort Chemotherapy (excluding capecitabine) will be administered after atezolizumab and tiragolumab infusion followed by an observation period.

During the induction phase, chemotherapy cycles count toward the prespecified number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once during the 21-day cycle. Cycles in which no chemotherapy component is administered are not counted in the total number of induction chemotherapy cycles.

Patients who demonstrate evidence of clinical benefit during treatment (induction or maintenance) will be allowed to continue treatment after RECIST v 1.1 criteria for PD are met.

Patients receive chemotherapeutic antiemetics and IV hydration according to local standard of care and manufacturer's instructions. However, due to the immunomodulatory effects of steroids, premedication with steroids is minimized to the extent clinically feasible.

Guidelines for dose modification and treatment interruption or discontinuation for chemotherapy are provided.

Cohort A: Atezolizumab + Tiragolumab + Carboplatin/Cisplatin + Pemetrexed On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:
Induction: atezolizumab→tiragolumab→pemetrexed→carboplatin or cisplatin After 4-6 cycles of the induction phase, patients will begin maintenance therapy with the following dosing sequence.
Maintenance: atezolizumab → tiragolumab → pemetrexed

Table 33 lists suggested premedications for pemetrexed. Table 7 lists recommended infusion times for treatment administration of pemetrexed and carboplatin or cisplatin during the induction phase and for pemetrexed during the maintenance phase.

Cohort B: Atezolizumab + Tiragolumab + Carboplatin + Paclitaxel On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:
Run-in: atezolizumab → tiragolumab → paclitaxel → carboplatin After 4-6 cycles of the run-in phase, patients will be enrolled on Day 1 of each 21-day cycle if enrolled on Protocol Version 4, or on Protocol Version 5 or later. maintenance therapy will begin on Day 1 of each 28-day cycle if enrolled in . All eligible patients will receive drug infusions in the following order of administration:
Maintenance: atezolizumab → tiragolumab

Table 8 lists the recommended premedications for the induction treatment of Cohort B patients. Table 9 lists recommended infusion times for treatment administration of paclitaxel and carboplatin during the induction phase.

Cohort C: Atezolizumab + Tiragolumab + Carboplatin or Cisplatin On Day 1 of each 21 cycle, all eligible patients will receive study drug infusions in the following order.
Run-in: atezolizumab→tiragolumab→cisplatin or carboplatin→etoposide After the run-in phase, patients begin maintenance therapy on Day 1 of each 28-day cycle with the following dosing sequence.
Maintenance: atezolizumab → tiragolumab

Table 10 lists recommended infusion times for treatment administration of carboplatin or cisplatin and etoposide during the induction phase.
Cohort D: Capecitabine + Atezolizumab + Tiragolumab On Day 1 of each 21-day cycle, all eligible patients will receive study drug in the following order:
Capecitabine → atezolizumab → tiragolumab

Table 34 lists recommended lengths, dose routes and regimens for treatment administration of capecitabine.

Cisplatin Guidelines for administration of cisplatin in different cohorts are shown in Table 11.

Carboplatin Guidelines for administration of carboplatin in different cohorts are shown in Table 12.

Guidelines for administration of pemetrexed in Pemetrexed Cohort A are shown in Table 13.

Guidelines for paclitaxel dosing in Paclitaxel Cohort B are shown in Table 14.

Etoposide Guidelines for administration of etoposide in Cohort C are shown in Table 15.

Capecitabine Capecitabine is supplied as 150 mg and 500 mg tablets. Patients will receive treatment outlined in Table 35 until unacceptable toxicity or loss of clinical benefit as determined by the Investigator.

Take capecitabine with water within 30 minutes after meals. Patients will be instructed to return used and unused medication to the study site.

B. Combination therapy

Concomitant therapy includes any drug (eg, prescription drug, over-the-counter drug, herbal or homeopathic drug, and/or dietary supplement) used by the patient from 7 days prior to screening until the discontinuation visit.

Allowed Treatments Patients experiencing infusion-related symptoms in this study (Phase Ia or Phase Ib) should be treated according to standard practice (for regions outside the United States, equivalent medication may be substituted by local practice) It can be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine and/or ranitidine or another H2 receptor antagonist. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and β2-adrenergic agonist). Premedication with an antihistamine may be administered for cycles ≧2 of Phase Ia or Phase Ib, at the discretion of the treating physician.

Systemic corticosteroids, immunosuppressants and TNFα antagonists may attenuate the potentially beneficial immunological effects of treatment with tiragolumab as a single agent or in combination with anti-PD-L1/PD-1. However, it may be administered at the discretion of the treating physician in an emergency or after consultation with a medical monitor. Alternatives to corticosteroids, immunosuppressants or TNFα antagonists are considered where feasible. Tiragolumab, atezolizumab, bevacizumab, and pembrolizumab premedication may be administered for cycles ≧2 at the discretion of the treating physician after consulting the medical monitor. . The use of inhaled corticosteroids and mineralocorticoids (eg fludrocortisone for patients with orthostatic hypotension or adrenocortical insufficiency) is permitted. Physiological doses of corticosteroids for adrenal insufficiency are allowed. Megestrol, administered as an appetite stimulant, is also recognized. Planned use of other medications will be discussed with the medical monitor.

For patients in the Phase Ib chemotherapy expansion cohort, antiemetics and systemic steroids may also be given in the following circumstances.
• Appropriate antiemetic prophylaxis is administered. The use of nonsteroidal antiemetic regimens consisting of 5-HT3 receptor and NK1R antagonists is encouraged when feasible (Hesketh et al. J Clin Oncol 2017;35:3240-3261).
• Pretreatment with dexamethasone (or equivalent) may be given to all patients in Cohort A receiving pemetrexed to reduce the incidence and severity of skin reactions. In the clinical trial, 4 mg of dexamethasone was administered orally BID on the day before, the day of, and the day after pemetrexed administration.
• Pretreatment with dexamethasone (or equivalent) may be given to all patients in Cohort B receiving paclitaxel. In clinical trials, 20 mg of dexamethasone was given orally 12 hours and 6 hours before paclitaxel administration.

Planned use of prophylactic antibiotics (eg, after surgical intervention) will be discussed with the medical monitor. Study drug treatment is maintained until the antibiotic course is completed.

Patients using oral contraceptives, hormone replacement therapy, prophylactic or therapeutic anticoagulant therapy (e.g., low molecular weight heparin or warfarin at stable dose levels), or other maintenance therapy for non-malignant indications, must continue to use it. Men and women of reproductive potential must use highly effective means of contraception.

For patients in the chemotherapy expansion cohort, use the following agents with caution:
Caution when administering non-steroidal anti-inflammatory drugs (NSAIDs) to patients with mild to moderate renal insufficiency (creatinine clearance [CrCl] 45-79 mL/min) receiving pemetrexed (Cohort A). pay the NSAIDs with short elimination half-lives (eg, diclofenac, indomethacin) are avoided for a period of 2 days before, on, and 2 days after administration of pemetrexed. In the absence of data on potential interactions between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should be treated for at least 5 days prior to pemetrexed on that day. and 2 days later dosing will be discontinued. Patients are closely monitored for toxicity, particularly myelosuppression, renal and gastrointestinal toxicity, if co-administration of NSAIDs is required.
• Ototoxic agents such as aminoglycosides and loop diuretics can increase ototoxicity in patients receiving cisplatin or carboplatin. The use of antihistamines with cisplatin is closely reviewed as they may mask ototoxic symptoms such as vertigo and tinnitus. Levels of lithium and anticonvulsants (including phenytoin) are closely monitored in patients receiving cisplatin or carboplatin. INR is closely monitored in patients taking oral anticoagulants and cisplatin.
• Elevated clotting times, as evidenced by increases over baseline INR, have been reported in patients taking warfarin concurrently with etoposide (Cohort C). Patients receiving warfarin with etoposide are closely monitored for frequent INR.
• Patients on concomitant capecitabine (Cohort D) and oral coumarin derivative anticoagulant therapy should be monitored frequently for anticoagulant response (INR or prothrombin time) to appropriately adjust the anticoagulant dose. not. Altered coagulation parameters and/or bleeding and death have been reported in patients taking capecitabine concomitantly with coumarin derivative anticoagulants such as warfarin and phenprocoumon. Patients on capecitabine (Cohort D) taking the CYP2C9 substrates leucovorin and phenytoin require additional precautions.

For patients in non-chemotherapy expansion cohorts, use the following agents with caution:
• Osteonecrosis of the jaw has been reported primarily in patients receiving bevacizumab in combination with bisphosphonates. Therefore, caution must be exercised when using bevacizumab in patients receiving concomitant bisphosphonates.

Prohibited Therapies The following treatments are prohibited during the study:
Any drug, whether approved by health authorities or experimental, for the treatment of cancer, including (but not limited to) chemotherapy, hormone therapy, immunotherapy, radiation therapy, investigational drugs, or herbal therapies. combination therapy

Radiation therapy may be considered for pain relief (eg, treatment of known bone metastases) if the patient would benefit otherwise. For patients in the Phase Ia or Phase Ib dose escalation cohorts, defer palliative radiotherapy until completion of the DLT assessment window. Study treatment administration may be discontinued during radiotherapy with the consent of the medical monitor.

Patients experiencing a mixed response may receive local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of no more than three lesions with approval by the medical monitor. good;

Patients who have undergone radiation therapy to the target lesion or resection of the target lesion subsequently have the target lesion non-evaluable for response determination by RECIST v1.1.
• Live attenuated vaccines (eg, FluMist® influenza vaccine) are prohibited at any time during the study and for 5 months after the last dose of study treatment.
• Patients cannot receive immunostimulants, including but not limited to IFN-α, IFN-γ or IL-2, during the entire study. These agents in combination with atezolizumab may potentially increase the risk of autoimmune conditions.
• Traditional herbal medicines (typically because these characteristics are imperfect and can lead to unanticipated drug-drug interactions that can cause or confound assessments of toxicity).

Prohibited therapies specific for HCC patients being studied for cohort NC1:
• Current use of full-dose anticoagulants, therapeutic-dose thrombolytic therapy, and antiplatelet therapy is prohibited.

Local label recommended doses for prophylactic use of anticoagulant or thrombolytic therapy are acceptable.

Low-dose aspirin (<325 mg/day) is permitted. Co-administration of proton pump inhibitors is strongly recommended to reduce potential gastrointestinal damage.

If a patient experiences a venous thromboembolic event while still receiving study drug treatment, the patient may still be allowed to continue study drug despite anticoagulation.
• Current use of warfarin or coumadin-like products (including prophylactic use) is prohibited.

Prophylactic use of low-dose anticoagulant therapy, unfractionated heparin, or LMWH is permitted. A preferred choice for anticoagulant treatment is LMWH according to ASCO guidelines (Lyman GH et al. J Clin Oncol 2015;33:654-6).

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●血清妊娠検査（卵管結紮術を受けた女性を含む、妊娠の可能性がある女性のため）が行い、第１サイクルの１日目の前の１４日以内に陰性として文書化されなければならない；
●妊娠の可能性のある女性の場合：以下に定義するように、禁欲（異性間の性交を控える）又は避妊を使用することの同意、及び卵の提供を控えることの同意：
●女性は、処置期間中及びチラゴルマブの最終投薬後９０日間、アテゾリズマブの最終投薬後５ヶ月間、ペンブロリズマブの最終投薬後４ヶ月間、並びにベバシズマブ及び化学療法（ペメトレキセド、シスプラチン、カルボプラチン、パクリタキセル、エトポシド及びカペシタビン）の最終投与後６ヶ月間、禁欲を維持するか、又は年間＜１％の失敗率の避妊方法を使用しなければならない。女性は、この同じ期間中に卵を提供することを控えなければならない。
●女性は、月経後であり、閉経後の状態に達しておらず（閉経以外の特定された原因のない≧１２ヶ月間の無月経）、外科的滅菌（卵巣、卵管、及び／又は子宮の除去）又は治験責任医師によって決定される別の原因（例えば、ミュラー誘発）を受けたことがない場合、妊娠可能性があると考えられる。出産可能性の定義は、地域のガイドライン又は規制との整合に適合させることができる。
●年間失敗率＜１％の避妊方法の例としては、両側卵管結紮術、男性の不妊手術、排卵を阻害するホルモン避妊具、ホルモン放出子宮内避妊具、及び銅付加子宮内避妊具が挙げられる。
●ホルモン避妊法は、バリア法によって補完されなければならない。
●性的禁欲の信頼性は、臨床治験の期間、並びに、患者の好ましい、及び通常のライフスタイルに関連して評価される。周期性禁欲（例えば暦、排卵、症候体温法、又は排卵後法）及び禁断は、許容される避妊方法ではない。
●男性の場合：以下に定義するように、禁欲を維持する（異性間の性交を控える）こと、又は避妊手段を使用すること、及び精子の提供を控えることに同意すること：
●妊娠していない妊娠可能性のある女性パートナーの場合、外科的に避妊していない男性は、処置期間中及びチラゴルマブの最後の投薬後９０日間、カペシタビンの最後の投薬後３ヶ月間、及び任意の他の化学療法薬の最後の投薬後６ヶ月間、禁欲を維持するか、又は合わせて年間＜１％の失敗率をもたらすコンドーム及び追加の避妊方法を使用しなければならない。男性は、同期間中は精子提供をやめなければならない。
●妊娠中の女性パートナーの場合、男性は、処置期間中及びチラゴルマブの最終投薬後９０日間、カペシタビンの最終投薬後３ヶ月間、及び化学療法の最終投薬後６ヶ月間は、胚曝露を回避するため、禁欲を維持するか、又はコンドームを使用しなければならない。
●性的禁欲の信頼性は、臨床治験の期間、並びに、患者の好ましい、及び通常のライフスタイルに関連して評価される。周期性禁欲（例えば暦、排卵、症候体温法、又は排卵後法）及び禁断は、許容される避妊方法ではない。 Concomitant chronic use of NSAIDs while receiving study drug is prohibited, except for chronic low-dose aspirin (<325 mg/day). However, for symptomatic relief of medical symptoms (e.g., headache, fever), intermittent or short-term use of oral NSAIDs when co-administered with proton pump inhibitors to reduce potential gastrointestinal damage. Ingestion is permissible.
D. Inclusion Criteria Patients must meet the following study entry criteria:
General Criteria Signed Informed Consent Form (ICF)
Age ≥ 18 years As determined by the investigator to be able to comply with the study's protocol U.S. East Coast Oncology Group (ECOG) performance status of 0 or 1 Life expectancy ≥ 12 weeks Initial Adequate hematology and end-organ function as defined by the following laboratory test results obtained within 14 days prior to study treatment (Cycle 1, Day 1) of
● Absolute neutrophil count (ANC) ≥ 1,500 cells/μL
● White blood cell (WBC) count ≥ 2,500/μL
●Lymphocyte count≧500/μL
- Platelet count ≥ 100,000/μL (cycle 1, no transfusion within 14 days prior to day 1)
● Hemoglobin ≥ 9g/dL
• Patients may be transfused or undergo erythropoietic procedures according to local standard of care.
● Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Patients receiving paclitaxel (Cohort B) must have total bilirubin < 1.25 XULN.
● AST and ALT ≤ 3XULN
- alkaline phosphatase ≤ 2.5 XULN, with the following exceptions:
• Patients with documented liver or bone metastases may have alkaline phosphatase < 5XULN.
● Serum albumin ≥ 2.5 g/dL
PT and activated partial thromboplastin time (aPTT) < 1.5 XULN
This applies only to patients not receiving therapeutic anticoagulant therapy.
Patients receiving therapeutic anticoagulant therapy are dose stable.
- Creatinine clearance ≥50 mL/min measured or calculated based on the Cockcroft-Gault glomerular filtration rate estimate:

Patients receiving cisplatin (Cohort A or Cohort C) must have measured or calculated creatinine clearance ≧60 mL/min based on Cockcroft-Gault GFR estimates.
A serum pregnancy test (for women of childbearing potential, including those who have undergone tubal ligation) must be performed and documented as negative within 14 days prior to Day 1 of Cycle 1 not;
For women of childbearing potential: Consent to abstinence (abstinence from heterosexual intercourse) or use of contraception, and consent to abstain from donating eggs, as defined below:
- Women were allowed to receive treatment during the treatment period and for 90 days after the last dose of tiragolumab, 5 months after the last dose of atezolizumab, 4 months after the last dose of Must maintain abstinence or use a method of contraception with an annual failure rate of <1% for 6 months after the last dose of capecitabine. Females should refrain from donating eggs during this same period.
Females are postmenopausal, have not achieved postmenopausal status (≥12 months of amenorrhea with no identified cause other than menopause), have undergone surgical sterilization (ovaries, fallopian tubes, and/or uterus) Pregnancy potential is considered if the patient has not had any prior causes (e.g., Müller induction)) or another cause as determined by the Investigator. Fertility definitions can be adapted to match local guidelines or regulations.
● Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper-enriched intrauterine devices. be done.
• Hormonal contraception must be complemented by barrier methods.
- Reliability of sexual abstinence will be assessed in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.
For men: agreeing to maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and to abstain from donating sperm, as defined below:
In the case of nonpregnant female partners of childbearing potential, males who are not surgically contraceptive should receive a must maintain abstinence for 6 months after the last dose of any other chemotherapeutic agent or use condoms and additional methods of contraception that together result in a failure rate of <1% per year. Men must stop donating sperm during the same period.
For pregnant female partners, men avoid embryo exposure during treatment and for 90 days after last dose of tiragolumab, 3 months after last dose of capecitabine, and 6 months after last dose of chemotherapy Therefore, they must remain abstinent or use condoms.
- Reliability of sexual abstinence will be assessed in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.

E. Cancer-specific inclusion criteria Patients with histologically documented locally advanced, recurrent, or metastatic incurable malignancies that have progressed after at least one available standard therapy; Patients who have proven intolerable or are considered unsuitable; or who are the approved standard of care for clinical trials of investigational agents.
If a patient who has progressed after at least one available standard treatment has additional approved standard treatment options available, the study physician should be advised before informed consent to participate in this study is obtained. , the risks and benefits of these procedures must be discussed. This discussion must be documented in patient documentation.
For Phase Ib-only expansion cohorts, locally advanced, recurrent, or metastatic disease for which clinical trials of investigational agents in combination with anti-PD-L1 antibodies, with or without chemotherapy, are considered acceptable treatment options Patients with histologic documentation of incurable malignancies may also be eligible.
• Patients and associated pathology reports with confirmed availability of representative tumor specimens in formalin-fixed paraffin-embedded (FFPE) blocks (preferred) or ≧15 unstained slides.
Acceptable specimens also include core needle biopsy (minimum of 3 cores) for deep tumor tissue or excisional, incisional, punch, or forceps biopsy for cutaneous, subcutaneous, or mucosal lesions. can contain.
• Fine needle aspiration (FNA) samples, brushings, cell pellets from exudates or ascites, and lavage fluid samples are not allowed.
• Tumor tissue from bone metastases cannot be assessed for PD-L1 and/or TIGIT (T cell immunoreceptor with Ig and ITIM domains) expression and is therefore unacceptable.
If appropriate tissue from different time points (e.g., at initial diagnosis and at disease recurrence) and/or from multiple metastatic tumors is available, recently harvested (ideally following recent systemic therapy). subsequently) must be prioritized by the organization. Multiple samples may be taken from a given patient based on availability, but the requirement for a block or >15 or more unstained slides must be met by a single biopsy or excision.
• Prior to signing the Main Study Informed Consent Form (ICF), patients may sign a pre-screening ICF to specifically allow collection and examination of archival or fresh tumor specimens.
Patients with insufficient or unavailable archival tissue may be eligible if, upon discussion with the medical monitor, the patient either:
- Able to provide at least 10 unstained serial slides - Consent and willing to have excisional/incisional biopsy specimens of pretreatment core, punch, or tumor collected (acceptable specimens) See above for
• Enrolled in a dose escalation cohort • Enrolled in a chemotherapy expansion cohort (Phase Ib)
Enrolled in the Q4W dosing expansion cohort (Phase Ib) For backfill or expansion cohort patients, submitted archived tumor tissue must be assessed for PD-L1 and/or TIGIT expression prior to enrollment not.
• Patients with measurable disease by RECIST v 1.1 • Previously irradiated lesions are counted as target lesions.
• Lesions intended for biopsy are not counted as target lesions.

F. Additional Inclusion Criteria for Patients Who Have Backfilled Defined Phase Ia and Phase Ib Cohorts • Backfill cohort enrollment is limited to patients whose tumors have PD-L1 and/or TIGIT expression. Therefore, an archive of tumor tissue must be submitted and assessed for PD-L1 and/or TIGIT expression prior to enrollment. Therefore, an archive of tumor tissue must be submitted and assessed for PD-L1 and/or TIGIT expression prior to enrollment. PD-L1 and/or TIGIT expression can be assessed in either immune-infiltrating cells or tumor cells. If multiple tumor specimens are submitted (eg, archival specimens and tissues from recurrent disease), patients may be eligible if at least one specimen is evaluable for PD-L1 and/or TIGIT. A patient's PD-L1 and/or TIGIT score is the maximum PD-L1 and/or TIGIT score between samples, respectively.
- Patients must have a PD-L1-selected tumor and/or a TIGIT-selected tumor of one of the following tumor types: non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), triple- Negative breast cancer (TNBC), melanoma, head and neck squamous cell carcinoma (HNSCC), ovarian cancer (OC), gastric cancer (GC) including gastroesophageal junction (GEJ) cancer, urothelial bladder cancer (UBC) , and colorectal cancer (CRC), including microsatellite stable (MSS) and microsatellite instability low (MSI-Low).
Patients may receive a total of 1-2 biopsies (pretreatment and during treatment) or 1 biopsy (archive tissue instead of pretreatment biopsy) without unacceptable risk of significant procedural complications. must have accessible lesions to allow for treatment (if available).
• Acceptable samples include core needle biopsy for deep tumor tissue or lymph nodes, or excision, incision, punch, or forceps biopsy for skin, subcutaneous, or mucosal lesions. FNA, cell pellets from exudates or ascites, lavage fluid samples, and bone biopsies are not permitted. Target lesions considered for core needle biopsy are considered suitable for retrieval of a minimum of 3 and ideally 5 cores at a given time point (18-gauge minimum diameter).
- If multiple lesions are available, the same tumor lesion must be biopsied at all time points, if feasible, to avoid introducing heterogeneity related to tumor or metastatic sites .

G. Additional Inclusion Criteria for Patients in the Expansion Cohort • Enrollment in the expansion cohort is limited to patients whose tumors were selected for PD-L1 and/or TIGIT. Therefore, an archive of tumor tissue must be submitted and assessed for PD-L1 and/or TIGIT expression prior to enrollment. Patients whose tumor tissue is not evaluable for PD-L1 and/or TIGIT expression are not eligible. PD-L1 and/or TIGIT expression can be assessed in either immune-infiltrating cells or tumor cells. If multiple tumor specimens are submitted (eg, archival specimens and tissues from recurrent disease), patients may be eligible if at least one specimen is evaluable for PD-L1 and/or TIGIT expression. A patient's PD-L1 and/or TIGIT score is the maximum PD-L1 and/or TIGIT score between samples, respectively.
• Enrollment will be managed so that up to approximately half of the incident patients in each expansion cohort are those who consent to undergo a voluntary biopsy.
• A biopsy is required for patients enrolled in the Phase Ib serial biopsy expansion cohort.

H. Additional Inclusion Criteria for Patients in the Phase Ia Expansion Cohort Patients must have PD-L1-selected tumors and/or TIGIT-selected tumors, including the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC and CRC

I. Additional inclusion criteria for patients in each index-specific expansion cohort of phase Ib NSCLC cohort (CIT-naive): anti-PD-L1/PD-1 and/or anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) Patients with histologically confirmed incurable advanced NSCLC not previously treated with CIT (investigational or approved), including CIT (anti-PD-L1/PD-1 agent ) is approved by local regulatory authorities for the treatment of NSCLC, patients for whom a clinical trial of an investigational drug in combination with an anti-PD-L1 antibody is considered an acceptable treatment option are included.
• Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with an EGFR tyrosine kinase inhibitor(s);
- Patients whose tumors have known anaplastic lymphoma kinase (ALK) rearrangements must also not experience disease progression (during or after treatment) or intolerance to treatment with an ALK tyrosine kinase inhibitor(s). not;
• Patients whose tumors have known ROS1 rearrangements must also experience disease progression (during or after treatment) or intolerance to treatment with ROS1 tyrosine kinase inhibitor(s);
- Patients whose tumors have a known BRAF ^V600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib;
NSCLC cohort (CIT treatment): Histologically confirmed incurable advanced NSCLC patients previously treated with CIT (investigational or approved) containing anti-PD-L1/PD-1 Known tumor patients with sensitizing EGFR mutations must also have experienced disease progression (during or after treatment) or intolerance to treatment with an EGFR tyrosine kinase inhibitor(s);
• Patients whose tumors have known ALK rearrangements must also experience disease progression (during or after treatment) or intolerance to treatment with an ALK tyrosine kinase inhibitor(s);
• Patients whose tumors have known ROS1 rearrangements must also experience disease progression (during or after treatment) or intolerance to treatment with ROS1 tyrosine kinase inhibitor(s);
- Patients whose tumors have a known BRAF ^V600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib;
Patients must have had prior anti-PD-L1/PD-1 containing, CIT monotherapy and/or combination therapy (investigational or approved) with documented disease progression not.
• Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy must be the most recent systemic anticancer therapy administered prior to enrollment in this expansion cohort.
Investigator-assessed confirmed partial response (PR) or complete response (CR) at any time while receiving prior anti-PD-L1/PD-1 as monotherapy or combination therapy ) can be enrolled at least about 10 patients who experienced the best documented response to
Documented Investigator-rated stable disease (SD) per RECIST v 1.1 while receiving prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy At least about 10 patients who experienced the best response at any given time can be enrolled.
Documented Investigator-rated progressive disease (PD) by RECIST v1.1 while receiving prior anti-PD--L1/PD-1 as monotherapy and/or combination therapy At least about 10 patients who experienced the best response at any given time can be enrolled.
• Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy must be the most recent systemic anticancer therapy administered prior to enrollment in this expansion cohort.
• Patients who discontinued prior anti-PD-L1/PD-1 monotherapy and/or combination therapy primarily due to toxicity or intolerance are not eligible for enrollment in this expansion cohort.
TNBC cohort: histologically confirmed incurable advanced estrogen receptor (ER)-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast (triple-negative) Triple-negative status must be documented as defined by the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines:
- <1% of tumor cell nuclei are immunoreactive for ER and <1% of tumor cell nuclei are immunoreactive for progesterone receptor;
and • HER2 testing demonstrates immunohistochemistry (IHC) 1+, IHC0, or in situ hybridization (ISH) negative.
• CRC cohort: patients with histologically confirmed incurable advanced adenocarcinoma of the colon or rectum • Patients with tumors of appendiceal origin are not eligible.
GC cohort: Patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinoma who are not amenable to curative therapy Tumor center anatomic Patients with type 1 GEJ tumors, defined as adenocarcinoma of the distal esophagus located within 1-5 cm above the esophagogastric junction, are eligible for the study.
• Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with the medical monitor.
• Patients with known HER2-positive tumors must also have experienced disease progression (during or after treatment) or intolerance to treatment with HER2-targeting antibody/HER2 inhibitor(s).
HER2 positivity is either IHC3+ or IHC2+/ISH+ (ISH positivity is defined as a HER2:CEP17 ratio ≥2) as assessed by local laboratory testing for primary tumor or metastatic disease defined as
• Patients who have not undergone HER2 testing due to insufficient or unavailable tissue (e.g. storage and/or biopsy) and therefore whose tumor HER2 status is unknown may still may be eligible.
HNSCC cohort: Histologically confirmed inoperable, locally advanced or metastatic, recurrent or persistent squamous cell carcinoma of the head and neck (oral, oropharyngeal, inferior) not amenable to curative therapy HNSCC of any other primary anatomical location in the head and neck, HNSCC of unknown primary, or patients with tumors of non-squamous tissue are not eligible.
• Patients with nasopharyngeal HNSCC may be eligible after discussion with the medical monitor.
• The HPV status of HNSCC must be known.
UBC Cohort: Patients with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, bladder, and urethra) Patients with mixed histology were predominantly transitional Must have a cell pattern.
- Melanoma cohort: Patients with histologically confirmed incurable advanced metastatic melanoma - CIT (including anti-PD-L1/PD-1 and/or anti-CTLA-4 agents) melanoma Patients with melanoma for whom clinical trials of investigational drugs in combination with anti-PD-L1/PD-1 antibodies are considered an acceptable treatment option if approved by local regulatory authorities for the treatment of.
- Patients whose tumors have a known BRAFV 600 mutation must also have experienced disease progression (during or after treatment) or intolerance to BRAF inhibitors and/or mitogen-activated protein kinase (MEK) inhibitors. not.
• Enrollment will be managed so that approximately 20% or less of the patients in this cohort are patients with ocular (uveal) melanoma.
OC cohort: Patients with histologically confirmed incurable advanced epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer Borderline ovarian epithelial neoplasms (e.g., low-grade tumors, atypical proliferative tumors) are excluded.
- RCC cohort: patients with histologically confirmed incurable progressive RCC with components of clear cell pathology and/or sarcomatoid histology;
If CIT (including anti-PD-L1/PD-1 agents) is approved by local regulatory authorities for the treatment of RCC, clinical trials of investigational drugs in combination with anti-PD-L1 antibodies are an acceptable treatment option Patients with RCC considered as

J. Additional Inclusion Criteria for Patients in the Phase Ib Serial Biopsy Expansion Cohort Patients must have PD-L1-selected tumors and/or TIGIT-selected tumors, which may include the following tumor types: melanoma, OC, RCC and UBC
If CITs (including anti-PD-L1/PD-1 agents) are approved by local regulatory authorities for the treatment of these indication(s), clinical trials of investigational drugs in combination with anti-PD-L1 antibodies Patients with melanoma or RCC for whom testing is considered an acceptable treatment option.
Patients may receive a total of 1-2 biopsies (pretreatment and during treatment) or 1 biopsy (archive tissue instead of pretreatment biopsy) without unacceptable risk of significant procedural complications must have accessible lesions to allow for treatment (if available).
• Acceptable samples include core needle biopsy for deep tumor tissue or lymph nodes, or excision, incision, punch, or forceps biopsy for skin, subcutaneous, or mucosal lesions. FNA, cell pellets from exudates or ascites, lavage fluid samples, and bone biopsies are not permitted. Target lesions considered for core needle biopsy are considered suitable for retrieval of a minimum of 3 and ideally 5 cores at a given time point (18-gauge minimum diameter).

If multiple lesions are available, the same tumor lesion should be biopsied at all time points, if feasible, to avoid the introduction of tumor- or metastatic site-related heterogeneity.

K. Exclusion Criteria Patients meeting any of the following criteria are excluded:
General Exclusion Criteria ● Inability to comply with study and follow-up procedures ● Pregnancy, lactation or breastfeeding ● Significant cardiovascular disease, e.g., New York Heart Association heart disease (class II or higher), past 3 Myocardial infarction, unstable arrhythmia, and/or unstable angina pectoris within months.
- Known clinically significant liver disease, including active viral, alcoholic or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse - Screen hemoglobin A1 _C ≥8% or fasting plasma Uncontrolled type 2 diabetes defined as glucose ≥160 mg/dL (or 8.8 mmol/L) Major surgical procedure within 28 days prior to Day 1 of Cycle 1 or during the course of the study Anticipation of requiring major surgical intervention Reasonable suspicion of a disease or condition that contraindicates use of the investigational drug, could affect interpretation of results, Any other disease, metabolic dysfunction, physical examination findings, or clinical test findings that may put you at increased risk for disease

L. Cancer-Specific Exclusion Criteria Any anti-cancer therapy (whether investigational or approved) including chemotherapy, hormone therapy, and/or radiation therapy within 3 weeks prior to initiation of study treatment , with the following exceptions:
- hormone therapy with gonadotropin releasing hormone (GnRH) agonists or antagonists for prostate cancer;
● hormone replacement therapy or oral contraceptives;
Cycle 1, a tyrosine kinase inhibitor (TKI) approved by the local regulatory agency for treatment of cancer discontinued >7 days prior to Day 1; baseline scan obtained after discontinuation of previous TKI Must meet criteria for adverse events from previous cancer therapy >1 week prior to Cycle 1, Day 1 >2 weeks prior to Cycle 1, Day 1 , palliative radiotherapy for painful metastases or metastases in potentially sensitive locations (e.g., epidural space) Phase Ib studies with tiragolumab and atezolizumab from the Phase Ia portion of this study Patients crossing over to may have been treated with tiragolumab as a single agent prior to entering a Phase Ib trial.
• Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort in which the patient is being considered, as described below. Additionally, all criteria for adverse events attributable to prior cancer therapy must be met.

All Phase Ia and Phase Ib cohorts (dose escalation, backfill and expansion):
- No previous anti-TIGIT agents are allowed with the following exceptions:
• Patients treated with tiragolumab in a Phase Ia trial may be enrolled in a Phase Ib trial if specified criteria are met.
- Prior treatment with cancer vaccines and/or cytokines if at least 6 weeks or 5 half-lives of the drug, whichever is shorter, have elapsed between the final dose and proposed Cycle 1, Day 1 is possible.
• The minimum washout is 3 weeks for any previous systemic cancer therapy.
- Prior cancer immunotherapy not explicitly listed in this protocol should be discussed with the medical monitor to determine potential eligibility;

Dose escalation and backfill cohorts in Phase Ia and Phase Ib (enrollment during dose escalation):
- Prior treatment with immune checkpoint inhibitors (e.g., anti-PD-L1/PD-1), immunomodulatory MAbs and/or MAb-derived therapies with at least 5 elimination half-lives of the drug suggested as the final dose Cycle 1, permissible provided it has passed between Day 1 and Day 1.
Prior treatment with immunomodulatory agents, including toll-like receptor (TLR) agonists, inhibitors of indoleamine 2,3-dioxygenase or tryptophan-2,3-dioxygenase (IDO/TDO), or agonists of OX40 , is acceptable provided that at least 6 weeks have elapsed between the last dose and the proposed Cycle 1, Day 1.

Dose Expansion and Backfill Cohorts in Phase Ia and Phase Ib (enrollment during dose expansion):
- Prior treatment with an immune checkpoint inhibitor, immunomodulatory MAb and/or MAb-derived therapy, provided that at least 6 weeks have elapsed between the final dose and proposed Cycle 1, Day 1 with the following exceptions:
Prior anti-PD-L1/PD-1 with at least a 3-week washout period Prior anti-CTLA-4 with a 6-week washout period In the Phase Ib NSCLC CIT treatment expansion cohort, current systemic Treatment was anti-PD-L1/PD-1 as monotherapy or combination In the Phase Ib NSCLC CIT naive expansion cohort, immune checkpoint inhibitors (such as anti-PD-L1/PD-1), Prior treatment with immunomodulatory MAbs and/or MAb-derived therapies is not permitted.

Prior treatment with an immunomodulatory agent, including a TLR agonist, an inhibitor of IDO/TDO or an agonist of OX40, between the last dose of prior treatment and the proposed Cycle 1, Day 1, with the following exceptions: is acceptable provided that at least 5 half-lives of the drug or a minimum of 3 weeks have passed.

No prior treatment with other immunomodulatory agents is permitted in the Phase Ib NSCLC CIT naive expansion cohort.
- History of immune-mediated grade 4 adverse events attributed to prior cancer immunotherapy (other than endocrine insufficiency managed with replacement therapy or asymptomatic elevation of serum amylase or lipase)
- Immune-mediated Grade 3 adverse events (replacement Endocrine insufficiency managed with therapy, or history of other than asymptomatic elevation of serum amylase or lipase).
- Adverse events from previous anticancer therapy that have not resolved to Grade ≤ 1, except for alopecia, vitiligo or endocrine disorders managed with replacement therapy - Any immune-mediated event associated with previous cancer immunotherapy Adverse events (other than replacement therapy or endocrine insufficiency managed with stable vitiligo) must have resolved completely to baseline.
• Patients treated with corticosteroids for immune-mediated adverse events must demonstrate no associated symptoms or signs for >4 weeks after discontinuation of corticosteroids.
- Patients with pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC - Primary CNS malignancies, untreated CNS metastases, or active CNS metastases (advanced or requiring corticosteroids for symptomatic control) do)
Patients with prior treatment for CNS metastases are eligible provided they meet all of the following criteria:
No ongoing need for corticosteroids as treatment for CNS metastases, corticosteroids were discontinued ≥2 weeks prior to enrollment, no ongoing symptoms attributed to CNS metastases No • Stable doses of anticonvulsants are acceptable.
X-ray demonstration of improvement at completion of CNS-directed therapy and no interim evidence of progression between completion of CNS-directed therapy and screening X-ray study Screening CNS X-ray study after completion of radiotherapy Leptomeningeal disease Uncontrolled tumor-related pain Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) must be treated prior to enrollment. must.
Asymptomatic metastatic lesions (epidural metastases not currently associated with spinal cord compression) whose further growth may cause dysfunction or intractable pain should be treated locoregionally prior to enrollment, if appropriate. therapy should be considered;
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage (monthly or more frequently)
• Patients with indwelling catheters (eg, PleurX catheter) are allowed.
Exclude those with negligible risk of metastasis or death (e.g., appropriately treated cervical carcinoma in situ, basal or squamous skin cancer, localized prostate cancer, or ductal carcinoma in situ) , malignancy other than disease under study within 5 years prior to Day 1 of Cycle 1 Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or Ca >12 mg/dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.

Specifically, patients receiving bisphosphonate therapy or denosumab to prevent skeletal events and no history of clinically significant hypercalcemia are eligible. However, denosumab patients must be willing and eligible to receive a bisphosphonate instead of denosumab during the study.
Patients who have not been definitively treated with surgery and/or radiation or have previously diagnosed and treated spinal cord compression without evidence that their disease has been clinically stable for ≥2 weeks prior to Screening. have.

M. Treatment-specific exclusion criteria Systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy (autoimmune etiology only), Guillain- History of autoimmune disease, including but not limited to Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, with the following caveats:

Patients with a history of autoimmune hypothyroidism who receive stable doses of thyroid replacement hormone may be eligible.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin symptoms only (eg, no psoriatic arthritis) may be eligible if they meet the following conditions:
• Less than 10% of the body surface area must be covered by the rash.
- Disease is well controlled at baseline, requiring only low-potency topical steroids - No acute exacerbation of underlying symptoms within the past 12 months (e.g., psoralen plus ultraviolet A radiation (PUVA), methotrexate, does not require retinoids, biologics, oral calcineurin inhibitors, high-potency or oral steroids)
- Systemic immunosuppressants (including but not limited to prednisone >10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide and tumor necrosis factor-α [TNF-α] within 2 weeks prior to Cycle 1, Day 1) treatment with antagonists)

Patients receiving acute low-dose systemic immunosuppressants (e.g., single dose of dexamethasone for nausea) may be enrolled in the study after consultation and approval with the medical monitor:

Use of inhaled corticosteroids (e.g. fluticasone for chronic obstructive pulmonary disease) is permissible

Use of oral mineralocorticoids (e.g. fludrocortisone for patients with orthostatic hypotension) is permissible

Physiological doses of corticosteroids for adrenal insufficiency are allowed.
History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), organizing pneumonia (ie, bronchiolitis obliterans, subclinical organizing pneumonia, etc.), or active lung on screening chest CT scan A history of inflammation.

A history of radiation pneumonitis (fibrosis) in the radiology area is acceptable.
• Positive test for HIV infection • Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening).

Patients with previous or resolved hepatitis B infection (defined as having a negative HBsAg test and positive IgG antibodies to hepatitis B core antigen [anti-HBc]) are eligible. Hepatitis B virus (HBV) DNA must be obtained in these patients prior to Cycle 1, Day 1 and must demonstrate active infection.
• Active Hepatitis C Patients who are positive for hepatitis C virus (HCV) antibodies are eligible only if the polymerase chain reaction (PCR) is negative for HCV RNA.
Active EBV infection at screening and known or suspected chronic active EBV infection

Patients positive for EBV IgG and/or EBNA are eligible only if EBV IgM and/or EBV PCR are negative.
- Active tuberculosis - Severe infection within the 4 weeks prior to Day 1 of Cycle 1, including but not limited to complications of infection, bacteremia, or severe pneumonia - Severe disease, including: Recent infections not meeting the above criteria for infections:
o Signs or symptoms of infection within the 2 weeks prior to Cycle 1, Day 1 o Oral or IV antibiotics received within the 2 weeks prior to Cycle 1, Day 1 o Prophylactic antibiotics (e.g., urinary for prophylaxis of tract infections or chronic obstructive pulmonary disease) are eligible;
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation - Administration of a live attenuated vaccine within 4 weeks prior to Cycle 1, Day 1, or evidence that such a live attenuated vaccine is required during the study Predict.
• Influenza vaccination should be given only during the influenza season. Patients may not receive a live attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1, or at any time during the study and for 5 months after the last study treatment. not.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, or fusion proteins.
- Known hypersensitivity to CHO cell products - Allergy or hypersensitivity to components of atezolizumab preparations

N. Chemotherapy expansion cohort-specific exclusion criteria Known severe allergy or hypersensitivity to platinum or platinum-containing compounds Cisplatin-specific exclusion criteria Patients with known hearing impairment (cisplatin treatment only)
- Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v 4.0 criteria (cisplatin treatment only)
- Creatinine clearance < 60 mL/min measured or calculated based on Cockcroft-Gault GFR estimates (cisplatin treatment only):

O. Exclusion criteria specific to Cohort A Known severe allergy or hypersensitivity to pemetrexed

P. Exclusion Criteria Specific to Cohort B Known severe allergy or hypersensitivity to paclitaxel Known history of severe hypersensitivity reaction to products containing Cremophor® EL (e.g., cyclosporine for injection concentrate and injection teniposide for concentrates)

Q. Exclusion criteria specific to Cohort C Known severe allergy or hypersensitivity to etoposide

R. Exclusion criteria specific to Cohort D Hypersensitivity to any component of the capecitabine formulation Inability to swallow pills Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colon inflammation history of known dihydropyrimidine dehydrogenase deficiency or severe and unexpected response to fluoropyrimidine therapy requirement for concomitant use of the antiviral agent sorivudine (an antiviral agent) or chemically related analogues such as brivudine drug use is not permitted within 4 weeks of initiation of study treatment, including capecitabine)

S. Exclusion Criteria Specific to Cohort NC1 Poorly controlled hypertension (defined as systolic BP >150 mmHg and/or diastolic BP >100 mmHg based on the mean of ≥3 blood pressure measurements in ≥2 sessions antihypertensive therapy to achieve these parameters is acceptable History of hypertensive crisis or hypertensive encephalopathy Significant vascular disease (e.g., requiring surgical repair) within 6 months prior to initiation of study treatment aortic aneurysm or recent peripheral arterial thrombosis)
- History of hemoptysis (≥2.5 mL bright red blood per episode) within 1 month prior to initiation of study treatment
Bleeding diathesis or evidence of significant coagulopathy (in the absence of therapeutic anticoagulation)
- Current or recent (≤10 days prior to initiation of study treatment) use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day) - Note: Use of full-dose oral or parenteral anticoagulants for therapeutic purposes INR and/or aPTT are within therapeutic limits (according to institutional criteria) within 7 days prior to initiation of study treatment and patient is on a stable dose of anticoagulant for ≥2 weeks prior to initiation of study treatment A core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the start of the study procedure. Before the start of the study procedure. History of abdominal or tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months Routine parenteral hydration, parenteral nutrition within 6 months prior to initiation of study treatment or within 6 months prior to initiation of study treatment or clinical signs or symptoms of gastrointestinal obstruction, including sub-obstructive or obstructive syndromes related to history of need for tube feeding and/or underlying disease Have signs or symptoms of obstructive or obstructive syndrome at initial diagnosis or Alternatively, patients with intestinal obstruction may be enrolled if they undergo definitive (surgical) treatment for symptom relief.
- Evidence of abdominal free air not accounted for by puncture or recent surgical procedure - Serious non-healing or dehiscent wound, active ulcer, or untreated fracture - ≥2+ protein and protein on dipstick urinalysis Grade ≥2 proteinuria as demonstrated by ≥1.0 g protein on 24 hour urine collection All patients with ≥2+ protein on dipstick urine test at screening will have a 24 hour urine collection for protein have to receive.
• Patients with <2+ protein on dipstick urinalysis are eligible for the study.
- Metastatic disease with airways or great vessels, or a large volume of centrally located mediastinal mass (<30 mm from carina) - Including, but not limited to, peptic ulcer disease, diverticulitis or colitis History of an intra-abdominal inflammatory process within 6 months prior to initiation of study treatment Radiation therapy within 28 days or abdominal/pelvic radiation therapy within 60 days prior to initiation of study treatment Major surgery within 28 days prior to initiation of study treatment surgical procedure, incisional biopsy, or significant traumatic injury; or abdominal surgery, abdominal intervention, or significant abdominal traumatic injury within 60 days prior to the start of study procedures; or the need for major surgical procedures during the course of the study. lack of anticipation of sex or recovery from side effects of such treatment

T. Assessment Patients will be closely monitored for safety and tolerability and evaluated for toxicity prior to each dose of tiragolumab as a single agent (Phase Ia) or in combination with: atezolizumab, atezolizumab plus chemotherapy. , atezolizumab and bevacizumab, or pembrolizumab (Phase Ib). Dosing will occur only if clinical evaluation and local laboratory results are acceptable.

All assessments will occur on the scheduled visit unless a time window is specified. Assessments scheduled on the day of study treatment will be performed prior to study drug infusion unless otherwise specified.

Medical history, baseline symptoms, concomitant medications and demographic data Medical history includes cancer history (previous cancer therapy and/or previous CIT and procedures and tumor characteristics such as hormone receptor status or mutational status). (including but not limited to), other clinically significant disease, surgery, smoking history, alcohol and/or drug use of abuse, reproductive status, and any other clinically significant disease used by the patient within 7 days prior to the Screening Visit. Drugs (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic drugs, and dietary supplements) are included.

For patients crossing over from the Phase Ia to Phase Ib portion of the trial, the rescreening history at reinitiation of treatment at disease progression should include: including cancer-related or study treatment-related adverse events that occurred after discontinuation of treatment for

Demographic data includes age, gender, and self-reported race/ethnicity. Race/ethnicity is recorded because of the potential contribution of this variable to observed differences in PK, pharmacodynamics, toxicity, and/or response to treatment.

Vital Signs Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a sitting position.

On study treatment days, vital signs are measured within 60 minutes prior to the first study drug infusion of the day.

The first infusion of Phase Ia tiragolumab was administered every 15 (±5) minutes during the infusion, at the end of the infusion (±5 min), and at 30 (±10), 120 (±15), and 240 (±15) minutes after the end of the infusion. ±15) Measure vital signs every minute.

For the first infusion of tiragolumab in Phase Ib, vital signs will be measured every 15 (±5) minutes during the infusion, at the end of the infusion (±5 min), and every 30 min (±10 min) after the end of the infusion. For all Phase Ib cohorts without chemotherapy, the first infusion of atezolizumab or pembrolizumab will be administered 60 minutes after completion of the tiragolumab infusion. The first infusion of bevacizumab is administered 60 minutes after completion of the atezolizumab infusion.

For Phase Ib cohorts with chemotherapy, the first infusion of tiragolumab is administered 60 minutes after completion of the atezolizumab infusion.

For the first infusion of atezolizumab and pembrolizumab and subsequent infusion of tiragolumab, vital signs will be taken during and 30 (±10) minutes after the infusion if clinically indicated or if symptoms occurred on the previous infusion. is measured to

For the first infusion of bevacizumab, vital signs were taken during the infusion, at the end of the infusion (± 5 min), and 30 min after the infusion (± 10 minutes).

Between subsequent tiragolumab and atezolizumab or pembrolizumab, or between atezolizumab and bevacizumab (for all Phase Ib cohorts without chemotherapy), or between atezolizumab and tiragolumab (Phase Ib cohorts with chemotherapy) ) is 30 minutes if the previous tiragolumab or atezolizumab infusion was tolerated without IRR, or 60 minutes if the patient experienced an IRR on the previous tiragolumab or atezolizumab infusion.

In chemotherapy expansion A, B, and C cohorts, additional vital signs are measured and recorded in cycle 1 within 30 (±10) minutes after completion of the last chemotherapy infusion (e.g., cohort A: carboplatin or cisplatin after, cohort B: after carboplatin, cohort C: after etoposide). On subsequent cycles, if clinically indicated, additional vital signs will be measured and recorded after chemotherapy infusion.

Vital signs collected at the screening visit will be recorded. For each subsequent visit, any adverse event (e.g. fever temperature) or cardinal symptom of an adverse event (e.g. blood pressure or arrhythmia related to infusion-related reaction) obtained prior to the first study drug infusion of the day Record only the vital signs that make up the associated heart rate). All vital signs collected per protocol will be documented in the patient's medical documentation.

Blood oxygen saturation is measured at baseline by pulse oximetry.

Physical Exam A complete physical exam performed at Screening includes head, eyes, nose, and throat, as well as cardiovascular, dermatological, musculoskeletal, respiratory, digestive, genitourinary, and neurological systems. system is included.

Assess ECOG performance status.

At subsequent visits (or as clinically indicated), a limited symptom-directed physical examination is performed. Changes from baseline abnormalities are recorded in the patient's medical record. New or worsening clinically significant abnormalities are recorded as adverse events.

As part of the tumor evaluation, the physical examination also includes assessment of lymphadenopathy, splenomegaly, hepatomegaly, and cutaneous neoplasms or metastases. All patients are monitored for symptoms of CNS metastases and undergo a complete neurological examination after such reported symptoms. A magnetic resonance imaging (MRI) scan or contrast-enhanced head CT scan is performed as clinically indicated to confirm or rule out new or worsening brain involvement.

Tumor and Response Assessment Screening All known sites of disease must be documented at screening and reevaluated at each subsequent tumor assessment.

Screening and subsequent tumor assessment should include a CT scan (with IV contrast unless contraindicated, and oral contrast when appropriate according to institutional standards) or MRI scans of the chest, abdomen, and pelvis. If CT scans for tumor assessment are performed on a Positron Emission Tomography (PET)/CT scanner, the CT acquisition should conform to the standard for full contrast-enhanced CT scans.

Brain imaging (either MRI or CT with contrast) is required at screening for patients with treated brain metastases and if clinically indicated based on symptoms or signs indicative of new or worsening CNS metastases. In the case of equivocal head CT, a brain MRI is required to clarify the presence or extent of suspected brain metastases.

Further investigations, such as neck bone scans and CT scans, are also demonstrated by the underlying disease (e.g., head and neck CT scans are indicated for patients with HNSCC) and by the minimum schedule of assessments listed above. It is performed when there is clinical suspicion of disease at any site that cannot be At the investigator's discretion, other methods of measurable disease assessment according to RECIST v1.1 may be used.

The same radiological procedure used to assess disease sites at screening must be used throughout the study (eg, same imaging protocol for CT scan). Stable brain metastases must be evaluated at each tumor assessment using the same radiographic procedure as the baseline study. Patients without brain metastases do not require brain scans for tumor evaluation unless clinically justified. Responses will be assessed by the investigator using RECIST v1.1 based on physical examination and imaging modalities detailed above. Investigator assessment of overall tumor response at all time points is based solely on RECIST v1.1. Ratings will be performed by the same raters where possible to ensure internal consistency between visits.

The following assessments will be made: At the discretion of the Investigator, scans can be performed whenever PD is suspected.

After discontinuation of first study treatment (if discontinuation was for reasons other than disease progression), either death, disease progression, initiation of another systemic anticancer therapy, lost to follow-up, consent withdrawal, or study termination A follow-up tumor assessment is performed until the tumor occurs sooner.

Patients continuing treatment after radiological disease progression by RECIST v1.1 will be scheduled after 6 (±2) weeks (i.e., at the next scheduled tumor assessment if the scan frequency is every 2 cycles, or at the scan If the frequency is every 4 cycles, as an unscheduled tumor assessment) or sooner as clinically indicated with follow-up scans. Tumor assessment should continue every 2 cycles thereafter until 2 consecutive scans show improvement over the first scan showing stable or radiological disease progression, at which point the scan frequency should be Return or transition every 4 cycles if applicable. Investigator assessment of overall tumor response at all time points is based solely on RECIST 1.1.

Laboratory, Biomarkers, and Other Biological Specimens Phase Ia and Phase Ib Local Laboratory Testing The following laboratory testing is performed in the laboratory's local laboratory.

• Hematology (CBC including WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)).
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 women of childbearing potential (including those who have had tubal ligation) have a serum pregnancy test at screening. Urine pregnancy tests are performed at regular intervals throughout the study treatment. If the urine pregnancy test result is positive, dosing is delayed until the patient's status is determined by serum pregnancy test.
Urinalysis (specific gravity, pH, glucose, protein, ketones, blood)
Thyroid function tests (thyroid stimulating hormone [TSH], free T3 and free T4)
EBV serology (EBV IgM, EBV IgG and/or EBNA]) and/or EBV PCR

An EBV IgM test and/or an EBV PCR test is required prior to Day 1 of Cycle 1 to consider eligibility if the patient has positive serology for EBV IgG and/or EBNA.
●CMV serology (CMV IgG)
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core antigen)

HBV DNA test must be obtained before Cycle 1, Day 1 if the patient has positive serology for anti-HBc.
● HCV serology (anti-HCV)

If a patient has positive serology for anti-HCV, an HCV RNA test is required prior to Cycle 1, Day 1 to consider eligibility.
• All patients will be tested for HIV prior to inclusion in the study and HIV-positive patients will be excluded from the study.
- Tumor markers (as applicable and beneficial)

Central Laboratory for Phase Ia and Phase Ib The studies listed below are conducted in the central laboratory. Samples collected for PK or ADA analysis may be required for further immunogenicity characterization, PK, biomarker, and/or immunogenicity assay development and validation; , within five years of completion of the final clinical study report, or sooner depending on local regulations.

Ratings performed on blood samples ADA assay

Serum samples are obtained for measurement of ADA to tiragolumab using validated assays (Phase Ia and Phase Ib).

Serum samples will be obtained for measurement of ADA to atezolizumab using validated assays (Phase Ib only).
● PK assay

Serum samples are obtained for determination of tiragolumab concentrations using validated assays (Phase Ia and Phase Ib).

Serum samples will be obtained for determination of atezolizumab concentrations using validated assays (Phase Ib only).

Plasma samples are obtained for determination of cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine and etoposide concentrations using validated assays (Phase Ib chemotherapy expansion cohort only).
● Autoantibody test

Serum samples are obtained for autoantibody testing including, but not necessarily limited to, antinuclear antibodies, anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, and thyroid peroxidase antibodies, either for individual patients or study populations. , based on clinical events during the study.
●Biomarker assay in blood

Blood samples for biomarker evaluation will be obtained from all eligible patients at screening visits and during treatment.
● Whole Genome Sequencing (WGS)

A single blood sample can be taken for WGS and sent to one or more laboratories for analysis. WGS data and related clinical data may be shared with testers not participating in the trial, or may be approved by governments or other parties for broad sharing with other testers to conduct human health and disease studies. May be submitted to a health test database. Study participants are not identified by name or other personally identifiable information.

WGS is subject to review and approval by each site's IRB/EC and, where applicable, appropriate regulatory bodies. If the facility is not WGS approved, this rating is not applicable at the facility.

The WGS data will be analyzed in the context of this study and will be explored together with other studies to better understand disease pathobiology and guide the development of new therapeutic approaches. Given the complexity and exploratory nature of these analyses, WGS data and analyzes are for study purposes only and will not be shared with investigators or study participants.

These samples are stored indefinitely until exhausted or until the patient requests destruction of the sample.

Assessments performed on tumor samples Immune-related and tumor-related biomarkers, including but not limited to PD-L1, TIGIT, PVR and/or CD 226 expression on specific cell types; prevalence and/or activation) status can be assessed in both archived and fresh tumor samples using methods including, but not limited to, IHC, IF, and qRT-PCR. Tumor RNA and/or DNA can be purified and subjected to RNA sequencing and characterization by WGS. Additional exploratory biomarkers can also be assessed when guided by clinical and non-clinical data.
Archived tumor tissue: for all patients enrolled in the study

If available, archive tumor tissue samples obtained outside of the study for other purposes will be collected from all patients (paraffin blocks preferred; at least 15 unstained slides acceptable ). For all Phase Ia or Phase Ib patients, the availability of archived tumor tissue must be confirmed prior to entry into the study. Fine needle aspirates, cell pellets from exudates or ascites, lavage samples, and bone biopsies do not meet archival tissue requirements.

If appropriate tissue from different time points (e.g., at initial diagnosis and at disease recurrence) and/or from multiple metastatic tumors is available, recently harvested (ideally following recent systemic therapy). organization).

Patients with insufficient or unavailable archive tissue may still be eligible.

Harvested tumor tissue is used to evaluate potential predictive biomarkers using characterized assays for protein, RNA and DNA analysis.
Required tumor biopsy: For patients enrolled in the Phase Ib serial biopsy expansion cohort

Time points: Serial biopsies will be obtained at 2 time points: 1) pretreatment-biopsies will be obtained at baseline after all eligibility criteria are met, 2) approximately 2 weeks after the first dose of both tiragolumab and atezolizumab. Obtain in-treatment biopsies at (ie, on or during Cycle 1 Days 15-21).

Additional optional biopsies may be collected at the discretion of the investigator, preferably at radiographic progression (particularly if pseudoprogression is suspected) or at response.

Serial tumor biopsies are used to evaluate tumor pharmacodynamic and potential predictive biomarkers using characterized assays for protein, RNA and DNA analysis.
In-progress tumor tissue biopsy for crossover from Phase Ia to Phase Ib: Investigator-assessed crossover from Phase Ia to Phase Ib of the study after radiological disease progression about the patient under consideration

A progression biopsy is required if sample collection is deemed clinically feasible by the investigator and if the patient provides written informed consent. Tumor tissue samples are obtained consisting of core needle biopsies of deep tumor tissue or lymph nodes, or excisional, incisional, punch or forceps biopsies of skin, subcutaneous or mucosal lesions.

Biopsies at progression are used for evaluation of tumor pharmacodynamic and potential predictive biomarkers using characterized assays for protein, RNA and DNA analysis.
Optional tumor biopsy: For patients who provide specific informed consent to undergo an optional biopsy, especially in up to half of patients enrolled in Phase Ia or Phase Ib expansion cohorts

Patients who consented to a voluntary biopsy were selected after all eligibility criteria were met and approximately 2 weeks after the first dose of tiragolumab as a single agent (Phase Ia) or approximately 2 weeks after the first dose of tiragolumab and atezolizumab (Phase Ia). Provide a tumor biopsy at baseline during or during Phase Ib) (ie, Days 15-21 of Cycle 1).

For patients with documented long-term CR and/or PR (e.g., duration of about 1 year) with accessible residual mass, a biopsy of the residual mass should be evaluated for viable tumor cells (vs. fibrotic or necrotic tissue). recommended for grading.

Tumor tissue samples can be collected using core needle, punch, excisional biopsy (as described above), or forceps biopsy. See the sample specifications above for required tumor biopsies for additional guidance related to the selected biopsy technique.

Any tumor biopsy is used to evaluate tumor pharmacodynamics biomarkers and potential predictive biomarkers using characterized assays for protein, RNA and DNA analysis.
• Specimen Specifications: For all Phase Ia and Ib patients, required and optional biopsies must meet the following specimen requirements.

Tumor tissue samples are obtained consisting of core needle biopsies of deep tumor tissue or lymph nodes, or excisional, incisional, punch or forceps biopsies of skin, subcutaneous or mucosal lesions. Fine needle aspirates, cell pellets from exudates or ascites, lavage samples, and bone biopsies are not permitted. Target lesions considered for core needle biopsy are considered suitable for retrieval of at least 3 cores at a given time point (minimum diameter of 18-gauge). If possible, consecutive paths through the same lesion will be ≧1 cm apart.

If multiple lesions are available, obtain a periprocedural biopsy from the same lesion (or organ) as the pretreatment biopsy, if practicable, to avoid introducing heterogeneity related to metastatic sites is preferred.

RECIST target lesions are not biopsied.

Tissue samples and their derivatives (such as DNA and RNA) are stored indefinitely or until exhausted or until the patient requests destruction of the samples.
Use of Remaining Samples for All Phase Ia and Phase Ib Patients

Tiragolumab as a single agent (Phase Ia), or chemo Not required for medical diagnosis if tumor tissue or other tissue is available that may signal the activity (either antitumor or autoimmune) of tiragolumab (Phase Ib) in combination with atezolizumab with or without therapy. The remaining sample or portion of the sample (bodily fluid sample or residual tumor tissue) can be obtained for exploratory analysis. Patients must provide specific informed consent for these samples to be collected and evaluated.

Remaining tumor samples are used for evaluation of tumor pharmacodynamic biomarkers and potential predictive biomarkers using characterized assays for protein, RNA and DNA analysis.

Electrocardiogram Triplicate ECG recordings will be obtained at the indicated time points for the dose escalation and backfill cohorts of tiragolumab alone (Phase Ia) and one ECG recording will be obtained for all other patients. ECGs acquired on different days are time-matched as closely as practicable. Three interpretable ECG recordings (eg, no artifact) must be acquired at each time point (±5 minutes). An average of the three readings is used to determine the ECG interval (eg PR, QRS, QT). Additional ECGs can be obtained at unscheduled time points as clinically indicated.

All ECG recordings must be made using a standard, high quality, high fidelity digital electrocardiograph with computer-based interval measurements. Lead placement is as consistent as possible. ECG recordings must be taken after the patient has rested in the supine position for at least 10 minutes. All ECGs should be obtained prior to other concurrently scheduled procedures (eg, biometric measurements, blood draws) and should not be obtained within 3 hours after meals. If it may be difficult for the patient to follow this guidance, the time between meal intake and ECG recording may be shortened to 2.5 hours or institutional standards as long as the same minimum time is maintained at all time points. . Situations that can induce heart rate changes, including environmental distractions (eg, television, radio, talking) must be avoided during the pre-ECG rest period and during ECG recording.

For safety monitoring purposes, the investigator must review, sign, and date all ECG records. An overall rating of the ECG as normal or abnormal, whether clinically relevant or not, is recorded. A paper or electronic copy of the ECG record is maintained on site as part of the patient's permanent test file.

If the mean QT interval corrected using the Fridericia formula (QTcF) is >500 ms and/or >60 ms longer than the baseline value at a given post-dose time point, ideally within the next 5 minutes Another ECG must be recorded at 10:00 a.m. and ECG monitoring continues until QTcF is stable in two consecutive ECGs. At the discretion of the Investigator, standard of care treatment may be initiated. If a PK sample is not scheduled at that time, an unscheduled PK sample is obtained. The investigator will evaluate the patient for potential co-risk factors (eg, electrolyte imbalances, co-medications known to prolong the QT interval, severe bradycardia).

Cancer-Related Treatments Cancer-related medical, surgical and radiological treatment collections began on Day 1 and were followed throughout the treatment period and survival in both the Phase Ia and Ib portions of the study. It will be implemented during the upgrade period.

Anti-Drug Antibody Testing Tiragolumab and/or atezolizumab can induce an immune response against themselves. Tiragolumab and atezolizumab before, during and after treatment with tiragolumab as single agents in Phase Ia or with or without chemotherapy in Phase Ib using validated screening, confirmation and potency assays ADA is detected at multiple time points after treatment in combination with ADA responses are correlated with relevant clinical endpoints to understand their clinical significance. Additional ADA assays (eg, neutralizing antibody assays) can be used to further characterize the ADA response.

U.S.A. Withdrawal of Patients and Study Treatment Patient withdrawal Patient withdrawal from a study is distinct from discontinuation of study treatment and occurs when a patient dies, fails follow-up, or withdraws consent for follow-up.

Patients have the right to voluntarily withdraw from the study at any time for any reason. Additionally, the investigator has the right to withdraw a patient from the study at any time. Reasons for withdrawal from the study may include, but are not limited to:
- patient withdrawal at any time of consent - any medical condition that the investigator determines may jeopardize the patient's safety if the investigator continues the study - the investigator does not determined to be most beneficial to

Every effort will be made to obtain information regarding patients withdrawing from the study. The primary reason for withdrawal from the study or follow-up is documented. However, patients are not followed for any reason after consent is revoked. Patients who withdraw from the study are not replaced.

Discontinuation of Study Treatment Patients must discontinue study treatment if they experience any of the following:
- Symptomatic exacerbation due to disease progression as determined by the investigator after integrated assessment of all radiographic data, biopsy results and clinical status (i.e., uncontrolled pain secondary to disease or uncontrolled ascites, etc.) ).
- Unacceptable treatment-related toxicities, including the occurrence of immune-mediated adverse events that the investigator deems unacceptable given the individual patient's potential response to treatment and the severity of the event - Investigator Any medical condition that the investigator determines may jeopardize the patient's safety if the patient continues study treatment Use of a non-protocol systemic anticancer therapy Pregnancy You have the right to voluntarily discontinue study treatment at any time for any reason. Additionally, the investigator has the right to withdraw a patient from study treatment at any time. Reasons for withdrawal from study treatment may include, but are not limited to:
● Investigator's decision to be in the best interest of the patient ● Patient non-compliance

Patients who discontinue study treatment primarily for reasons other than disease progression will continue to have tumor assessments, and all patients who discontinue study treatment will continue to be followed for survival every 3 months unless consent is revoked.

Patients who discontinue study treatment will be asked to return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study treatment.

A visit with a response rating of PD (which is discontinuation of tiragolumab (Phase Ia) or tiragolumab in combination with atezolizumab, tiragolumab in combination with atezolizumab in combination with bevacizumab, or tiragolumab in combination with pembrolizumab (Phase Ib)) ) can optionally be used as a discontinuation visit, where all assessments associated with the discontinuation visit are made at that time.

After discontinuation of study treatment, all patients are followed for survival and subsequent anticancer therapy. Survival and subsequent anticancer therapy follow-up information will be obtained by phone call, patient's medical records approximately every 3 months until death, loss of follow-up, or study termination, unless the patient requests discontinuation from follow-up. , and/or collected via clinic visits. Information regarding subsequent anticancer therapy includes systemic therapy (eg, chemotherapy, targeted therapy, hormone therapy, or CIT), surgery (eg, removal of metastatic disease), and radiation treatment (eg, radiation to tumor lesions). therapy).

If a patient is withdrawn from the study, site staff can only obtain information on survival status using public sources (eg, county records).

V. ANALYSIS Objectives and endpoints To assess the safety, PK, pharmacodynamics and preliminary anti-tumor activity of tiragolumab. The specific objectives and corresponding endpoints of this study are outlined in Table 36.

Activity Analysis The analysis described below is based on the definition of objective response according to RECIST v 1.1.

Response rating data, duration of objective response, PFS and OS are listed by dose level or tumor type for all treated patients, as appropriate.

Objective Response Rate The ORR analysis includes Phase Ia or Phase Ib patients who have received any amount of study treatment and who have measurable disease at baseline. An objective response is defined as a CR or PR as determined by the investigator's assessment and confirmed by a repeat assessment >4 weeks after initial documentation. Patients with missing baselines or no response ratings are classified as non-responders. Objective response rates are estimated and summarized by tumor type and dose, if applicable.

Duration of Response Among patients with an objective response, the duration of objective response is defined as the time from the first complete or partial response to disease progression or death (whichever occurs first). For patients who do not die, experience disease progression, or are lost to follow-up before the end of the study, the duration of objective response shall be canceled on the date of the last tumor assessment. .

Progression-Free Survival The analysis of PFS included patients who received any dose of study treatment. PFS is defined as the time from the first day of study treatment to documented disease progression or death (whichever occurs first). For patients with no documented PD or death before the end of the study, or who fail to follow up, PFS will be censored on the day of the last tumor assessment. Patients with no post-baseline tumor assessment will have PFS censored on Day 1 of study treatment.

Overall Survival The analysis of OS includes patients who received any amount of study treatment. OS is defined as the time from the first dose of any study treatment to death from any cause during the study. For patients who do not die before the end of the study or are lost to follow-up, OS is censored on the last known alive date.

Safety Analysis Safety was measured by DLTs, adverse events, laboratory changes, vital signs and ECG changes, and any study treatments (tiragolumab, atezolizumab, bevacizumab, pembrolizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine, etoposide). ) through a summary of exposure to All patients who receive any dose of study treatment will be included in the safety analysis.

Map verbal descriptions of adverse events to synonyms. Adverse event data are listed by study site, dose cohort or tumor type as appropriate, patient number and study date. Events occurring during or after treatment on Day 1 will be summarized by mapped terms, appropriate synonym level, and NCI CTCAE v 4.0 grade. In addition, separate listing and summarization of serious adverse events, including death.

Adverse events leading to treatment discontinuation will be listed. Patients who withdraw from the study for reasons other than DLT before completing the DLT assessment window will be considered non-evaluable for DLT and MTD assessment.

Relevant laboratory, vital signs, and ECG data are displayed in chronological order specifying NCI CTCAE Grade 3 and Grade 4 values as appropriate. Incidence of ADA response (presence of serum anti-tiragolumab or anti-atezolizumab) and potential correlation with PK, pharmacodynamics, and safety parameters can be assessed.

Pharmacokinetic Analysis For the Phase Ia study, individual and mean serum tiragolumab concentration versus time data will be aggregated and plotted by dose level. The pharmacokinetics of tiragolumab are summarized by estimating total AUC, C _max , C _min , total CL, V _ss , and terminal half-life (if appropriate for collected data). Estimates of these parameters are tabulated and summarized (mean, standard deviation, and coefficient of variation). Patient-to-patient variability and drug accumulation are assessed.

In Phase Ib studies, serum tiragolumab and atezolizumab concentration data (C _max and C _min ) will be aggregated and summarized by dose level for each cycle collected. Descriptive statistics include mean, median, standard deviation, and range as appropriate. Other PK parameters can be determined and summarized as data validity. These results provide preliminary information as to whether tiragolumab or atezolizumab PK is altered by co-administration of other agents, so the data can be compared with historical data.

In the Phase Ib chemotherapy expansion cohort, serum concentrations of tiragolumab and atezolizumab and plasma concentrations of carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide will be collected. Concentrations of tiragolumab, atezolizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide are summarized using descriptive statistics as described above. These results provide preliminary information as to whether tiragolumab, atezolizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide PK are altered by co-administration of other agents, and the data are compared with historical data.

Pharmacodynamic analysis includes evaluation of pharmacodynamic biomarkers in both tumor tissue and blood, when available. Additional PK and pharmacodynamic analyzes are performed as appropriate. Potential adjustments to biomarker sampling times may be applied as needed based on biomarker responses observed in previous patients.

Immunogenicity Analysis Patients are considered to have a treatment-induced ADA response if they are ADA negative at baseline and subsequently develop an ADA response after administration of study drug. If the patient is ADA-positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater than the titer of the baseline sample (i.e., ≧0.60 titer units), the patient is eligible for treatment. is thought to have an enhanced ADA response by Patients are considered negative for ADA if they are ADA negative at all time points. Patients are considered unaffected by treatment if they are ADA positive at baseline but do not have a post-baseline sample with a titer that is at least 4-fold greater than the baseline sample titer.

The ADA results for tiragolumab and atezolizumab are summarized and listed by patient and cycle for the Phase Ia and Ib portions of the study.

Interim Analysis in the Phase Ia and Phase Ib Expansion Cohorts An interim analysis will be conducted by the IMC on each of the Phase Ia and Phase Ib expansion cohorts to guide possible early termination of enrollment in the absence of evidence of activity. After approximately 20 patients enrolled in the expansion cohort have completed 1-2 tumor assessments, the IMC will convene for an interim analysis. Interim analysis of objective tumor response with tiragolumab (Phase Ia) or tiragolumab in combination with atezolizumab, or tiragolumab in combination with atezolizumab and bevacizumab, or tiragolumab in combination with pembrolizumab (Phase Ib), with or without chemotherapy suggests that the activity indicated by is below the threshold of interest for that patient group (e.g., no response is observed in the first 20 patients), the IMC will consider enrollment in the expansion cohort. Discontinuation may be recommended.

For example, if the true ORR is 5%, there is approximately a 35% chance that no response will be observed in the first 20 patients, and if the true ORR is 10%, there will be no response in the first 20 patients. There is about a 12% chance of not being observed.

IMC may also be used if there is evidence of activity or if not enough specific patients are enrolled to allow adequate evaluation (e.g., specific tumor types, specific tumor PD-L1 and/or TIGIT expression status, and/or a specific history of CIT), it may be recommended to continue enrollment in the expansion cohort.

In all cases, the decision to discontinue enrollment in the expansion cohort on the basis of futility will be made in consultation with the study investigator and according to IMC recommendations by the medical monitor. The medical monitor may also request an additional ad hoc meeting of the IMC to review ongoing data in each of the Phase Ia or Phase Ib expansion cohorts.

W. Overview of Tiragolumab Clinical Trials Preliminary clinical data are available from this ongoing trial (GO30103) evaluating tiragolumab in patients with locally advanced or metastatic tumors. As of the clinical cut-off date of December 2, 2019, the GO 30103 study had 190 patients enrolled, with 42 patients enrolled in the Phase Ia portion and 171 patients in the Phase Ib portion. Partially enrolled, 23 patients crossed over from Phase Ia after disease progression.

An ongoing phase II trial (GO40290, also called CITYSCAPE) is investigating locally advanced unresectable or metastatic PD-L1, except in patients with sensitizing epidermal growth factor receptor (EGFR) mutations or ALK translocations. - Evaluating the efficacy and safety of tiragolumab and atezolizumab compared to placebo plus atezolizumab in chemotherapy-naive patients with elective NSCLC.

Clinical Pharmacokinetics and Immunogenicity As of the data cut-off date of December 2, 2019, available data (tiragolumab 2-1200 mg every 3 weeks for Phase Ia portion of study GO 30103 and Preliminary PK analysis was performed using standard non-compartmental PK methodology (based on 2-1200 mg tiragolumab given every 3 weeks in combination with 1200 mg atezolizumab given every 3 weeks for the Phase Ib portion). . The pharmacokinetics of tiragolumab in combination with atezolizumab appeared to be consistent with that of tiragolumab administered as a single agent. Preliminary population-PK analysis showed that tiragolumab exposure was nearly dose-proportional following IV administration at doses ranging from 100 mg to 1200 mg every 3 weeks as monotherapy or in combination with 1200 mg atezolizumab every 3 weeks. increased. A preliminary population PK analysis estimated a tiragolumab clearance of 0.28 L/day with a linear drug elimination half-life of approximately 15 days. In the Phase Ib portion of study GO 30103, development of anti-drug antibodies (ADA) to tiragolumab was observed in 3 of 154 evaluable patients (1.9%). Preliminary data suggest that tiragolumab ADA had no apparent effect on PK. However, the small number of positive ADA patients was not sufficient to assess the impact of ADA on the pharmacokinetics of tiragolumab.

Clinical Safety As of the data cut-off date of December 2, 2019, safety data were available for 42 patients in the Phase Ia portion of study GO 30103. Commonly reported adverse events in Phase Ia (reported in ≥10% of all patients) included fatigue, constipation, vomiting, anorexia, anemia, cough, Included were dyspnea, headache, infusion-related reactions (IRR), malignant neoplasm progression, nausea and pruritus. Commonly reported adverse events associated with tiragolumab (reported in >10% of patients) included fatigue and IRR.

Grade ≥3 adverse events (based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0]), regardless of study drug attribution, in 16 patients in the phase Ia portion of study GO30103 patients (38.1%), and 3 patients (7.1%) experienced treatment-related Grade ≥3 adverse events. Grade ≧3 adverse events considered by the investigator to be related to tiragolumab included increased amylase, increased blood creatinine, liver failure (described below), IRR and rash.

As of the data cut-off date of December 2, 2019, 171 patients were enrolled in the Phase Ib portion of study GO30103, including 23 patients who crossed out from Phase Ia after disease progression. Of the 171 patients treated in Phase Ib, 163 patients (95.9%) experienced at least one adverse event, including 110 patients who experienced at least one treatment-related adverse event. Patients (64.7%) are included. Regardless of relationship to tiragolumab, commonly reported adverse events in phase Ib (reported in ≥10% of all patients) included pruritus, fever, anemia, rash, malignant neoplastic progression, constipation, appetite Included were malaise, diarrhea, cough, asthenia, vomiting and fatigue. Commonly reported adverse events associated with tiragolumab and/or atezolizumab (reported in >10% of patients) included pruritus and rash.

Grade ≥3 adverse events (according to NCI CTCAE v4.0) were reported in 91 patients (53.5%) and 21 patients in the phase Ib portion of the GO30103 study, regardless of study drug attribution (12.4%) experienced treatment-related grade ≧3 adverse events. Grade ≥3 adverse events considered by the investigator to be related to tiragolumab and/or atezolizumab included decreased lymphocyte count, increased lipase, lymphopenia, increased amylase, adrenal insufficiency, asthenia, Included were cardiac tamponade, headache, hyperglycemia, hyperlipidemia, hypertransaminasemia, pneumonitis, pruritic rash, rhabdomyolysis, diabetes, diabetic ketoacidosis, and lipase.

Fatal cases of hepatotoxicity leading to fatal liver failure occurred in patients enrolled in the Phase Ia monotherapy expansion cohort of the GO30103 trial. At screening, the patient's transaminases were within normal limits. AST and ALT were elevated to Grade 1 in C1D1 prior to dosing. During tiragolumab administration to C1D1, the patient developed an infusion reaction that responded to dose interruptions and standard treatment, and the patient received the intended 1200 mg dose of tiragolumab of approximately 733 mg. On Study Day 8, ALT/AST had risen to Grade 3, associated with Grade 3 rash, and the patient was treated with 60 mg prednisone daily. By study day 12, rash had improved but AST and ALT were grade 4 (normal bilirubin and PT - international normalized ratio (INR)) and a second immunosuppressant (azathioprine) was added. . The patient progressively worsened despite the use of two immunosuppressants, developed frank liver failure and progressive hepatic encephalopathy with elevated bilirubin, and finally died on study day 30. Multiple alternative etiologies of hepatitis were excluded, including viruses (HBV, HCV), concomitant medications, or anatomic abnormalities. A liver biopsy performed on study day 16 showed confluent submassive necrosis with minimal inflammatory infiltrates interpreted as toxic hepatitis.

After this event, analysis of safety data showed no significant changes to adverse event findings, and no new significant adverse events were noted for subjects dosed in the Phase Ia and Ib portions of study GO30103. I didn't.

As of the data cut-off date of June 30, 2019, the phase II blinded study GO 40290 enrolled 135 safety-evaluable patients with tiragolumab (600 mg every 3 weeks) in combination with atezolizumab or atezolizumab either placebo in combination with The safety profiles of tiragolumab and atezolizumab included all grade adverse events (98.5% vs. 95.6%), grade ≥3 AEs (41.8% vs. 44.1%), serious AEs (34.3% vs. 35.3%) and AEs leading to treatment discontinuation (7.5% vs. 10.3%) were similar to the safety profiles of placebo and atezolizumab. Adverse events of particular interest were reported in 47.8% of patients in the tiragolumab and atezolizumab groups and 32.4% of patients in the placebo plus atezolizumab group. The December 2019 update data showed a similar safety profile.

A potentially fatal case of EBV reactivation and secondary hemophagocytic lymphohistiocytosis (HLH) occurred in a Taiwanese patient with metastatic lymphoepithelioma-like carcinoma subtype (PD-L1 positive) of NSCLC. It was reported in a 69-year-old man, which may be related to EBV infection in Asian patients. At screening, the patient had a positive serum Epstein-Barr nuclear antigen (EBNA) antibody test, but had no clinical signs of active EBV infection as confirmed by the treatment investigator. On Day 1 of Cycle 1, the patient received both study drug, atezolizumab and tiragolumab, and tolerated the treatment well. On day 10, the patient developed a fever believed to be due to an upper respiratory tract infection, which was treated with antibiotics. On Day 1 of Cycle 2, the patient received atezolizumab and developed grade 2 fever 20 minutes after infusion. Tiragolumab was not administered in Cycle 2 because the fever was presumed to be atezolizumab IRR. The patient was hospitalized for fever, but workup for infectious causes was negative. Once the fever resolved, the patient was discharged on Day 8 of Cycle 2. On day 15 of cycle 2, the patient was readmitted for intermittent fever, shock with hypotension, metabolic acidosis, acute kidney injury, pancytopenia, coagulopathy, hemorrhage, altered mental status, He developed transaminitis, hyperbilirubinemia, and respiratory failure and was transferred to the intensive care unit. The patient had a high EBV titer in blood and a bone marrow biopsy consistent with HLH. Cultures for other infectious etiologies were negative. Despite treatment with steroids and multiple immunosuppressants (tocilizumab, hydroxychloroquine and etanercept), the patient deteriorated and died on Day 31 of Cycle 2. In total, patients received 1 dose of tiragolumab (cycle 1) and 2 doses of atezolizumab (cycles 1 and 2). At the time of this amendment, the exact cause of the event is unknown and investigations are ongoing, but the information available indicates that this patient has a rare histologic subtype of NSCLC and chronic active EBV infection. was suspected, suggesting that it was reactivated by administration of tiragolumab and atezolizumab. Given the temporal relationship between study drug exposure and the patient's clinical course, it is likely that the patient developed secondary HLH. Because of this index case of EBV reactivation in a patient with pulmonary lymphoepitheliomatous carcinoma, safety data have been carefully reviewed and no phase II study (GO40290) or current phase I study (GO30103) showed that the virus No other cases of reactivation have been observed.

As of the data cutoff date of December 2, 2019, 42 patients are being treated with tiragolumab alone. Patients receiving single-agent tiragolumab have experienced IRR. In Phase Ia, 5 patients (12%) experienced IRR. Signs and symptoms associated with IRR were generally mild and included fever, chills, flushing, hypertension, lymphadenopathy, nausea, myalgia and skin lesions. All cases of IRR were successfully treated with supportive treatment. IRR moved from potential to identified risk due to IRR occurring during and after infusion of single-agent tiragolumab in 12% of patients. Although tiragolumab has no further identified risks, involvement of the TIGIT co-inhibition pathway may increase the risk of autoimmune inflammation when tiragolumab is administered as a single agent. Therefore, tiragolumab as a single agent may cause adverse events similar to atezolizumab. Such immune-mediated adverse events have been well characterized for other immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-L1/PD-1.

This is the first clinical evaluation of tiragolumab in combination with an anti-PD-L1/PD-1 agent. Although clinical evaluation of tiragolumab in combination with atezolizumab is limited and not all risks are known, as of December 2, 2019, over 200 patients have been treated with tiragolumab in combination with atezolizumab. there is Although there are currently no identified risks specific to tiragolumab administered in combination with atezolizumab, involvement of the TIGIT co-inhibition pathway has been implicated in several risks, including HLH and MAS, when tiragolumab is administered in combination with atezolizumab. may increase the risk of some immune reactions. Thus, when administered with atezolizumab, tiragolumab may exacerbate atezolizumab-related adverse events or have toxicities that do not overlap with atezolizumab.

The greatest clinical experience to date with combinations of complementary regulators of adaptive immunity comes from trials of ipilimumab in combination with nivolumab. Another anti-TIGIT antibody MK-7684 (vivostolimab) showed an acceptable safety profile and promising anti-tumor activity in patients with advanced tumors when combined with pembrolizumab. Based on these data, the frequency and severity of immune-mediated adverse events may be increased with combination when compared to either single agent inhibitor, although combined immune-mediated adverse events are is expected to be easier to monitor and manage.

Clinical Efficacy As of the data cut-off date of December 2, 2019, no objective responses have been reported for patients enrolled in the Phase Ia portion of the GO30103 study, with the best response being There was stable disease (SD) in 8 of 42 patients at tumor assessment. Complete response (CR) in 4 of 171 patients in cancer immunotherapy (CIT)-naïve patients with multiple tumor types including NSCLC, HNSCC and triple-negative breast cancer in the Phase Ib portion of the study and objective responses including partial responses (PR) in 23 of 171 patients were observed.

As of the data cut-off date of June 30, 2019, data from the blinded, randomized phase II study GO 40290 showed that the combination of tiragolumab and atezolizumab compared to placebo and atezolizumab in the ITT population had an ORR and improved PFS. ORR for tiragolumab and atezolizumab was 31.3% (95% CI: 6.7-25.7) compared to 16.2% for placebo and atezolizumab (95% CI: 19.5-43.2) Met. Investigator-assessed PFS for tiragolumab and atezolizumab was 5.4 months (95% CI: 4.2, not reached) compared to 3.6 months (95% CI : 2.7-4.4) and the HR was 0.57 (95% CI: 0.37-0.90).

Phase Ib with Tiragolumab and Atezolizumab with Chemotherapy In multiple large randomized phase III trials in advanced solid tumors, the addition of anti-PD-L1/PD-1 to standard chemotherapy compared with chemotherapy alone improved the patient's OS and PFS. In these studies, pemetrexed and platinum-based chemotherapy in non-squamous NSCLC (Gandhi et al. N Engl J Med 2018;378:2078-92) and to pemetrexed and platinum-based chemotherapy in squamous NSCLC (Paz-Ares et al. N Engl J Med 2018;379:2040-51) tested the addition of anti-PD-1 to carboplatin and paclitaxel or nab-paclitaxel. These studies also investigated carboplatin and etoposide in extensive-stage SCLC (Horn et al. N Engl J Med 2018;379:2220-9) and to nab-paclitaxel in TNBC (Schmid et al. N Engl J Med 2018;379: 2108-21) was investigated with anti-PD-L1. 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 nonclinical data suggest that concurrent anti-TIGIT and anti-PD-L1/PD-1 enhance anti-tumor immune responses more than single-agent anti-PD-L1/PD-1 alone, chemotherapy It is hypothesized that the addition of anti-TIGIT to anti-PD-L1/PD-1 in combination with anti-PD-L1/PD-1 may be more effective than the addition of anti-PD-L1/PD-1 to chemotherapy.

The safety profile resulting from combining anti-PD-L1/PD-1 with chemotherapy is generally consistent with the known toxic effects of each agent observed in multiple clinical trials in advanced solid tumors (Gandhi et al. Horn et al.N Engl J Med 2018;379:2220-9;Paz-Ares et al.N Engl J Med 2018;379:2040-51;Schmid et al.N Engl J Med 2018;379:2108-21). Given the similarities in the mechanism of action between tiragolumab and atezolizumab, the safety profile of tiragolumab administered in combination with atezolizumab and chemotherapy is associated with combined anti-TIGIT and anti-PD-L1 immune-related toxicity and individual It is expected that this may be consistent with the toxicity of chemotherapeutic agents. Therefore, the design and safety management plan for the Phase Ib chemotherapy expansion cohort will require extensive clinical experience with chemotherapy and anti-TIGIT in combination with anti-PD-L1 to reduce potential risks to participating patients. Incorporate the considerations noted.

Phase Ib with Tiragolumab and Atezolizumab with Bevacizumab Strong Evidence and Emerging Clinical Data Suggest that Combined Inhibition of PD-L1, VEGF and TIGIT May Be Clinically Beneficial in Several Tumor Types are doing.

In chemotherapy-naive patients with stage IV NSCLC, results from the GO29436 trial (IMpower150) show that atezolizumab plus bevacizumab and chemotherapy lead to significantly longer OS compared to bevacizumab and chemotherapy alone (Socinski et al.N Engl J Med 2018;378:2288-301). For patients with inoperable, locally advanced, or metastatic RCC, results from study WO29637 (IMmotion 151) show that the combination of atezolizumab and bevacizumab compared to sunitinib in a treatment-naive patient population demonstrated improved PFS after treatment (Motzer et al. J Clin Oncol 2018;36(6_suppl):578, Rini et al. Lancet 2019;393:2404-15). The phase Ib GO30140 trial in frontline HCC found an ORR of 65% in 23 evaluable patients across etiology, geography, baseline alpha-fetoprotein levels, and extrahepatic spread (Stein et al. J Clin Oncol 2018;36(Suppl 15):4074, Lee et al. Lancet Oncol.2020 Jun;21(6):808-820). Based on these results, this treatment was granted breakthrough therapy designation, and results were confirmed in a randomized phase III trial, the YO40245 (IMbrave150) trial. The YO40245 trial (IMbrave 150) was designed to evaluate the efficacy and safety of atezolizumab and bevacizumab versus sorafenib in patients with advanced or metastatic HCC who had not received prior systemic treatment. The trial enrolled 501 patients randomized in a 2:1 ratio. Recent study results demonstrated statistically significant and clinically significant improvements in PFS and OS. The risk of death was reduced by 42% in the atezolizumab + bevacizumab group compared to the sorafenib group (stratified HR = 0.58 (95% CI: 0.42-0.79); median OS, NE vs. 13.24 months). Independent revisability assessment PFS by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 demonstrated an improvement in favor of combination treatment (stratified HR = 0.59 (95% CI: 0.47 to 0.76); median PFS, 6.83 vs. 4.27 months) (Cheng et al. Ann Oncol 2019;30:ix186-ix187, Finn et al. N Engl J Med 2020;382:1894-1905 ).

These are examples of potential synergistic effects between atezolizumab and bevacizumab in different tumor types, which support further exploration of the combination with tiragolumab.

Example 5. Pharmacokinetics, pharmacodynamics, safety and efficacy in a Phase Ia/Ib dose escalation study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab as a single agent in patients with advanced solid tumors. Patient Characteristics Patient baseline characteristics for the Phase Ia and Phase Ib portions of the study are shown in Table 37. Both Phase Ia and Phase Ib patients comprised a heavily pretreated population, with 42% of Phase Ia patients and 37% of Phase Ib patients having 4 or more previous cancer treatments have Phase Ia and Phase Ib patients share similar baseline characteristics.

Most patients in the Phase Ia and Phase Ib portions of the trial discontinued treatment due to disease progression (42% in Phase Ia and 76% in Phase Ib). None of the Phase Ib crossover patients showed a response. Patient status is shown in Table 38.

B. Pharmacokinetics and Pharmacodynamics of Tiragolumab The pharmacokinetics of tiragolumab as a single agent (Phase Ia) and in combination with atezolizumab (Phase Ib) were determined. Tiragolumab exposure increased with dose as a single agent and in combination with atezolizumab (Figure 9). Tiragolumab pharmacokinetics are unchanged in combination with atezolizumab

The pharmacodynamics of tiragolumab (Phase Ia) as a single agent were determined (Figure 10). Peripheral TIGIT receptor occupancy on CD8 ⁺ T cells and on NK cells was measured at doses of 2 mg, 8 mg, 30 mg, 100 mg, 400 mg, 600 mg and 1200 mg every 3 weeks. Complete and sustained occupancy of peripheral TIGIT receptors after day 2 (C1D2) was observed at tiragolumab doses of 30 mg and above.

C. safety

A summary of adverse events is shown in Table 39. The overall rate of Grade 3-5 adverse events was low for the Phase Ia and Phase Ib portions, neither had a Grade 5 adverse event. No dose-limiting toxicity was observed for tiragolumab alone or in combination with atezolizumab. All adverse events present in ≥10% of Phase Ia and Phase Ib patients are shown in Figures 11 and 12, respectively. All immune-mediated adverse events are shown in Table 40. Tiragolumab was well tolerated as a single agent in combination with atezolizumab.

D. Efficacy A preliminary efficacy analysis was performed for the Phase Ia and Phase Ib dose escalation studies. In the Phase Ia portion, a decrease in tumor size was observed in neuroendocrine, ovarian and rectal cancers (Figure 13). Although there were no objective responses in the Phase Ia portion of the trial, most patients either had tumor types that typically do not respond to cancer immunotherapy (CIT) or had tumors with low PD-L1 expression. or had been heavily pretreated. Objective responses were seen in the phase Ib portion of the trial in NSCLC, TNBC, HNSCC and esophageal cancer types (Figure 14).

The size of PD-L1-positive NSCLC tumors, including CIT-naive tumors, was greatly reduced in patients treated with tiragolumab in combination with atezolizumab (FIG. 14). CIT-naïve PD-L1-positive NSCLC treated with tiragolumab in combination with atezolizumab had an overall response rate of 46%, including two complete responses and some responses that were durable (Fig. 15 and Figure 16).

Example 6: Atezolizumab in combination with tiagorumab and bevacizumab for advanced liver cancer Liver cancer is the fifth most common cancer and the second most common cause of cancer-related deaths worldwide, with 854,500 per year. 000 new cases and 810,000 deaths. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for about 90% of all primary liver malignancies. Less common primary liver cancers include intrahepatic cholangiocarcinoma (iCCA), angiosarcoma and hepatoblastoma.

The YO40245 trial (IMbrave150) is an ongoing randomized Phase III trial evaluating atezolizumab plus bevacizumab versus sorafenib as first-line treatment in patients with advanced or metastatic HCC. This trial is the first to demonstrate a statistically significant and clinically significant improvement in OS and progression-free survival (PFS) for a novel treatment combination in head-to-head comparisons with sorafenib. At the time of the primary analysis, the risk of death was reduced by 42% in the atezolizumab + bevacizumab group compared to the sorafenib group (stratified hazard ratio [HR] = 0.58 [95% CI: 0.42-0.79]; p=0.0006; median OS, not estimable [NE] vs. 13.24 months). Independent-review trial site-assessed PFS by RECIST v 1.1 also demonstrated a statistically significant and clinically significant improvement in favor of combination treatment (stratified HR = 0.59 [95% CI: 0.47-0.76]; p<0.0001; median PFS, 6.83 vs. 4.27 months). Overall, the combination of atezolizumab plus bevacizumab in HCC was generally well tolerated with manageable toxicity, and the safety profile was consistent with the known risks and underlying disease of the individual study treatments (Cheng et al. IMbrave150: Ｅｆｆｉｃａｃｙ ａｎｄ Ｓａｆｅｔｙ Ｒｅｓｕｌｔｓ Ｆｒｏｍ ａ Ｐｈ ３ Ｓｔｕｄｙ Ｅｖａｌｕａｔｉｎｇ Ａｔｅｚｏｌｉｚｕｍａｂ（ａｔｅｚｏ）＋Ｂｅｖａｃｉｚｕｍａｂ（ｂｅｖ）ｖｓ Ｓｏｒａｆｅｎｉｂ（Ｓｏｒ）ａｓ Ｆｉｒｓｔ Ｔｒｅａｔｍｅｎｔ（ｔｘ）ｆｏｒ Ｐａｔｉｅｎｔｓ（ｐｔｓ）Ｗｉｔｈ Ｕｎｒｅｓｅｃｔａｂｌｅ Ｈｅｐａｔｏｃｅｌｌｕｌａｒ Ｃａｒｃｉｎｏｍａ（ＨＣＣ）．Ｐｒｏｃｅｅｄｉｎｇｓ ｏｆ ＥＳＭＯ Ａｓｉａ ２０１９：２２－ 24 November 2019 [cited: 27 November 2019]; Singapore.

This is a Phase Ib/II, open-label, multicenter, randomized, comprehensive study in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for their disease.

Patients are randomized to a control group (atezolizumab + bevacizumab [Atezo + Bev]) or a treatment group consisting of atezolizumab and bevacizumab in combination with tiragolumab (Atezo + Bev + Tira).

Control group (Atezo + Bev)

Patients in the atezolizumab + bevacizumab (Atezo + Bev) group receive the treatments outlined in the table below.

Patients in the atezolizumab + bevacizumab + tiragolumab (Atezo + Bev + Tira) group will receive the treatments outlined in the table below.

B. Inclusion Criteria Patients must meet all of the following criteria:
● Age ≥ 18 years old.
• ECOG performance status of 0 or 1 within 7 days prior to procedure.
- Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/cytology or clinically by AASLD criteria in patients with cirrhosis
Patients with cirrhosis without histologic confirmation of diagnosis require clinical confirmation according to AASLD criteria.
- Child-Pug Class A within 7 days prior to randomization
• Disease not amenable to curative surgery and/or locoregional therapy Patients with progressive disease after surgical and/or locoregional therapy are eligible.
No prior systemic treatment (including systemic investigational drugs) for HCC Prior treatment with herbal remedies containing traditional herbal medicines with labeled anticancer activity, discontinuing these agents prior to randomization permissible provided that
● Life expectancy ≧3 months.

The efficacy and safety objectives and endpoints are described in the table below. Patients treated with the triple combination of Atezo + Bev + Tira herein had acceptable toxicity compared to placebo , OS, DOR and/or disease control).

Example 7. Phase III, randomized, double-blind, placebo-controlled study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with previously untreated extensive-stage small cell lung cancer, as measured by OS, PFS, ORR and DOR in this example A randomized trial designed to assess whether the antitumor effects of atezolizumab plus chemotherapy could be improved by the addition of the anti-TIGIT antibody tiragolumab to atezolizumab and chemotherapy in patients with ES-SCLC. A Phase III global, multicenter, double-blind, placebo-controlled study is described. To compare the safety and efficacy of tiragolumab in combination with atezolizumab and CE to treatment with placebo in combination with atezolizumab and CE in patients with ES-SCLC who are chemotherapy-naïve for their extensive-stage disease.

A. Study Design To evaluate the safety and efficacy of tiragolumab in combination with atezolizumab and CE compared to treatment with placebo in combination with atezolizumab and CE in patients with ES-SCLC who are chemotherapy naive for their extensive-stage disease. Details of a randomized Phase III, multicenter, double-blind, placebo-controlled study to Figure 17 shows the study plan.

Eligible patients were evaluated according to US East Coast Clinical Trials Group (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 randomized in a 1:1 ratio to receive one of the following treatment regimens as shown in Table 46. Further details regarding ECOG performance states can be found in Oken et al. , Am. J. Clin Oncol. 1982, 5:649-655.

A total of approximately 470 patients will be randomized in this study. The primary population (PP) includes approximately 400 patients, assuming a baseline prevalence of brain metastases or history of 15%. The intent to treat (ITT) population includes all patients.

Induction treatment was administered in 21-day cycles for 4 cycles. After the induction phase, patients continue maintenance therapy with either atezolizumab plus tiragolumab (Arm A) or atezolizumab plus placebo (Arm B). During the maintenance phase, prophylactic cranial irradiation (PCI) was permitted per local standard of care and reported on the electronic prophylactic cranial irradiation case report form (eCRF). Palliative radiation for symptomatic treatment is acceptable. The dosing and dosing schedules for the treatment regimens of Table 46 are provided in Table 47 below.

On Day 1 of each cycle, all eligible patients will receive study drug infusions in the following order:
Group A: atezolizumab, tiragolumab, carboplatin and etoposide Group B: atezolizumab, placebo, carboplatin and etoposide

Patients can receive carboplatin and etoposide antiemetics and IV hydration according to the local standard of care and manufacturer's instructions. Premedication with corticosteroids is minimized to the extent clinically feasible. All medications will be recorded on the appropriate Concomitant Medications eCRF.

During the run-in phase, study treatment must be administered on Day 1 in the following manner:
1. Atezolizumab 1200 mg intravenously over 60 (±15) minutes (for the first infusion, shortened to 30 [±10] minutes for subsequent infusions) (see Table 48) followed by
2. Tiragolumab/placebo 600 mg intravenously over 60 (±15) minutes (for the first infusion and shortened to 30 [±10] minutes for subsequent infusions) (see Table 48) followed by
3. Carboplatin was administered intravenously over 30-60 minutes to achieve an initial target area with a concentration-time curve (AUC) of 5 mg/mL/minute (Calvert dosing);
4. Followed by etoposide (100 mg/m ² ) administered intravenously over 60 minutes. Etoposide (100 mg/m ² ) is also administered intravenously over 60 minutes on days 2 and 3 during the lead-in phase.

Cycles without chemotherapy are not counted in the total number of induction chemotherapy cycles. After the run-in phase, patients will begin maintenance therapy with atezolizumab plus tiragolumab/placebo. Suggested infusion times for carboplatin and etoposide are adapted according to local standard of care. Administration of atezolizumab and tiragolumab/placebo will be conducted in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Radiological data, biopsy results (if available), and Treatment is continued unless there is unacceptable toxicity or symptomatic exacerbation due to disease progression after integrated assessment of clinical status. Patients meeting criteria for disease progression by RECIST v1.1 will be allowed to continue study treatment (tiragolumab + atezolizumab or placebo + atezolizumab) if all inclusion criteria are met.

Atezolizumab Patients receive 1200 mg atezolizumab administered by IV infusion on Day 1 of each 21-day cycle. Atezolizumab dose is fixed and independent of body weight. Atezolizumab infusions will be administered according to the instructions outlined in Table 48. Atezolizumab dose will not be changed. Further details of dose preparation, storage and dosing instructions for atezolizumab can be found in the Investigational Product Management Protocol and/or the Atezolizumab Investigator's Brochure.

Tiragolumab/Placebo After administration of atezolizumab and an observation period (see Table 48), patients receive 600 mg tiragolumab/placebo administered by IV infusion on Day 1 of each 21-day cycle. The tiragolumab/placebo dose is fixed and independent of body weight. Tiragolumab/placebo infusions will be administered according to the instructions outlined in Table 48. The tiragolumab/placebo dose will not be changed. Further details of tiragolumab/placebo dose preparation, storage, and dosing instructions can be found in the Investigational Drug Administration Procedures and/or Investigator's brochure.

Carboplatin During the run-in phase, carboplatin is administered by IV infusion over 30-60 minutes to achieve an initial target AUC of 5 mg/mL/min (Calvert regimen) with standard antiemetics according to local clinical practice guidelines. Administered after completion of tiragolumab/placebo. Premedication with corticosteroids can be minimized to the extent clinically feasible. Carboplatin infusion times are adapted according to local standard of care.

The AUC 5 carboplatin dose is calculated using the Calvert formula (Calvert et al., J. Clin. Oncol. 1989, 7:1748-56):
Calvert formula:
Total Dose (mg) = (Target AUC) X (Glomerular Filtration Rate [GFR] + 25)
Note: The GFR used in the Calvert formula to calculate AUC-based dose should not exceed 125 mL/min.

As used herein, GFR is considered equivalent to creatinine clearance (CRCL). CRCL is calculated by institutional guidelines or by the method of Cockcroft and Gault, Nephron 1976, 16:31-41, using the following formula:
CRCL = (140-age) X (weight)
(For women, X0.85)
72X Scr
Where: CRCL = creatinine clearance in mL/min Age = patient age in years Weight = patient weight in kg Scr = serum creatinine in mg/dL Note: For patients with abnormally low serum creatinine levels , use a minimum creatinine level of 0.8 mg/dL to estimate GFR, or cap the estimated GFR at 125 mL/min.

If a patient's GFR is estimated based on serum creatinine measurements by isotope dilution mass spectrometry, the physician should titrate the dose of carboplatin for the desired exposure (AUC) to avoid potential toxicity from overdose. Consider capping. Based on the Calvert formula on the carboplatin label, the maximum dose can be calculated as follows:
Maximum Carboplatin Dose (mg) = Target AUC (mgX min/mL) X (GFR + 25 mL/min)

Maximum dose is based on GFR estimates capped at 125 mL/min for patients with normal renal function. Higher estimated GFR values should not be used.

For target AUC=5, the maximum dose is 5×(125+25)=5×150=750 mg.

For target AUC=4, the maximum dose is 4×(125+25)=4×150=600 mg.

Etoposide During the induction phase, on Day 1 of each cycle, etoposide (100 mg/m ² ) is administered by IV infusion over 60 minutes after carboplatin administration. Etoposide (100 mg/m ² ) is administered by IV infusion over 60 minutes on days 2 and 3 of each cycle. Premedication is administered according to local standard of care. Premedication with corticosteroids can be minimized to the extent clinically feasible. Etoposide infusion time can be adapted according to local standard of care.

Rationale for Evaluating Patients Without Brain Metastases at Baseline (Primary Population for Statistical Analysis)
The brain is a common site of metastasis in ES-SCLC patients, with some studies showing as high as 18% of patients with brain metastases at diagnosis and up to 80% during the first 2 years after diagnosis. are expected to have brain disease involvement (Seute et al., Cancer, 100:801-806, 2004; Pacheco and Bunn, Clin Lung Cancer, 20:148-160, 2019). In general, benefit from a combination of immunotherapy and chemotherapy has been shown in ES-SCLC patients. However, as seen in the IMpower 133 trial, the hazard ratio (HR) for this patient subgroup was 1.07, compared to a HR of 0.68 for patients without brain metastases at baseline. This benefit may be attenuated in patients with brain metastases (Horn et al., New Engl J Med, 379:2220-2229, 2018).

KEYNOTE-604 is another Phase 3 study in which ES-SCLC patients with brain metastases at diagnosis improved overall survival to first-line immunotherapy plus chemotherapy compared to those without Benefits cannot be achieved or imply that they cannot be achieved. Indeed, patients with brain metastases had an OS HR of 1.32, whereas those without brain metastases had an OS HR of 0.75 (Rudin et al., J Clin Oncology, 38: 2369-2379, 2020). The CASPIAN trial originally reported an OS HR of 0.69 in patients with brain metastases, but an updated analysis yielded an HR of 0.79. The OS HR for patients without brain metastases in the original and updated reports was 0.74 and 0.76, respectively Paz-Ares et al. , N Engl J Med, 379:2040-2051, 2018; Paz-Ares et al. , Am Soc Clin Oncol 2020, abstract 9002, 2020).

It was important to understand the benefit of the trial regimen in both patient subgroups, therefore a trial statistical test hierarchy was performed to test PP first and then ITT.

B. Assessments Patients undergo tumor assessments at baseline and every 6 weeks (±7 days) for 48 weeks after Cycle 1, Day 1. Pretreatment tumor tissue (archived or freshly obtained) samples will be submitted within 4 weeks before or after randomization. This specimen is accompanied by an associated pathology report. Although any available tumor tissue sample can be submitted, a representative tumor specimen (preferably) in a paraffin block or 10 (or more) serial freshly cut unstained slides will be biopsied. For marker analysis (e.g., PD-L1 status, markers related to immunity or SCLC biology, e.g., T cell markers, or identified by NGS on extracted DNA, RNA or other biological molecules) non-genetic biomarkers). Exemplary sample types include formalin-fixed, paraffin-embedded, prepared from excision, core needle, excision, incision, punch, forceps biopsy, fine needle aspiration, and cell pellet specimens (e.g., from pleural effusion and lavage samples). FFPE) samples. Tumor tissue must be of good quality based on total tumor content and viable tumor content. Tumor tissue from bone metastases subject to decalcification is not recommended.

After completion of the Week 48 tumor assessment, tumor assessments will be performed every 9 weeks (±7 days) thereafter. Patients treated beyond disease progression by RECIST v1.1 will undergo tumor assessments until treatment is discontinued. Patients who discontinue treatment for reasons other than radiographic disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic worsening) are eligible for Cycle 1 regardless of whether the patient begins new anticancer therapy. , followed by scheduled tumor assessments for 48 weeks after Day 1, then every 9 weeks (±7 days), then every 6 weeks (±7 days).

Serum samples are collected to monitor the pharmacokinetics of tiragolumab and atezolizumab. Plasma samples are collected for chemotherapy pharmacokinetics in selected patients. Safety assessments will include the incidence, nature and severity of adverse events, protocol defined vital signs, and laboratory abnormalities.

A tumor biopsy is performed at radiological progression. Exemplary sample types include FFPE samples prepared from excision, core needle, dissection, incision, punch, forceps biopsy, fine needle aspiration, and cell pellet specimens (eg, from pleural fluid and lavage fluid samples). DNA and/or RNA extraction from tissue can be performed.

C. Patient Reported Outcomes Patent Reported Outcomes (PRO) data will be collected to document treatment efficacy and to more fully characterize the clinical profile of tiragolumab plus atezolizumab. PRO data are collected using the following instruments: EORTC QLQ-C30, single-item EORTC IL46, selected items from PRO-CTCAE, and EQ-5D-5L.

The EORTC QLQ-C30 measures five aspects of patient functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), general health/life and six single items (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial difficulties). et al., J. Natl. Cancer Inst. 1993, 85:365-76; Fitzsimmons et al., Eur. J. Cancer 1999, 35:939-41). Scale scores can be obtained for multiple-item scales.

The EORTC QLQ-C30 module takes approximately 15 minutes to complete. In addition, the single entry EORTC IL 46 is retrieved. This validated single-item question assesses overall side effect impact.

PRO-CTCAE had 78 patient-reportable symptomatic treatment toxicities (Basch et al., J. Natl Cancer Inst. 2014, 106:1-11; Dueck et al., JAMA Oncol. 2015, 1:1051-52). is a validated item bank used to characterize the presence, frequency, severity, and interference with daily functioning of The PROCTCAE contains 124 questions rated on either a 5-point Likert scale (frequency, severity and interference) or dichotomous (presence or absence). Treatment toxicity terms included can be subjective with or without observable components (eg, vomiting and nausea, respectively) or can be primarily observable with subjective components (eg, rash). The standard PRO-CTCAE recall period is "last 7 days". Three subsets of symptoms were selected for this study that were considered most applicable to current treatment.

The EQ-5D-5L are used to construct a composite patient well-being survey of general preferences including questions on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It is a health utility measure based on EQ-5D-5L takes about 2 minutes to complete. EQ-5D-5L will be utilized in this study for economic modeling.

The paper version of the PRO device is self-answered during the procedure visit, and the interviewer answers the patient by phone during the follow-up visit by on-site personnel, thus collecting data without requiring the patient to travel to the clinical site can do. PRO data are entered into the trial database by field personnel.

To ensure device efficacy and data specifications meet health authority requirements, questionnaires scheduled to be completed during clinic visits should be completed prior to receiving information on disease status, unless otherwise specified. , completed in its entirety by the patient, prior to administration of non-PRO assessments that may bias the patient's responses, and prior to administration of study treatment.

Completed questionnaires (EORTC QLQ-C30, EORTC IL46, PRO-CTCAE (optional), and EQ-5 D-5L) during the run-in phase on Cycle 1, Day 1 (Baseline) prior to administration of study drug. Each study treatment cycle is then completed prior to study drug administration (ie, Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1). During the Maintenance Phase, questions will be asked at every other study treatment cycle prior to administration of study drug (i.e., Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1, etc.) and at the Study Treatment Discontinuation Visit. complete the ballot. During survival follow-up, PROs are collected at the first survival follow-up at 3 months (±30 days) and at the second survival follow-up at 6 months (±30 days). Patients who discontinue study treatment for any reason other than radiological disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic worsening) will be assessed for radiological disease progression, death, loss of follow-up according to RECIST v1.1, EORTC QLQ-C30, PRO-CTCAE (optional) and EQ-5 D-5L will be completed at each tumor assessment visit until withdrawal of consent or termination of the study by the sponsor (whichever occurs first). Patients whose native language is not available on the questionnaire are exempt from completing all PRO assessments.

No adverse event reports were derived from PRO data.

D. Endpoints Investigator-assessed PFS (assessed by the inventors according to RECIST v 1.1) and OS in PP are co-primary endpoints of this study. Objective response rate in the PP and ITT population, duration of response in the PP and ITT population, and PFS and OS in the ITT population are secondary endpoints.

Progression-Free Survival PFS is measured between the date of randomization and the date of first documented disease progression (as assessed by the investigator according to RECIST v1.1) or the date of death, whichever occurs first. It's time for Patients who have never experienced disease progression or who do not die by the data cutoff date will be censored at the last tumor assessment. Patients with no post-baseline tumor assessment will be censored at the date of randomization.

PFS as an endpoint can reflect tumor growth, can be assessed prior to determination of survival benefit, and that determination is generally not confounded by subsequent treatment. Whether improvement in PFS represents a direct clinical benefit or a surrogate for clinical benefit depends on the efficacy and benefit-risk magnitude of the new treatment compared to available therapies (U S. Food and Drug Administration (2007) Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologies).

To ensure efficacy of investigator-assessed PFS as the primary endpoint, a number of measures have been performed: enabling a robust target size of benefit and benefit-risk assessment. Study assessment (conventional RECIST v1.1 criteria for defining radiographic disease progression at regular assessment intervals that are identical in both treatment arms, and robust definition of PFS, as well as PFS assessment including sensitivity analysis; predictively defined methods for quantification and analysis).

The primary analysis of the co-primary endpoint of PFS will be performed when approximately 300 PFS events (75% of 400 patients) were observed in PP. It provides 96% power to detect the target HR of 0.56 for PFS at a two-sided significance level of 0.001 based on: PFS curves follow an exponential distribution; median PFS is 5.2 months in the placebo + atezolizumab + EC group and 9.2 months in the tiragolumab + atezolizumab + EC group (equivalent to a target HR of 0.56); dropout rate is 5% for PFS over 12 months; and no interim analysis for PFS.

An observed HR of 0.68 or greater for PFS corresponds to a statistically significant difference between treatment groups. Thus, an HR of 0.68 is the minimum detectable difference for analysis. This corresponds to a median PFS improvement of 2.4 months, from 5.2 months in the placebo + atezolizumab + CE group to 7.6 months in the tiragolumab + atezolizumab + CE group.

The Kaplan-Meier method is used to estimate the median PFS for each treatment group and construct Kaplan-Meier curves to visually illustrate differences between treatment groups. A 95% CI for the median PFS for each treatment group is constructed using the Brookmeyer-Crowley methodology (Brookmeyer and Crowley, Biometrics 1982, 38:29-41).

PFS rates at 6 months and 1 year after randomization were estimated using the Kaplan-Meier method for each treatment group, with 95% CIs calculated using standard errors derived from the Greenwood equation. be done. The 95% CI for the difference in PFS rates between the two treatment groups is estimated using routine approximation.

Overall survival OS is the co-primary endpoint in this trial. OS is the time between the date of randomization and death from any cause. Improvement in OS is generally accepted as the best measure of clinical benefit for patients with advanced/unresectable or metastatic lung cancer.

PFS and OS are compared between treatment groups using a stratified log-rank test. HR for PFS and OS are estimated using a stratified Cox proportional hazards model. A 95% CI for HR is provided. Stratification factors were used for randomization from IxRS (ie, ECOG performance status and lactate dehydrogenase (LDH)). If there is a risk of over-stratification, the stratification factor(s) may be removed from the stratification analysis. Analysis based on stratification factors recorded on electronic case report forms (eCRFs) is also provided if substantial discrepancies between IxRS and eCRF records are observed. Results of non-stratified analyzes are also provided.

A final analysis of the co-primary endpoint of OS will be performed when approximately 288 deaths (72% of 400) were observed in PP. This provides 85% power to detect a target HR of 0.70 for OS at a two-sided significance level of 0.049 based on: OS curves follow an exponential distribution; median OS of 12.3 months for the placebo + atezolizumab + EC group and 17.6 months for the tiragolumab + atezolizumab + EC group (equivalent to a target HR of 0.70); dropout rate of 24 months for OS 5% over a period of time; and with tentative bounds of statistical significance determined based on the Lan-DeMets approximation of the O'Brien-Fleming function, one planned number of OS at about 70% of the information fraction. provisional analysis.

An observed HR of 0.789 or greater for OS in PP corresponds to a statistically significant difference between treatment groups. That is, an HR of 0.789 was the minimal detectable difference for analysis, corresponding to a median OS improvement of 3.3 months, from 12.3 months in the placebo + atezolizumab + CE group to tiragolumab + up to 15.6 months in the atezolizumab + CE arm.

The timing of the interim and final analysis of OS is summarized in Table 49 below, showing additional assumptions of development.

A preliminary OS analysis is performed during the final PFS analysis. The Kaplan-Meier method is used to estimate median OS for each treatment group, and Kaplan-Meier curves are constructed to visually illustrate differences between treatment groups. A 95% CI for median OS for each treatment group is constructed using the Brookmeyer-Crowley methodology (Brookmeyer and Crowley, Biometrics 1982, 38:29-41).

OS rates at 1 month and 2 years after randomization were estimated using the Kaplan-Meier method for each treatment group, with 95% CIs calculated using standard errors derived from the Greenwood equation. be done. The 95% CI for the difference in OS rates between the two treatment groups is estimated using routine approximation.

Secondary Efficacy Endpoints Progression-free survival and overall survival in the intent-to-treat population. following the same α assignment ratio (1:49) and α recycling strategy for ITT population. PFS and OS in the ITT population are analyzed simultaneously with PP using the same method as above except for all three stratifications.

Factors used for randomization from IxRS (ie, ECOG performance 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 over-stratification, the stratification factor(s) may be removed from the stratification analysis.

Confirmed Objective Response Rate A confirmed objective response is a confirmed CR on two consecutive occasions ≥4 weeks apart, as determined by the investigator using RECIST v 1.1. or PR. Patients who do not meet these criteria, including those who do not have a post-baseline tumor assessment, are considered non-responders.

Confirmed ORR is defined as the proportion of patients with a confirmed objective response. Analysis populations for confirmed ORR are PP and ITT populations with measurable disease at baseline. Estimates of the confirmed ORR and its 95% CI are calculated using the Clopper-Pearson method for each treatment group. The CI of the confirmed ORR difference between the two treatment groups is determined using the normal approximation of the binomial distribution.

Duration of Response The DOR of confirmed response will be assessed in patients with a confirmed objective response as determined by the investigator using RECIST v 1.1 in the PP and ITT populations. The DOR for a confirmed response is calculated from the date of first occurrence of a confirmed objective response to the first date of documented progressive disease or death as determined by the investigator according to RECIST v1.1 (either whichever occurs earlier). Patients who have not progressed and died at the time of analysis will be censored at the date of the last tumor assessment. DOR is based on a non-randomized subset of patients (specifically those who achieve an objective response); therefore, no formal hypothesis testing is performed for this endpoint. Comparisons between treatment groups are made for illustration. The methodology detailed for PFS analysis is used for DOR analysis.

Stratification Factors Stratification factors are those used for randomization from IxRS (ie, ECOG performance status, LDH, and presence or history of brain metastases). At least one stratum (i.e., a combination of stratification factor levels across ECOG performance status [0 vs. 1], LDH [≤ULN vs. >ULN], and presence or history of brain metastases per IxRS [with vs. no]) If having <10 events (PFS or OS events), stratification factor (1 of 3 stratification factors: ECOG performance status including lowest number of patients, brain metastases per LDH and IxRS) (presence or history of ) are excluded from the stratification analysis. Removal of stratification factors continues until there are no strata (PFS or OS events) with less than 10 events. The final stratification factor set used for stratification analysis will be applied to all endpoints for which stratification analysis is planned. Analysis based on stratification factors recorded on electronic case report forms (eCRFs) is also provided if substantial discrepancies between IxRS and eCRF records are observed.

E. Eligibility Patients are eligible if they are naive to chemotherapy for ES-SCLC and meet the following eligibility criteria: 18 years of age or older; ECOG performance status 0 or 1; histologically or cytologically confirmed ES-SCLC (modified Veterans Administration Lung Study Group (VALG) staging system (Micke et al., Lung Cancer 2002, 37:271-6); no prior systemic treatment for ES-SCLC; , there must be a treatment-free interval of at least 6 months between the last dose/cycle of chemotherapy, thoracic radiotherapy, or chemoradiation and the diagnosis of ES-SCLC; measures as defined in RECIST v1.1 Possible disease (previously irradiated lesions are the only disease in which (1) disease progression is clearly documented at the site since radiotherapy and (2) previously irradiated lesions are measurable) can be considered measurable disease only if it is not at the site of the tumor); submission of pretreatment tumor tissue samples; for patients on therapeutic anticoagulation: stable anticoagulant regimen; Negative HIV test, negative hepatitis B surface antigen (HBsAg) test at Screening; Adequate, as defined by the following laboratory results obtained within 14 days prior to initiation of study treatment (Day 1 of Cycle 1) hematological and organ end function: absolute neutrophil count (ANC) ≥1.5 x 10 ⁹ /L (1500/μL) without granulocyte colony stimulating factor support; lymphocyte count ≥ 0.5 x 10 ⁹ platelet count ≧100×10 ⁹ /L (100,000/μL), no transfusion; hemoglobin ≧90 g/L (9 g/dL) (to meet this criterion, patients were INR or aPTT ≤ 1.5 x ULN (Patients not on therapeutic anticoagulants, INR, or aPTT ≤ 1.5 x ULN) AST, ALT, and ALP ≤ 2.5 x ULN, with the following exceptions: (Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN; documented liver or patients with bone metastases: ALP ≤ 5 bilirubin ≤ 1.5 x ULN (with the following exceptions: patients with known Gilbert's disease: bilirubin ≤ 3 x ULN); creatinine ≤ 1.5 x ULN; albumin ≥ 25 g/L (2.5 g/dL) ).

Exclusion criteria include: Asymptomatic patients with symptomatic or actively developing CNS metastases Eligible if: Measurable disease exists outside the CNS according to RECIST v1.1; patient has no history of intracranial or spinal cord hemorrhage due to CNS lesions; metastasis to cerebellum or supratentorial region Limited (ie, no midbrain, vascular, medulla, or spinal cord metastases); patient has no symptoms of CNS disease (ie, headache, nausea, vomiting, seizures, paralysis, etc.); No ongoing need for anticonvulsants for neurological disease; patient has no ongoing need for dexamethasone/corticosteroids for central nervous system disease intermediate progression of the central nervous system between completion of CNS-directed therapy and randomization for patients with previously treated CNS metastases; no evidence of cerebral edema (e.g., vasogenic edema) associated with CNS lesions in previously untreated patients; contrast agents used at screening in previously untreated patients; A brain magnetic resonance imaging (MRI) scan is required and is the preferred modality for all subsequent scheduled follow-up tumor assessments (CT) scans may be acceptable at all subsequent scheduled follow-ups: both brain MRI and CT scan with contrast at Screening to assess untreated central nervous system disease contrast-enhanced CT scan can be used to reliably evaluate lesions identified by contrast-enhanced screening MRI; contrast-enhanced MRI scans should be used for all subsequent scheduled follow-up tumor assessments, unless lesions identified in 2010-2011 can be reliably assessed with contrast; Use the same modalities for assessment; spinal cord compression without definitive treatment with surgery and/or radiation or without evidence of clinical stability >1 week prior to randomization. received spinal cord compression; leptomeningeal disease; uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage (monthly or more frequently); Wearing patients are allowed regardless of drainage frequency; uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, total serum calcium >12 mg/dL, or corrected calcium >ULN); Known clinically significant liver disease, such as viral, alcoholic, other hepatitis, cirrhosis, hereditary liver disease, or current alcohol abuse; malignancy other than SCLC within 5 years prior to randomization, provided that Except those with negligible risk of metastasis or death (e.g., 5-year OS expected >90%) and expected curative outcome (adequately treated cervical carcinoma in situ, baseline or squamous cell skin cancer, localized prostate cancer surgically treated with curative intent, ductal carcinoma in situ surgically treated with curative intent, etc.); autoimmune disease or active immunodeficiency or medical history, with the following exceptions: (Patients with a history of autoimmune-related hypothyroidism receiving thyroid replacement hormone therapy are eligible for this study; Patients with type diabetes are eligible for the study; patients with eczema, psoriasis, lichen simplex, or vitiligo with dermatologic symptoms only (e.g., patients with psoriatic arthritis are excluded) meet the following conditions: is eligible for the study if: rash must cover less than 10% of body surface area; disease must be well controlled at baseline and require only low-potency topical corticosteroids; No acute exacerbation of underlying disease requiring psoralen plus UV A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the past 12 months; idiopathic History of pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on screening chest CT scan; history (fibrosis) allowed; active EBV infection at screening or known or suspected chronic active EBV infection; Eligible only if polymerase chain reaction (PCR) is negative active tuberculosis; severe infection at randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia; New York Heart Association cardiology (Class II or above), myocardial infarction, or significant cardiovascular disease such as cerebrovascular disease, unstable arrhythmia, or unstable angina within 3 months prior to randomization; known coronary artery disease, not meeting the above criteria Patients with congestive heart failure or left ventricular ejection fraction less than 50% should receive a stable medical regimen optimized in the opinion of the treating physician, in consultation with a cardiologist if necessary. non-diagnostic major surgical procedure within 28 days prior to randomization, or anticipation of need for major surgical procedure during the course of the study; prior allogeneic bone marrow or solid organ transplantation; use of study drug other diseases, metabolic dysfunctions, physical examination findings, which impair the interpretation of results or give reasonable suspicion of a disease or condition that may put the patient at increased risk for procedural complications; or laboratory findings; patients with a disease or condition that interferes with their ability to understand, follow, and/or adhere to study procedures; treatment with other investigational agents within 28 days prior to initiation of study treatment; antiviral against HBV or HCV Current treatment with therapy; Administration of live attenuated vaccine within 4 weeks prior to randomization, or anticipation that such live attenuated vaccine will be required during the study; Patients will be administered within 4 weeks prior to randomization , during treatment, and for 5 months after the last dose of study treatment, should not receive a live attenuated influenza vaccine (e.g., FLUMIST®); Pretreatment with TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies; systemic immunostimulants (interferon and interleukin-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to randomization (including but not limited to IL-2)); systemic immunosuppressants (corticosteroids, cyclo treatment with fosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents), except: acute, low-dose systemic immunosuppressants, or systemic immunosuppression Medications (eg, corticosteroids for 48 hours for contrast allergy) ) are eligible for the study after obtaining medical monitor confirmation; mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose mineralocorticoids for orthostatic hypotension, or low-dose mineralocorticoids and corticosteroids for adrenal insufficiency are eligible for this study; chimeric or humanized antibodies, or fusions History of severe allergic anaphylactic reaction to protein; Known hypersensitivity to Chinese Hamster Ovary Cell Products or any component of tiragolumab or atezolizumab formulations; History of allergic reaction to carboplatin or etoposide; Pregnancy or lactation, or study treatment Intention to become pregnant during or within 90 days after the last dose of tiragolumab or placebo, within 5 months after the last dose of atezolizumab, or within 6 months after the last dose of carboplatin or etoposide; A negative serum pregnancy test result must be obtained within 14 days prior to initiation.

F. Cytokine Release Syndrome No premedication for Cycle 1 administration of tiragolumab/placebo or atezolizumab was indicated. However, patients experiencing cytokine release syndrome (CRS) with tiragolumab/placebo or atezolizumab may receive premedication with antihistamines, antipyretics and/or analgesics (eg, acetaminophen) for subsequent infusions. CRS is defined as a supraphysiologic response following administration of any immunotherapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive and always include fever at onset and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al., Biol Blood Marrow Transplant, 25 (4). ): 625-638, 2019). CRS is well documented with chimeric antigen receptor T-cell therapy and bispecific T-cell engager antibody therapy, but has also been reported with immunotherapies targeting PD-1 or PD-L1, including atezolizumab. (Rotz et al., Pediatr Blood Cancer, 64:e26642, 2017; Adashek and Feldman, J Oncol Practice, 15:502-504, 2019).

Example 8. Phase II, Randomized, Double-Blind, Placebo of Tiragolumab in Combination with Atezolizumab + Pemetrexed and Carboplatin/Cisplatin Versus Pembrolizumab + Pemetrexed and Carboplatin/Cisplatin in Patients With Previously Untreated Advanced Non-Squamous Non-Small Cell Lung Cancer Controlled Study This example demonstrates the efficacy of tiragolumab in combination with atezolizumab plus pemetrexed and carboplatin/cisplatin in patients with previously untreated locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC). A randomized, phase II, global, multicenter, double-blind study designed to evaluate pembrolizumab plus pemetrexed and safety compared to placebo in combination with carboplatin/cisplatin is described.

A. test plan

Eligible patients for this study had locally advanced unresectable or metastatic non-squamous NSCLC with no EGFR or ALK genomic aberrations, US East Coast Cancer Clinical Trials Group (ECOG) Performance Status (0 Previously untreated male and female patients ≧18 years of age with pair 1) are included.

Patients whose tumors have known EGFR or ALK rearrangements are excluded from this study.

Patients with tumors with unknown EGFR or ALK mutational status should be tested prior to enrollment. Eligible patients were evaluated for PD-L1 expression (tumor percentage score (TPS)/tumor cell (TC) <1% vs. 1%-49% vs. ≧50% by local or central assay), geographic region (Asia vs. non-Asia ) and ECOG performance status (0 vs. 1) and randomized 1:1 to receive the following treatment regimens.
Group A: Tiragolumab in combination with atezolizumab + pemetrexed and cisplatin/carboplatin;
Group B: Pembrolizumab + pemetrexed and placebo in combination with cisplatin/carboplatin.

The choice of carboplatin or cisplatin is at the investigator's choice. The choice of carboplatin or cisplatin was made prior to randomization and cannot be changed after Day 1 of Cycle 1.

The randomization scheme ensures that approximately equal numbers of patients with adequate presentation of all PD-L1 expressing subgroups (TPS/TC <1%, 1%-49%, and ≧50%) are enrolled designed to be To reflect the natural distribution of PD-L1 expression observed in primary NSCLC patients, the proportion of patients enrolled in each PD-L1 subgroup was calculated using the investigational VENTANA PD-L1 (SP263) Companion Diagnostics (CDx) assay. Limited to approximately 80 patients (approximately 40% of planned total enrollment) per central study using To account for differences between local and central results, selective enrollment based on local PD-L1 status will be performed if enrollment into the subgroup defined by the central outcome is on track to exceed the upper bound.

Induction treatments in Groups A and B are administered in 21-day cycles for 4 cycles. After the induction phase, patients continue maintenance therapy as outlined below.
Arm A: tiragolumab in combination with atezolizumab + pemetrexed Arm B: pembrolizumab + placebo in combination with pemetrexed

Patients undergo tumor assessments at baseline and every 6 weeks (±7 days) for 48 weeks after Cycle 1, Day 1, regardless of delay in treatment dosing. After completion of Week 48 tumor assessment, until radiographic disease progression per RECIST v 1.1, consent withdrawal, study termination or death (whichever occurs first), then 9 weeks regardless of dose delay Tumor assessments are required every (±7 days). Patients treated beyond disease progression by RECIST v1.1 will have tumor assessments at the frequency described above until study treatment is discontinued. Patients who discontinue treatment for reasons other than radiographic disease progression according to RECIST v 1.1 (e.g., toxicity, symptomatic worsening), regardless of whether the patient is starting new anticancer If treatment was continued (i.e., cycle 1, every 6 weeks [±7 days] for 48 weeks after day 1, then every 9 weeks [±7 days], according to RECIST v 1.1 Scheduled tumor assessments will continue with the same frequency as radiographic disease progression, withdrawal of consent, study termination or death, whichever occurs first.

Patients will be asked to complete patient-reported outcome questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL46) during treatment, at study treatment discontinuation, and at the study treatment discontinuation visit.

Safety assessments at study visits should include the incidence, nature and severity of adverse events, protocol-specified vital signs, laboratory abnormalities, and other factors considered important to the safety assessment of the study. included protocol-specified studies.

During the study, serum samples will be collected to monitor the pharmacokinetics of tiragolumab and atezolizumab and to detect the presence of antibodies to tiragolumab and atezolizumab.

Patient samples, including archival and fresh tumor tissue, serum, plasma, and blood samples, are collected for exploratory biomarker assessment.

During the study, patients who met criteria for disease progression by RECIST v 1.1 and demonstrated evidence of clinical benefit were allowed to receive tiragolumab/placebo and atezolizumab at the investigator's discretion, provided the patient met all of the following criteria: / Treatment with pembrolizumab can be continued.
- Evidence of clinical benefit as assessed by the investigator - Absence of symptoms and signs of definite disease progression (including deterioration of laboratory values (e.g., new or worsening hypercalcemia) - Disease No decline in ECOG performance status that could be attributed to progression Lack of tumor progression in critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical intervention Patients must provide written informed consent to approve deferment of other treatment options in order to continue study treatment at first radiographic progression per RECIST v 1.1.

Investigator assessment of overall tumor response at all time points is based solely on RECIST v 1.1. The objective response by iRECIST is calculated by the program based on the investigator's assessment of individual lesions at each specified time point.

B. Dosing and Administration The treatment regimen is summarized in FIG.
atezolizumab and pembrolizumab

Patients will receive 20 mL (1200 mg) of fixed dose atezolizumab in Arm A or 8 mL (200 mg) of pembrolizumab in Arm B on Day 1 of each 21-day cycle. Atezolizumab/pembrolizumab infusions will be administered according to the instructions outlined in Table 50.

Tiragolumab and Placebo Patients will receive 10 mL (600 mg) fixed dose tiragolumab in Group A or 10 mL placebo in Group B on Day 1 of each 21-day cycle. Tiragolumab/placebo infusions will be administered according to the instructions outlined in Table 50.

Pemetrexed, Cisplatin and Carboplatin Table 51 lists doses and recommended infusion times for treatment administration of pemetrexed, carboplatin or cisplatin.

Patients receive antiemetics and IV hydration for platinum-pemetrexed treatment according to local standard of care and manufacturer's instructions. However, because of these immunomodulatory effects, steroid premedication was limited to cases where it was clinically feasible. Additionally, for pemetrexed-related skin rashes, topical steroid use is recommended as a front-line treatment whenever clinically feasible.

Table 52 lists suggested premedications for pemetrexed.

During the induction phase, chemotherapy cycles count toward 4 cycles of induction chemotherapy as long as at least one platinum-based chemotherapy component is administered at least once during the 21-day cycle. Cycles without chemotherapy are not counted in the total number of induction chemotherapy cycles.

Dose Modifications Dose modifications of pemetrexed and cisplatin/carboplatin are acceptable for toxicity according to prescribing information and local standard of care.

Dose modification guidelines are provided below. Once reduced, the dose cannot be returned to 100%.

Treatment with pemetrexed or cisplatin/carboplatin was 2 dose reductions or treatment delayed >63 days due to toxicity if the patient experienced any hematologic or non-hematologic grade 3 or grade 4 toxicity. discontinued after

Hematologic Toxicity At the start of each cycle, ANC is ≧1500/μL and platelet count is ≧100,000/μL. Treatment could be delayed up to 63 days to allow sufficient time for recovery. Growth factors can be used according to the American Society of Clinical Oncology (ASCO) and NCCN guidelines (Smith et al. 2015; NCCN 2019). Upon recovery, dose adjustments at the start of the next cycle are made based on the lowest platelet and neutrophil values from the previous cycle (Table 53). If a dose adjustment is required for both ANC and platelets, the patient will receive the lower dose.

Investigators should be alert and alert to early and overt signs of myelosuppression, infection or febrile neutropenia so that these complications can be managed promptly and appropriately. Patients are encouraged to recognize these symptoms and seek medical attention at the earliest opportunity.

If chemotherapy is withheld due to hematologic toxicity, complete blood counts (including WBC differentials) are obtained weekly as outlined until counts reach the lower limit of treatment. Then resume treatment.

Dose reduction for anemia is not recommended. Patients will be assisted according to the investigator's institutional guidelines.

Non-Hematological Toxicity For non-hematologic toxicity (Table 54), treatment is maximal until recovery to below the patient's baseline value (or Grade ≤ 1 if the patient did not have the toxicity at baseline). Delayed for 63 days. Dose reductions at the start of the next cycle are based on non-hematologic toxicities from the dose administered in the previous cycle. Table 54 provides recommended dose modifications for non-hematological toxicities.

Diarrhea is controlled with appropriate antidiarrheals. Nausea and/or vomiting can be controlled with appropriate antiemetics. For Grade 3 or 4, neurotoxic chemotherapy is resumed at 50% of the previous dose after improvement (based on the investigator's clinical judgment) or discontinued immediately.

C. Combination therapy

Concomitant therapy includes any medication used by the patient (e.g., prescription or over-the-counter medication, vaccine, herbal therapeutic or homeopathic remedies, dietary supplements). All such medications will be reported to the investigator and recorded.

Allowed Treatments Patients will be allowed to use the following treatments during the study.
● Oral contraceptives with <1% annual failure rate ● Hormone replacement therapy ● Palliative radiation therapy (eg, treatment of known bone metastases or symptomatic relief of pain) as outlined below:

In patients without documented radiographic disease progression, maximizing supportive care for symptomatic treatment and avoiding radiation therapy that interferes with assessment of tumor target lesions is strongly encouraged. Treatment with tiragolumab/placebo and atezolizumab/pembrolizumab may be continued during palliative radiotherapy.
- Receptor activator of nuclear factor κB ligand-targeted therapy to increase bone density - Bisphosphonates to slow progression of bone loss - Prophylactic or therapeutic anticoagulant therapy (such as stable dose warfarin or low molecular weight heparin) )
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
Inhaled or low-dose corticosteroids given for chronic obstructive pulmonary disease or asthma Low-dose mineralocorticoids given for orthostatic hypotension or low-dose mineralocorticoids for adrenal cortical insufficiency and corticosteroid

Premedication for pemetrexed and cisplatin or carboplatin is permitted. Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent atezolizumab/pembrolizumab and tiragolumab/placebo infusions at the investigator's discretion.

In general, the investigator will manage patient care according to local standard practice, using supportive care other than those defined as clinically indicated attentional or prohibitive care. Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine) or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and β2-adrenergic agonist).

Treatments requiring caution Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with tiragolumab and/or atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines are considered. If alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors can be administered at the investigator's discretion.

Systemic corticosteroids are recommended at the Investigator's discretion for the treatment of specific adverse events when associated with tiragolumab and/or atezolizumab therapy.

Prohibited Therapies The use of the following concomitant therapies is prohibited as described below:
• Study treatment (other than protocol-defined study treatment) is prohibited within 28 days prior to and during study treatment.
- Combination therapy for the treatment of cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), depending on the drug, to initiate study treatment At various times prior to and during study treatment, disease progression is documented and is prohibited until the patient discontinues study treatment, with the exception of palliative radiotherapy under certain circumstances.
• Live-attenuated vaccines are prohibited within 4 weeks prior to initiation of study treatment, during study treatment, and 5 months after the final dose of study treatment.
o Within 4 weeks or 5 drug elimination half-lives (either within 4 weeks prior to initiation of study treatment and during study treatment due to potential increased risk of autoimmune symptoms when administered in combination with study treatment) systemic immunomodulators (including but not limited to interferon and IL-2) within the longer term)
- Systemic immunosuppressants (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment (because drugs can potentially alter the efficacy and safety of study treatment)

D. Inclusion Criteria Patients must meet the following study entry criteria:
● A signed informed consent form ● Age ≥18 years at the time of signing the informed consent document ● Ability to comply with the study protocol ● ECOG performance status 0 or 1
- Histologically or cytologically documented locally advanced unresectable or metastatic nonsquamous NSCLC

Patients with tumors of mixed NSCLC histology must be classified as non-squamous based on major histologic components. Patients with mixed NSCLC and small cell lung cancer are not eligible for the study.
No prior systemic treatment for metastatic non-squamous NSCLC

Patients who have previously received neoadjuvant, adjuvant chemotherapy, radiotherapy or chemoradiotherapy with curative intent for non-metastatic disease will be excluded from randomization since the last chemotherapy dose and/or last radiotherapy. Must have experienced a treatment-free period of at least 12 months.
Use of a local health authority approved assay (SP263 [preferred], or 22C3 only if SP263 is not available) or a central laboratory assay (Investigational VENTANA [SP263]) if an approved local test is not available Known tumor PD-L1 status by CDx assay)

The availability of representative tumor specimens along with relevant pathology reports was confirmed in formalin-fixed, paraffin-embedded (FFPE) blocks (preferred) or at least 15-20 unstained serial slides. If central testing for EGFR mutations and/or ALK translocations is required, an additional 5 unstained slides must be provided.

Tumor tissue is of good quality based on total tumor content and viable tumor content (ie, a minimum number of 100 viable tumor cells with preserved cellular context and histology). Acceptable specimens include specimens from excisions, core needle biopsies of deep tumor tissue (with a minimum of 3 cores for freshly collected biopsies), or excisional biopsies of cutaneous, subcutaneous, or mucosal lesions. Includes biopsy, incisional biopsy, punch or forceps biopsy, or endobronchial ultrasound (EBUS) core needle biopsy.

Endobronchial Ultrasound: Transbronchial Needle Aspiration (EBUS-TBNA), sometimes referred to as fine needle aspiration (especially when larger gauge needles are used), should the tissue be of good quality as described above. acceptable (ie, a minimum number of 100 viable tumor cells with preservation of cellular contents and tissue architecture). For needle aspiration, an 18 gauge or larger needle is recommended.

Fine-needle aspiration, which does not preserve tissue architecture and does not preserve cell suspensions and/or cell smears, brushes, cell pellets from pleural effusions, and lavage fluid samples, is not acceptable.

Tumor tissue from bone metastases cannot be assessed for tumor PD-L1 expression by IHC and is therefore not accepted.

If archival tissue is insufficient or unavailable, patients may undergo a biopsy at screening if the biopsy site is safely accessible. If a biopsy cannot be provided, the patient may still be eligible during discussion with the medical monitor if ≧10 consecutive unstained slides can be provided.
- Measurable disease as defined by RECIST v 1.1

Previously irradiated lesions should only be measured if disease progression is clearly documented at that site, as radiation and previously irradiated lesions are not the only sites of disease measurable. can be considered a possible disease.
- Life expectancy ≥ 12 weeks - Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment (Day 1 of Cycle 1):
- ANC ≧1.5×109/L (≧1500/μL) without granulocyte colony stimulating factor support
- Lymphocyte count ≥0.5 X 109/L (≥500/μL)
- Platelet count ≥100 X 109/L (≥100,000/μL) without transfusion
- Hemoglobin ≧90 g/L (≧9 g/dL).

Patients can receive blood transfusions or erythropoietic procedures according to local standard of care to meet this criterion.
- AST, ALT and ALP ≤ 2.5X upper limit of normal (ULN), excluding:
Patients with documented liver metastases: AST and ALT ≤ 5XULN
Patients with documented liver or bone metastases: ALP ≤ 5XULN
- Total bilirubin ≤ 1.5 XULN, with the following exceptions:
Patients with known Gilbert's disease: bilirubin level ≤ 3XULN
- Creatinine clearance (CrCl) ≥ 40 mL/min (≥ 60 mL/min required for cisplatin), calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection to determine CrCl
- Albumin ≥25 g/L (≥2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5XULN
● Patients receiving therapeutic anticoagulants: stable anticoagulant regimen ● Negative HIV test at screening ● Negative hepatitis B surface antigen (HBsAg) test at screening ● Hepatitis B surface antibody (HBsAg) test at screening HBsAb) positive test or HBsAb negative at screening with any of the following:
- total hepatitis B core antibody (HBcAb) negative - total HBcAb test positive followed by hepatitis B virus (HBV) DNA test negative (according to local laboratory definitions).
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening. HCV RNA testing is performed only for patients who test positive for HCV antibodies.
For women of childbearing potential: Consent to abstinence (abstinence from heterosexual intercourse) or use of contraception, and consent to abstain from donating eggs, as defined below:

Women had a <1% failure rate per year during the treatment period and for 90 days after the last dose of tiragolumab or placebo, 5 months after the last dose of atezolizumab or pembrolizumab, and 6 months after the last dose of pemetrexed and carboplatin or cisplatin. Must remain abstinent from alcohol or use contraceptive methods. Females should refrain from donating eggs during this same period.

Females are postmenopausal, have not achieved postmenopausal status (amenorrhea with no identified cause other than menopause for ≧12 consecutive months), and have had surgery (i.e., ovarian, fallopian tube, and/or uterine Ablation) or another cause determined by the Investigator (eg, Müllerian agenesis) is considered fertile if not permanently infertile. Fertility definitions can be adapted to match local guidelines or regulations.

Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, hormonal devices that inhibit ovulation, hormone-releasing intrauterine devices, and copper-added intrauterine devices. .

Reliability of sexual abstinence will be assessed in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle.

Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not suitable methods of contraception.

Women who wish to become pregnant after discontinuation of study treatment should seek advice regarding oocyte storage prior to initiation of study treatment due to the potential for irreversible infertility resulting from treatment with carboplatin.
For men: agreeing to maintain abstinence (abstain from heterosexual intercourse) or use contraceptive methods and to abstain from donating sperm, as defined below:

For non-pregnant female partners of childbearing potential, non-surgically contraceptive males should receive 100 mg/kg during the treatment period and after the last dose of tiragolumab or placebo to avoid embryo exposure and/or genotoxicity. Maintain abstinence for 90 days, 4 months after the last dose of atezolizumab or pembrolizumab, 6 months after the last dose of pemetrexed and carboplatin or cisplatin, or add-on contraception combined with a condom that results in <1% failure rate per year method must be used. Men must stop donating sperm during the same period.

For pregnant partners, men receive carboplatin and paclitaxel throughout the procedure and for 90 days after the last dose of tiragolumab or placebo and 4 months after the last dose of atezolizumab or pembrolizumab to avoid embryo exposure. OR must maintain abstinence or use a condom for 6 months after the last dose of nab-paclitaxel.

Reliability of sexual abstinence will be assessed in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle.

Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not suitable methods of contraception.

Men who wish to have children after initiation of study treatment should seek advice on sperm storage prior to initiation of study treatment due to the potential for irreversible infertility resulting from treatment with pemetrexed, cisplatin, or carboplatin.

E. Exclusion Criteria Patients with NSCLC known to have mutations in the EGFR gene or the ALK fusion oncogene are excluded from study participation. Patients with non-squamous NSCLC with unknown EGFR or ALK status are examined at pre-screening or screening. EGFR and/or ALK status will be assessed by a local or central laboratory. A local assessment of EGFR status is performed on tissue or cytology using a validated, health authority-approved test that detects mutations in exons 18-21. Additional slides are provided if the sample is subjected to central EGFR and/or ALK testing.

F. Assessments Patients will be closely monitored for safety and tolerability throughout the study. Patients will be assessed for toxicity prior to each dose; dosing will be administered only if clinical evaluation and local laboratory values are acceptable.

Medical history, baseline symptoms, concomitant medications and demographic data Clinically significant disease, surgery, cancer history (including previous cancer therapies and procedures) and lung cancer mutational status (e.g., EGFR and ALK), reproductive Medical history, including condition, smoking history, and alcohol and drug use of abuse are recorded at baseline. In addition, all drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, dietary supplements) used by the patient within 7 days prior to initiation of study treatment are recorded. At each follow-up check-up, an interval medical history is obtained and changes in medications and allergies are recorded.

Demographic data includes age, gender, and self-reported race/ethnicity.

Physical Exam A complete physical exam is performed at Screening, including the head, eyes, nose, and throat, as well as the cardiovascular, dermatological, musculoskeletal, respiratory, digestive, genitourinary, and genitourinary systems. Includes nervous system. Record any abnormalities identified at baseline.

Limited, symptomatic physical examinations will be performed as clinically indicated at designated post-baseline visits. Changes from baseline abnormalities are recorded in patient notes. New or worsening clinically significant abnormalities are recorded.

Vital Signs Vital signs include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressure and body temperature while the patient is in a sitting position.

Any abnormalities observed at baseline on the General Medical History and Baseline Symptom eCRF will be recorded. New or worsening clinically significant abnormalities are recorded at subsequent visits.

ECOG Performance Status Performance status will be measured using the ECOG Performance Status at baseline and assessed at regular intervals throughout the study.

Tumor and Response Assessment Screening and subsequent tumor assessment must include a CT scan of the abdomen and chest (using IV contrast unless contraindicated and appropriate oral contrast according to institutional standards). A CT scan with contrast of the pelvis is indicated at screening and as clinically indicated or according to local standard of care with subsequent response assessment. Patients for whom contrast-enhanced CT scans are contraindicated (i.e., patients with iodine-based contrast allergy or impaired renal clearance) should receive contrast-enhanced MRI of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest. Scanning can be used.

A CT of the head (with contrast) or MRI with contrast (if CT is contraindicated) must be performed at screening to assess CNS metastases in all patients. If a CT with contrast agent is performed and the presence of brain metastases is considered ambiguous, an MRI of the head is required to confirm or rule out the diagnosis of CNS metastases at baseline.

If CT scans for tumor assessment are performed on a Positron Emission Tomography (PET)/CT scanner, the CT acquisition must conform to the standard for full contrast-enhanced diagnostic CT scans.

Further investigations such as bone and CT scans of the neck are performed if clinically indicated. At the investigator's discretion, other methods of measurable disease assessment according to RECIST v1.1 may be used.

Tumor assessments performed prior to obtaining informed consent and within 28 days of Day 1 of Cycle 1 as standard of care can be used rather than repeating the test. All known sites of disease, including measurable and/or non-measurable disease, must be documented at screening and reevaluated at each subsequent tumor evaluation.

Patients undergo tumor assessments at baseline and every 6 weeks (±7 days) for 48 weeks after Day 1 of Cycle 1, regardless of any delay in treatment. Radiographic disease progression by RECIST v 1.1 (or loss of clinical benefit for patients continuing study treatment after disease progression by RECIST v 1.1) after completion of tumor assessment at week 48, withdrawal of consent; Tumor assessments are required every 9 weeks (±7 days), regardless of treatment delay, until death or study termination (whichever occurs first). At the investigator's discretion, scans may be performed whenever progressive disease or loss of clinical benefit is suspected.

Response will be assessed by the investigator for imaging as detailed above using RECIST v1.1. Investigator assessment of overall tumor response at all time points is based solely on RECIST v1.1. Ratings will be performed by the same rater when possible to ensure internal consistency between visits. Results should be reviewed by the investigator prior to dosing in the next cycle.

Clinical benefit assessed by the investigator in the absence of unacceptable toxicity or exacerbation due to disease progression after integrated assessment of radiographic data, biopsy results (if available), and clinical status Study treatment with tiragolumab/placebo and atezolizumab/pembrolizumab can continue as long as the patient experiences Patients who meet the criteria for disease progression according to RECIST v 1.1 will be allowed to continue study treatment if they meet all of the specified criteria and provide written consent.

Patients who discontinue treatment for reasons other than radiological disease progression according to RECIST v1.1 (e.g., toxicity, worsening of symptoms) will be assessed for radiological disease progression, withdrawal of consent, death, or study Scheduled tumor assessments will continue at the above frequency until termination (whichever occurs first). Patients starting new anticancer therapy in the absence of radiographic disease progression by RECIST v1.1 will be assessed for radiographic disease progression by RECIST v1.1, withdrawal of consent, death, or study end ( Tumor evaluations will continue at the above frequency until (whichever occurs first).

Investigator assessment of overall tumor response at all time points is based solely on RECIST v1.1. Global tumor ratings are from iRECIST and are based on entries of all target lesions, non-target lesions, and new lesions. To facilitate assessment of response by iRECIST, tumor assessment should be continued after disease progression by RECIST v1.1 for patients who received study treatment beyond progression. This includes continuous measurement of target lesions, assessment of non-target lesions (including monitoring for further deterioration of any non-target lesion that has demonstrated definite progression), and any new Evaluation of identified lesions (including measurements if lesions are measurable) is included.

Electrocardiogram An ECG is required at screening and when clinically indicated. Each patient's ECG is obtained from the same machine whenever possible. Lead placement is as consistent as possible. ECG recordings must be taken after the patient has rested in the supine position for at least 10 minutes.

For safety monitoring purposes, the investigator must review all ECG recordings. A copy of the ECG recording is kept on site as part of the patient's permanent test file. Any morphological waveform changes or other ECG abnormalities must be documented.

Clinical Outcome Assessment A PRO instrument will be completed to document treatment benefit and more fully characterize the clinical profile of tiragolumab and atezolizumab plus carboplatin with paclitaxel/nab-paclitaxel. PRO data are collected using the following instruments: single items from EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL46.

Questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL46) will be completed on Day 1 of Cycle 1 (Baseline) prior to administration of study drug and then on Day 1 of each treatment cycle through Cycle 4. (ie, Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1).

In Cycle 5, from 1 day prior to study drug administration (i.e., Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; etc.) to the study treatment discontinuation visit and study treatment discontinuation At the visit, the questionnaire will be completed at every other study treatment cycle.

Blood Samples for Whole Genome Sequencing or Whole Exome Sequencing At participating centers, blood samples will be collected for DNA extraction to more severe disease states where WGS or WES predicts response to study drug. associated with the progression of disease, associated with acquired resistance to the study drug, associated with susceptibility to the occurrence of adverse events, can lead to improved monitoring or investigation of adverse events, or knowledge and understanding of disease biology and drug safety It allows us to identify variants that can enhance our understanding. Somatic variants can be identified by comparing DNA extracted from blood to DNA extracted from tissue to distinguish germline variants from somatic variants. Samples can be sent to one or more laboratories for analysis.

Collection and submission of blood samples for WGS or WES is subject to review and approval of the investigative study by each institution's IRB/EC and, where applicable, appropriate regulatory bodies.

Genomics is increasingly facilitating investigator's understanding of disease pathobiology. WGS and WES provide comprehensive genomic and exome characterization, respectively, along with the clinical data collected in this trial, to monitor efficacy and safety, or to determine which patients will respond to drug or adverse events. It may increase opportunities to develop new therapeutic approaches or new methods to predict whether an event is more likely to develop. Data will be analyzed in relation to this study, but can also be examined together with data from other studies. The availability of larger data sets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

Blood samples collected for WGS or WES must be stored until no longer needed or until exhausted.

Samples for the Research Biosample Repository The Research Biosample Repository (RBR) is a centralized repository used for long-term storage of human biological samples, including body fluids, solid tissues and their derivatives (e.g. DNA, RNA, proteins, peptides). Facility group. The collection, storage, and analysis of RBR samples may facilitate the rational design of new pharmaceuticals and development of diagnostic tests, enabling personalized drug therapy for future patients.

RBR samples are collected from patients who specifically consent to participate in this optional study. RBR samples are analyzed to achieve one or more of the following objectives:
• To test the association of biomarkers with efficacy or disease progression • To identify safety biomarkers that are associated with susceptibility to adverse event development or that may lead to improved monitoring or surveillance of adverse events • To enhance knowledge and understanding of disease biology and drug safety To test drug effects and drug responses, including processes of drug absorption and disposition To develop biomarker or diagnostic assays and characterize the performance of these assays to establish

Sample Collection The following samples will be stored in the RBR and used for testing purposes, including but not limited to testing for tiragolumab, atezolizumab, non-squamous NSCLC, or biomarkers related to drug safety.
- Residual blood, serum, including residual tissue samples from medically designated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the discretion of the Investigator during the course of the study , plasma and tumor tissue samples (excluding remaining archival tissue blocks returned to the field) and any derivatives thereof (e.g. DNA, RNA, proteins, peptides)
• Any stool sample collected pre-dose on Cycle 1, Day 1 and Cycle 2, Day 15 and Cycle 3, Day 1 pre-dose. These samples may be collected at home.

The samples can be sent to one or more laboratories for analysis of germline or somatic variants by WGS, WES, or other genomic analysis methods. Genomics is increasingly facilitating investigator's understanding of disease pathobiology. WGS and WES provide comprehensive genomic and exome characterization, respectively, along with the clinical data collected in this trial, to monitor efficacy and safety, or to determine which patients will respond to drug or adverse events. It may increase opportunities to develop new therapeutic approaches or new methods to predict whether an event is more likely to develop.

Data generated from the RBR samples are analyzed in conjunction with this study, but can also be examined together with data from other studies. The availability of larger data sets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

G. Treatment and Patient Discontinuation Treatment Discontinuation Patients must permanently discontinue study treatment if they experience any of the following:
- unacceptable treatment-related toxicity, including the occurrence of immune-mediated adverse events that the investigator judged to be unacceptable given the individual patient's potential response to treatment and the severity of the event; Any medical condition that the investigator determines may endanger his or her safety if he or she continues to receive treatment. Pregnancy Use of non-protocol anticancer therapy Radiographic disease progression per RECIST v1.1 (unless study treatment continues beyond radiographic progression)
For patients treated beyond radiographic disease progression, a combined assessment of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic worsening). Loss of clinical benefit later determined by the investigator (if treatment with tiragolumab/placebo and atezolizumab/pembrolizumab is continued beyond radiographic disease progression)

The primary reason for discontinuing study treatment will be documented in the appropriate eCRF. Patients who discontinue study treatment early are not replaced.

Patients return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study drug. Visits where response ratings indicate progressive disease may be used as treatment discontinuation visits. Patients who discontinue study treatment for any reason other than progressive disease or loss of clinical benefit (patients continuing treatment beyond radiological disease progression) will continue to receive tumor response assessments and PRO assessments.

After discontinuation of study treatment and disease progression per RECIST v1.1, information regarding survival follow-up and new anti-cancer therapy will be collected via telephone, patient medical records and/or clinic visits approximately every 3 months until death. (unless the patient withdraws consent).

H. Analysis Efficacy analysis Efficacy analysis will be performed in the ITT population with patients grouped according to randomized treatment. Estimates of the ORR difference between the two treatment groups and PFS HR are calculated with their 95% CIs.

n-hypothesis tests for co-primary efficacy endpoints are also performed in the ITT population.

All primary analyzes of disease progression and objective response are based on the investigator's review of tumor assessments using RECIST v1.1.

Primary Efficacy Endpoints Co-primary efficacy endpoints will be identified with ORR and PFS.

Confirmed ORR is defined as the proportion of patients who achieved two consecutive objective responses characterized by CR or PR, ≧4 weeks apart.

Objective response will be assessed by treatment arm, and patients who do not have a post-baseline overall response assessment will be counted as non-responders.

An estimate of the difference between the ORRs in the two groups is calculated with its 95% CI. The Mantel-Haenszel test will be used to compare the ORR between the two treatment groups at a two-sided significance level of 5% stratified by protocol-defined stratification factors.

PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first. Patients who have never experienced disease progression or who have not died at the time of analysis will be censored at the last tumor assessment. Patients with no post-baseline tumor assessment will be censored at the date of randomization.

PFS will be compared between treatment groups using a stratified log-rank test.

The HR of PFS and its 95% CI are estimated using a stratified Cox proportional hazards model.

The Kaplan-Meier method is used to estimate median PFS for each treatment group and construct Kaplan-Meier curves to provide a visual description of differences between treatment groups.

Secondary Efficacy Endpoints Overall Survival OS is defined as the time from randomization to death. Data for patients alive at the time of data cutoff are censored on the last day known to be alive. Data from patients with no post-baseline information are censored at the date of randomization. A stratified Cox proportional hazards model is used to estimate the OS HR and its 95% CI. The Kaplan-Meier method is used to estimate the OS curve and median OS for each treatment group.

Duration of Acknowledgment DOR is defined as the time from the first occurrence of a documented objective response to disease progression or fat due to any cause (whichever occurs first). Only patients who achieved an objective response to study treatment were included in the DOR analysis. DOR is estimated using the Kaplan-Meier method. No formal hypothesis testing is performed as the determination of DOR is based on a non-randomized subset of patients.

Patient Reported Outcomes TTCD with cough, dyspnea, and chest pain symptoms using physical functions using the EORTC QLQ-LC13, GHS/QoL, and EORTC QLQ-C30 were first confirmed from the date of randomization. Defined as time to clinically meaningful deterioration. Confirmed clinically meaningful worsening of symptoms must be retained for at least 2 consecutive assessments of symptom score ≥ 10 point score increase from baseline or initial score ≥ 10 points from baseline Defined as an increase followed by death. Confirmed clinically significant decline in GHS/QoL and physical functioning must be maintained for ≥10 point score reduction from baseline in GHS/QoL or at least 2 consecutive assessments of the physical functioning scale Defined as the score, or the first >10 point drop from baseline followed by death.

For TTCD, patient data will be censored at the last time the patient completes the assessment if they have not experienced a confirmed clinically meaningful deteriorating event on the clinical cut-off date. If no baseline or post-baseline assessments are made, patients will be censored on the randomization day.

TTCD using the EORTC scale is analyzed using the same method as PFS.

Baseline summary statistics and linear transformation scores for all questionnaire items and subscales of the EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL46 (Suffering from Side Effects Item) according to manual guidelines for EORTC scoring. Report the mean change from .

Safety Analysis The safety analysis included all treated patients, defined as randomized patients who received any amount of study treatment.

Safety analyzes are performed by treatment group and are based on the actual treatment received. Specifically, patients are included in Group A in the safety analysis if they receive any dose of tiragolumab or atezolizumab, regardless of initial treatment assignment at randomization.

Drug exposure is summarized including duration, dosage and dose intensity. Verbal descriptions of adverse events are mapped to MedDRA thesaurus terms.

The severity of all adverse events will be graded by the investigator according to the NCI CTCAE v5.0, and the severity of CRS will also be graded by the investigator according to the ASTCT consensus grading scale. All adverse events will be summarized by treatment group and NCI CTCAE grade. CRS is also summarized by treatment group and ASTCT consensus grade. In addition, serious adverse events and adverse events leading to interruption or discontinuation of study treatment will be summarized as appropriate. Multiple occurrences of the same event are counted once at maximum severity. Experimental data with values outside the normal range are identified. In addition, selected experimental data, including ADA results, are summarized by treatment group. Summarize deaths and causes of death.

Pharmacokinetic Analysis PK samples are collected for PK analysis and exposures in this study are compared to those obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab are reported as individual values and summarized by treatment group and cycle (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Median individual and serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be pooled with data from other studies using established population PK models to derive data-assured PK parameters such as clearance, volume of distribution and AUC. . Potential correlations between relevant PK parameters and safety, efficacy or biomarker outcomes can be examined.

Immunogenicity Analysis The immunogenicity analysis includes patients with any ADA assessment and groups the patients according to the treatment received. The numbers and percentages of treatment-emergent ADA-positive and ADA-negative patients for both tiragolumab and atezolizumab are summarized by treatment group. Relationships between ADA status and safety, efficacy and PK endpoints can be analyzed and reported by descriptive statistics.

Biomarker Analysis Biomarker analysis can be performed to understand the association between relevant markers (eg, TIGIT) and efficacy of the study treatment. Efficacy outcomes can be investigated in a population of patients whose tumors have high biomarker expression as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data will be conducted in the context of this study and can be explored together with data from other studies to enhance the investigator's understanding of disease pathobiology and guide the development of new therapeutic approaches. . WGS does not apply to establishments that have never received regulatory approval for WGS sampling.

Exploratory Analysis Defined by demographic characteristics (e.g., age, sex, and race/ethnicity) and baseline prognostic characteristics (e.g., central laboratory PD-L1 expression, geographic region, and ECOG). Co-primary efficacy endpoints that confirmed ORR and PFS in these subgroups will be examined to assess the consistency of study results in these subgroups. Confirmed ORR and PFS summaries are generated separately for each level of the categorical variable for comparison between the two treatment groups.

Interim Analysis Periodic analyzes of cumulative safety data are planned for this study. The PFS efficacy interim analysis will be performed when approximately 86 PFS events were observed in the ITT population. This is expected to occur approximately 19 months after the first patient is randomized. Early analysis of ORR will also be performed when approximately 120 patients have had at least two tumor assessments. This is expected to occur approximately 14 months after the first patient is randomized.

Example 9. Neoadjuvant and adjuvant tiragolumab plus atezolizumab with or without platinum-based chemotherapy in patients with previously untreated locally advanced resectable stage II, IIIA or selected IIIB non-small cell lung cancer A Phase II, Open-label, Multicenter Study Evaluating the Safety and Efficacy of A. Study Design Overview GO42501 is a platinum-based chemotherapy in previously untreated, histologically or cytologically confirmed resectable stage II, IIIA, or selected IIIB (T3N2 only) NSCLC patients. A global phase II, open-label, multicenter study evaluating the safety and efficacy of the neoadjuvants and adjuvants atezolizumab (Atezo) plus tiragolumab (Tira) with or without (Chemo). This study provides proof-of-concept clinical data that neoadjuvant treatment with Atezo + Tira or Atezo + Tira + Chemo is safe, tolerable, and has no clinically significant negative effects on surgical outcomes in patients with early resectable NSCLC. Designed to establish This study is also designed to assess the potential anti-tumor effects of the neoadjuvants Atezo+Tira or Atezo+Tira+Chemo as measured by significant pathological response (MPR). The trial is designed with the flexibility to open new cohorts as new treatment combinations become available.

The study treatments administered are shown in Table 55. In this protocol, "study treatment" refers to the treatment combination assigned to a patient as part of this study (ie, Atezo+Tira, Atezo+Tira+Chemo, or chemotherapy).

Figure 19 shows an overview of the study plan. Patients are assigned to cohorts based on PD-L1 status and receive treatment as follows.

Cohort A (PD-L1 High): 4 cycles of neoadjuvant Atezo + Tira followed by surgical excision and either 16 cycles of adjuvant Atezo + Tira or 4 cycles of adjuvant chemotherapy.

Cohort B (PD-L1 all comers): 4 cycles of neoadjuvant Atezo+Tira+Chemo followed by 16 cycles of surgical excision and adjuvant Atezo+Tira.

The choice of platinum-based chemotherapy regimen is at the investigator's discretion, based on histologic subtype and documented at initiation. The following platinum-based chemotherapy options are allowed in this trial:
●For non-squamous NSCLC:
- cisplatin + pemetrexed - carboplatin + pemetrexed - carboplatin + paclitaxel For squamous NSCLC:
- cisplatin + gemcitabine - carboplatin + gemcitabine - carboplatin + paclitaxel

Surgical specimens will be evaluated for pathologic response (MPR and pathologic complete response (pCR)) by an independent central pathology laboratory as well as by the investigator's institutional pathology laboratory. In addition, exploratory biomarker analyzes can be performed on surviving surgical specimens (primary tumor tissue and resected lymph nodes).

Postoperative radiation therapy (PORT) is acceptable for patients with confirmed pathological N2+ disease or positive tumor margins present at surgical resection (ypN2 and/or R1/R2) prior to adjuvant Atezo+Tira treatment or adjuvant Must be administered after platinum-based chemotherapeutic agents.

All patients had scheduled tumor assessments of the chest and abdomen by both computed tomography (CT) and positron emission tomography (PET) at screening and by CT only after cycles 2 and 4 of neoadjuvant treatment. to complete. Tumor assessment will continue until recurrence after surgery. If disease follow-up assessments show evidence of disease recurrence, it must be confirmed pathologically and/or by clear radiological evidence from scans. If the scan shows clear findings (e.g., mediastinal nodes measure <1.5 cm on the short axis and pulmonary parenchymal or visceral lesions measure <1 cm on the longest diameter), the patient is considered alive. should be examined. A biopsy must be performed before starting the next anticancer therapy. If a biopsy is performed to confirm disease recurrence, it is strongly recommended that the remaining biopsy tissue be submitted for exploratory biomarker research. If biopsy is not feasible or safe, confirmatory scans should be repeated in 4-8 weeks.

If the biopsy shows no evidence of disease recurrence (eg, non-malignant infiltrates), the patient may continue with scheduled study treatment, evaluation and/or follow-up. In the absence of disease recurrence, disease follow-up assessment should continue until disease recurrence, withdrawal of consent, death, loss of follow-up, or sponsor termination of the study, whichever occurs first.

All patients undergo safety, tolerability and exploratory assessments on Day 1 of each cycle in the neoadjuvant treatment phase (both cohorts) and the adjuvant treatment phase. After treatment discontinuation, patients are followed up regularly for survival status and any additional anti-cancer treatment. Safety assessment should include the incidence, nature and severity of adverse events, protocol-specified vital signs, laboratory abnormalities, and other protocol considerations considered important to the safety assessment of the study. including tests specified in the Adverse events will be graded by the investigator according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (v5.0).

Archived and fresh tumor and/or lymph node tissue and patient samples including serum, plasma and blood will be collected for future exploratory biomarker assessments. In addition, patients are provided the opportunity to consent to the collection of any stool for exploratory microbiota studies.

The specific objectives and corresponding endpoints of this study are outlined in Table 56.

B. Treatment Allocation and Safety Lead-in Patients must be eligible for curative R0 extraction at screening and must meet all eligibility criteria specified herein. Patients who do not meet the entry criteria for this study (screen failure) may be eligible for two rescreening opportunities (a total of 3 screens per participant) at the investigator's discretion.

After providing treatment assignment and safety lead-in informed consent based on tumor PD-L1 status, patients underwent SP263 immunohistochemistry (IHC), a central assessment of PD-L1 status by tumor cell (TC)-based assay. undergo screening procedures, including

Enrollment was completed in stages as follows (see Figure 20), with approximately 41 patients enrolled in each cohort:

1. First there is the safety lead-in.
- Six patients with tumors with a PD-L1 Tumor Proportion Score (TPS) > 50% at screening will be enrolled in Cohort A (PD-L1 High Cohort).
- Cohort B (PD-L1 all-comer cohort) will start with enrollment of 6 patients with tumors with PD-L1 TPS<50%.

2. Evaluate the safety of each cohort and if considered safe:
- Patients including patients with tumors with PD-L1 TPS ≥50% will be enrolled in Cohort B (PD-L1 all comer) only.
- The remainder of Cohort B patients then includes 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 (PD-L1 all comers), enrollment resumed in Cohort A (PD-L1 high) and PD- All subsequent patients with tumors with L1 TPS≧50% will be enrolled in the cohort.

Safety lead-in Approximately 6 patients completed neoadjuvant treatment, suspending enrollment within each cohort to account for potential surgical delays, malignant transformation or complications associated with the study procedure and allow safety assessment after surgery is completed or after a change in surgical plan. Cohorts will not be enrolled at the same rate and each cohort will be evaluated separately and independently.

Safety evaluations are based on safety and surgical data. Based on review of the data, it is recommended to continue enrolling in the cohort or terminate the cohort. During the safety lead-in period, patients may be replaced if they do not proceed to surgery for reasons other than special concerns or adverse events of disease progression.

Surgery and Adjuvant Treatment Patients will undergo surgical excision of the tumor upon completion of 4 cycles of neoadjuvant therapy. Prior to surgery, the attending physician and medical oncologist will reassess the patient.

A preoperative visit should occur within 30 days after the last dose of neoadjuvant treatment; Practice should be followed. Surgery should be performed within 30 days of the preoperative visit if judged clinically feasible by both the attending physician and the medical oncologist.

Patients with disease progression at scheduled tumor assessments (after Cycles 2 and 4) or at any time during neoadjuvant treatment and still considered resectable and non-metastatic were included in all study treatments and If suitable for evaluation and remains eligible, proceed to surgery.

If the investigator plans to proceed to surgery in the absence of disease progression before completing all four cycles of neoadjuvant treatment, the medical monitor should be consulted.

Patients who discontinue neoadjuvant treatment early due to disease progression and do not proceed to surgery will be discontinued from additional clinical trial procedures and proceed to receive other treatments as determined by the investigator. Such patients remain in the study for survival follow-up. For patients responding to neoadjuvant therapy but not proceeding to surgery due to unforeseen medical problems (e.g., pulmonary embolism or myocardial infarction), patients will receive chemotherapy (Cohort A [PD-L1 high]) or continue protocol-specified treatments such as Atezo + Tira (Cohort A or B) and radiotherapy.

After surgical excision, patients continue to receive adjuvant Atezo + Tira or adjuvant chemotherapy (Cohort A [PD-L1 high] only) until one of the following occurs: up to 4 cycles of adjuvant per local standard of care (SOC). Administration of chemotherapy, 16 cycles of adjuvant Atezo+Tira, unacceptable toxicity, disease recurrence, death, or patient and/or physician decision to discontinue study treatment.

Study End and Study Duration The end of the study was defined as the date of the last patient's last visit, which occurs approximately three years after the last patient received the last dose of study drug after surgery.

The total length of the trial from initial patient screening to study termination is approximately 5-6 years.

C. Rationale for Study Design This study evaluates the surgical safety and feasibility of Atezo+Tira or Atezo+Tira+Chemo as a neoadjuvant treatment for previously untreated patients with locally advanced NSCLC. This study also evaluates the efficacy, pharmacokinetics, immunogenicity and safety of neoadjuvant Atezo+Tira or Atezo+Tira+Chemo followed by adjuvant Atezo+Tira or adjuvant chemotherapy.

Atezolizumab + Tiragolumab Dose and Schedule Rationale Atezolizumab is a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 21-day cycle), the approved dose of atezolizumab, as outlined in the prescribing information. administered at Antitumor activity has been observed over doses ranging from 1 mg/kg to 20 mg/kg Q 3 W. In study GO27381 (PCD 4989 g), the maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicity (DLT) was observed at any dose. Based on both nonclinical studies (Deng et al., MAbs, 8:593-603, 2016) and available clinical pharmacokinetic, efficacy and safety data, a fixed dose of 1200 mg Q3W (mean body weight-based A dose of 15 mg/kg Q3W) was selected.

Tiragolumab is administered intravenously at a fixed dose of 600 mg Q3W on Day 1 of each 21-day cycle. A fixed dose of tiragolumab 600 mg IV Q3W was selected based on available clinical pharmacokinetic, efficacy, and safety data from the GO30103 study in which patients received single-agent tiragolumab or tiragolumab plus atezolizumab. In study GO30103, the maximum tolerated dose was not reached and no DLT in combination with tiragolumab monotherapy or atezolizumab 1200 mg Q3W (tiragolumab dose range of 2-1200 mg Q3W) was observed. Complete occupancy of peripheral TIGIT receptors on CD4+, CD8+ and NK cells was observed starting at the 30 mg Q3W tiragolumab dose level and remained sustained at all higher doses. When administered in combination with atezolizumab 1200 mg Q3W, anti-tumor activity (as assessed by radiation partial response (PR)) was observed for tiragolumab in the dose range of 30-600 mg Q3W.

In the Phase II GO40290 trial, all patients enrolled in the atezolizumab plus tiragolumab arm received 600 mg tiragolumab. At this dose, tiragolumab was well tolerated and the combination of atezolizumab plus tiragolumab resulted in clinically significant improvement in PFS and higher ORR compared to placebo in combination with atezolizumab. Given the favorable benefit-risk ratio observed at 600 mg, this same dose of tiragolumab will be used in this study.

Patient Population Rationale This trial will enroll patients with resectable stage II, IIIA and select screen-determined IIIB (T3N2 only) NSCLC. Patients with tumors with high PD-L1 expression (TPS≧50% as determined by immunohistochemistry [IHC] with SP 263 in a central laboratory) are enrolled in Cohort A (PD-L1 high), while , all participants (regardless of PD-L1 expression level) will be enrolled in Cohort B (PD-L1 all comers).

Neoadjuvant and adjuvant chemotherapy have shown significant but moderate benefit for patients with early resectable NSCLC, but there is a substantial unmet need for improved outcomes in this treatment setting. still exists.

Killing tumor cells by cytotoxic chemotherapy can expose the immune system to high levels of tumor antigens. Boosting tumor-specific T cell immunity in this setting by blocking the PD-L1 and TIGIT pathways could result in deeper and more durable responses than those observed with standard chemotherapy alone (Merritt et al. et al., J Thorac Cardiovasc Surg, 126:1609-1617, 2003; Apetoh et al., Nat Med, 13:1050-1059, 2007), which could reasonably occur in tumors regardless of PD-L1 expression. .

Given the strong data from CITISCAPE showing the magnitude of benefit in the PD-L1 TPS≧50% population and the need to improve survival and reduce recurrence rates in resectable early-stage NSCLC patients, this trial will examine the efficacy of the combination of Atezo + Tira as a non-chemotherapy option. A chemotherapy-free option for patients with resectable NSCLC could be a landmark improvement for the patient, without the early and late toxicities associated with platinum-based chemotherapy. deaf.

Rationale for Pathological Response as Primary Endpoint The primary efficacy objective of the study was resectable Stage II, To evaluate the efficacy of neoadjuvant treatment with Atezo+Tira or Atezo+Tira+Chemo in patients with IIIA or selected IIIB (T3N2 only) NSCLC.

While overall survival (OS) is the standard for evaluating clinical utility in adjuvant and neoadjuvant NSCLC trials, OS readouts often take many years, especially in early-stage disease. . Employing meaningful surrogate endpoints can therefore expedite the evaluation of new treatments and bring new treatments to NSCLC patients sooner. Pathological response after surgical resection of NSCLC has been proposed as a surrogate endpoint for OS (Hellmann et al., Lancet Oncol, 15:e42-50, 2014). Hellmann et al. (2014) cited the US Food and Drug Administration's (FDA) definition of an alternative endpoint in which the endpoint should be "very likely to predict clinical benefit." They argue that using pathological response in the neoadjuvant setting meets this definition based on three observations: 1) pathological response is strongly correlated with OS; Response reflects neoadjuvant chemotherapy; 3) degree of pathological response correlates with degree of OS benefit.

The use of pathological response as a surrogate endpoint is not without precedent. Pathologic complete response (pCR) is used to assess efficacy of neoadjuvant treatment in breast cancer trials. However, pCR rates are variable in neoadjuvant NSCLC studies. Furthermore, the relatively low pCR rates reported in NSCLC may not translate into clinically significant OS benefits, thus limiting the usefulness of pCR as a surrogate survival endpoint in NSCLC trials. Indeed, few studies have reported survival data as a result of pCR in NSCLC due to the low rate of pCR (median rate 4%) (Hellmann et al., Lancet Oncol, 15:e42-50, 2014).

Instead of pCR, Hellman et al. proposed the use of MPR, defined as ≤10% viable tumor tissue, as a survival surrogate for resectable NSCLC patients undergoing neoadjuvant chemotherapy treatment (Hellmann et al., Lancet Oncol, 15:e42- 50, 2014). This is based on a study in which investigators examined other definitions of pathologic response, including residual viable tumor as a surrogate survival endpoint, in recognition of the rarity of pCR in NSCLC. Junker et al. (J Cancer Res Clin Oncol, 123:469-477, 1997) reviewed 40 tumors from patients with stage IIIA and IIIB disease who underwent a series of neoadjuvant chemotherapy treatments, chemoradiation, and surgical excision. pathological analysis was performed. Patients in this group with <10% residual tumor had a median survival of 36 months, and those with >10% residual viable tumor tissue had a median survival of 14 months.

Two prospective studies reported an MPR rate of approximately 22% with neoadjuvant chemotherapy in NSCLC. In the first study, among 90 patients with stage IIIA disease who received neoadjuvant chemotherapy (cisplatin + docetaxel), the median pathological response (amount of tumor necrosis and fibrosis) was < 60%. with a median OS of 61 months compared to 22 months in patients with 60% pathological response (Betticher et al., Br J Cancer, 94(8):1099-1106). , 2006). Another study showed that among 50 patients who received neoadjuvant chemotherapy (cisplatin + docetaxel) in combination with bevacizumab, patients with MPR were compared with those who did not achieve MPR (61 vs. 22 months, respectively). have been shown to have significantly longer 3-year survival rates in comparison (Chaft et al., J Thorac Oncol, 8:1084-1090, 2013). A retrospective study from the MD Anderson Cancer Center by William and colleagues (William et al., J Thorac Oncol, 8:222-228, 2013) found that MPR was a stronger predictor of OS than the Clinical Response Evaluation Criteria (RECIST) response in solid tumors.

Sponsors believe there is a strong rationale for using MPR as a surrogate endpoint, based on its correlation with the magnitude of improvement in OS. A global Phase III neoadjuvant registry trial of chemotherapy plus a PD-L1/PD-1 inhibitor versus chemotherapy alone evaluating MPR as a primary or secondary objective is currently underway. The use of MPR as a surrogate endpoint has the potential to enhance the effectiveness of clinical trials and accelerate new treatments for NSCLC patients.

Example 10. Materials and Methods for the GO42501 Trial Approximately 82 patients with stage II, IIIA or selected IIIB (T3N2 only) will be enrolled in the GO42501 trial.

A. Inclusion Criteria Patients must meet the inclusion criteria listed below to be eligible for study participation:
- Age ≥ 18 years at the time of signing the informed consent document - Ability to comply with the study protocol - Histologically or cytologically confirmed stage II, IIIA, or squamous or non-squamous tissue Select IIIB (T3N2 only) non-small cell lung cancer (NSCLC). Staging should be based on the 8th edition of the American Joint Committee on Cancer/Union International Contre le Cancer NSCLC staging system.
- Patients with T4 primary NSCLC are eligible based on size (tumor >7 cm) only. Patients with separate tumor nodule involvement of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerves, esophagus, vertebral bodies, tracheal carina, and different ipsilateral lobes are not eligible.
- NSCLC patients with mixed histology (squamous and non-squamous) must be eligible and classified based on the major histologic component (non-squamous or squamous).

Patients can be screened based on clinical stage, but for PET-positive N2 lymph nodes, N2 by invasive mediastinal staging (e.g., CT-guided biopsy, endobronchial ultrasound, mediastinoscopy) Mandatory preoperative documentation of nodal involvement is required. Preoperative staging of level 5 and level 6 nodes is optional.
• Appearance of solid or subsolid form of NSCLC on CT scan without appearance of pure ground-glass opacity (GGO). For subsolid lesions, tumor size (ie, clinical T stage) should be measured based on the solid component only, excluding the GGO component.
• Eligible for curative R0 extraction at screening and confirmed by the attending physician and participating medical oncologist prior to study enrollment.
Sufficient pulmonary function (including lung volume, spirometry and diffusing capacity) to be eligible for curative surgical resection as assessed by pulmonary function test (PFT) within 6 months of planned resection and repeated at Screening if clinically indicated, which meets at least 1 of the following criteria:
- Post-operative prediction (ppo) forced expiratory volume in 1 second (FEV1) and lung ppo diffusing capacity for carbon monoxide (DL _CO ) >40%.
- Maximum oxygen consumption (VO ₂ max) ≧15 mL/kg/min.

If either o ppoFEV ₁ or ppoDL _CO <40% or if pneumonectomy is planned, cardiopulmonary exercise testing must be performed and VO ₂ max ≧15 mL/kg/min. must.

o If PFTs were performed 6 months before the planned extirpation or were not previously performed, they must be performed during the screening period.
• Eligibility to receive a platinum-based chemotherapy regimen. The WARNINGS and PRECAUTIONS sections of the prescribing information for each individual chemotherapeutic treatment (ie, carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) in each patient's intended regimen are used to determine eligibility.
• Measurable disease as assessed by the investigator according to RECIST v 1.1.
• Availability of representative tumor specimens suitable for determination of PD-L1 status and other exploratory biomarkers by central laboratory.
• US East Coast Cancer Clinical Trials Group (ECOG) performance status of 0 or 1 • Normal life expectancy, excluding lung cancer mortality risk.
- Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:
- Absolute neutrophil count (ANC) ≥ 1.5 x ¹⁰⁹ /L (1500/μL) without the support of granulocyte colony stimulating factor.
- Lymphocyte count ≧0.5×10 ⁹ /L (500/μL).
- Platelet count ≧100×10 ⁹ /L (100,000/μL) without transfusion.
- Hemoglobin > 90 g/L (9 g/dL). Patients can be transfused to meet this criterion.
- Aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) < 2.5X upper limit of normal (ULN).
- total bilirubin ≤ 1.5 X ULN, except: patients with known Gilbert's disease: total bilirubin ≤ 3 X ULN.
- Creatinine clearance ≧45 mL/min (calculated using the Cockcroft-Gault formula). Patients intending to receive cisplatin: creatinine clearance ≧60 mL/min.
- Serum albumin ≥25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5XULN
• Patients on therapeutic anticoagulants: stable anticoagulant regimen • Negative HIV test at screening.
- Hepatitis B surface antigen (HBsAg) test negative at screening - Hepatitis B surface antibody (HBsAb) positive test at screening or HBsAb negative at screening with any of the following:
- total hepatitis B core antibody (HBcAb) negative - positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA <500 IU/mL Only performed for patients with a positive HBcAb test.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening. HCV RNA testing is performed only for patients who test positive for HCV antibodies.
• For women of childbearing potential: consent to abstinence (abstinence from heterosexual intercourse) or use of contraception, and consent to refrain from donating eggs.
●For men: Consent to abstinence (refrain from sexual intercourse with the opposite sex) or consent to use condoms, and consent to refrain from donating sperm.

B. Exclusion Criteria Patients meeting any of the criteria listed below will be excluded from study participation:
- NSCLC with large cell neuroendocrine carcinoma, sarcomatoid carcinoma, or NSCLC histology not otherwise specified.
- Histology of small cell lung cancer (SCLC) or NSCLC with any component of SCLC.
• A disease or condition that may interfere with the patient's ability to understand, comply with, and/or comply with study procedures.
- Any prior treatment for lung cancer, including immunotherapy, chemotherapy, or radiation therapy.
Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis Active or history of autoimmune disease or immunodeficiency activity, including but not limited to, excluding: patients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormones are eligible for testing. Patients with controlled type 1 diabetes on an insulin regimen are eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following conditions are met: is.
- The rash must cover <10% of body surface area.
- Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UVA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors within the past 12 months , or no acute exacerbation of underlying symptoms requiring high-potency or oral corticosteroids Idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia, or history of idiopathic interstitial pneumonia or evidence of active interstitial pneumonia on screening chest CT scan.
● Active tuberculosis.
- Significant cardiovascular disease (New York Heart Association Class II or greater heart disease, myocardial infarction, cerebrovascular accident, etc.), unstable arrhythmia or unstable angina pectoris within 3 months prior to initiation of study treatment.
• Major surgery within 4 weeks prior to initiation of study treatment, or anticipation of need for major surgery during study • NSCLC with activating EGFR mutation or ALK fusion oncogene. For patients with non-squamous NSCLC histology: EGFR and/or ALK status is unknown, requiring investigation at screening. ALK and/or EGFR status can be assessed locally or submitted to a central laboratory.
• A known c-ros oncogene 1 (ROS1) rearrangement. ROS1 testing at screening is not required for study entry; however, patients with known ROS1 rearrangements are excluded.
Appropriately treated cervical carcinoma in situ, nonmelanoma cutaneous carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer with negligible risk of metastasis or death (e.g., 5-year OS rate >90%) History of malignancy other than NSCLC within 5 years prior to screening, excluding malignancies.
- Severe infection (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia) within 4 weeks prior to initiation of study treatment, or opinion of investigator Any active infection that may affect patient safety.
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment be;
- Prior allogeneic stem cell or solid organ transplantation - Any other disease, metabolic dysfunction, physical examination findings, or laboratory findings that contraindicate study drug use may affect interpretation of results or may put the patient at increased risk of procedural complications.
- Treatment with a live-attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such vaccine during study treatment, within 90 days after last dose of tiragolumab, or within 5 months after last dose of atezolizumab treatment with live attenuated vaccines. Patients being treated with chemotherapy (ie carboplatin, cisplatin, pemetrexed, paclitaxel or gemcitabine) should not receive live vaccines.
• Current treatment with antiviral therapy for HBV.
• Positive Epstein-Barr virus (EBV) virus capsid antigen immunoglobulin M (IgM) test at screening. EBV PCR testing should be performed when clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.
- Treatment with study therapy within 42 days prior to initiation of study treatment.
- Pretreatment with CD137 agonist or immune checkpoint blockade therapy 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 or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
- Systemic immunosuppressants (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-tumor necrosis factor-α [TNF] within 2 weeks prior to initiation of study treatment, with the following exceptions - Prediction of the need for systemic immunosuppressive drugs during treatment with (including α] agents) or study treatment:
- Patients who received acute low-dose systemic immunosuppressants or single pulse doses of systemic immunosuppressants (eg, 48-hour corticosteroids for contrast allergy) are eligible for the study.
- patients who have received mineralocorticoids (e.g. fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency Eligible for testing.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese Hamster Ovary Cell Products or any component of the atezolizumab or tiragolumab formulations.
• Known allergy or hypersensitivity to any component of the chemotherapy regimen that the patient may experience during the study.
Pregnancy or lactation, or intention to become pregnant during the study treatment, within 90 days after the last dose of tiragolumab, within 5 months after the last dose of atezolizumab, or within 6 months after the last dose of pemetrexed, gemcitabine, paclitaxel, carboplatin, or cisplatin. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

C. Treatment Allocation This study is an open-label study.
Patients with high PD-L1 expression (TPS≧50% as determined by SP 263 IHC in the central laboratory) were enrolled in Cohort A (PD-L1 High) and all comers (PD-L1 regardless of expression level) will be enrolled in Cohort B (PD-L1 all comers). Enrollment was completed in stages as follows (see Figure 20), with approximately 41 patients enrolled in each cohort:

1. First there is the safety lead-in:
- Six patients with tumors with PD-L1 TPS > 50% at screening will be enrolled in cohort A (PD-L1 high cohort).
- Cohort B (PD-L1 all-comer cohort) will start with enrollment of 6 patients with tumors with PD-L1 TPS<50%.

2. Evaluate the safety of each cohort and if considered safe:
- Patients including patients with tumors with PD-L1 TPS ≥50% will be enrolled in Cohort B (PD-L1 all comer) only.
- The remainder of Cohort B patients then includes 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 (PD-L1 all comers), enrollment resumed in Cohort A (PD-L1 high) and PD- All subsequent patients with tumors with L1 TPS≧50% will be enrolled in the cohort.

D. Study Treatment Dosage, Administration and Compliance

Each study treatment component is administered at the dose and frequency specified in Table 57.

The neoadjuvant treatment phase consisted of 4 cycles of Atezo+Tira or Atezo+Tira+Chemo. The duration of each cycle is 21 days. On Day 1 of each cycle, all eligible patients will receive study drug infusions in the following order.
• Cohort A (PD-L1 high): (1) atezolizumab, (2) tiragolumab.
• Cohort B (PD-L1 all comers): Investigator will receive one of the listed regimens based on histologic subtype and local SOC.
- (1) atezolizumab, (2) tiragolumab, (3) paclitaxel, (4) carboplatin - (1) atezolizumab, (2) tiragolumab, (3) pemetrexed, (4) (carboplatin or cisplatin)
- (1) atezolizumab, (2) tiragolumab, (3) gemcitabine, (4) (carboplatin or cisplatin)

Atezolizumab (1200 mg) and tiragolumab (600 mg) will be administered at fixed doses. Patients will receive the first dose of study treatment on the day of enrollment if possible. If treatment on the day of enrollment is not possible, the first dose will be administered within 5 days after enrollment.

No premedication for primary prophylaxis (antihistamines, antipyretics and/or analgesics) for atezolizumab and tiragolumab is allowed in Cycle 1. Patients should receive antiemetics and IV hydration for their chosen chemotherapy backbone regimen according to the local SOC and manufacturer's instructions. However, due to the immunomodulatory effects of corticosteroids, premedication with corticosteroids should be minimized to the extent clinically feasible.

Adjuvant treatment with Atezo+Tira is initiated within 14-60 days after surgery or within 7-42 days after the last PORT treatment. If adjuvant chemotherapy is administered, treatment is initiated within 28-72 days after surgery, followed by PORT (if selected) within 21-60 days after adjuvant chemotherapy. During postoperative adjuvant treatment, infusions will be administered in the following order (one regimen per patient). Selection of the Cohort A (PD-L1 High) regimen is at the investigator's discretion for each patient.

• Cohort A (PD-L1 High): Investigator will administer one of the regimens listed below.
- (1) atezolizumab, (2) tiragolumab - (1) paclitaxel, (2) carboplatin - (1) pemetrexed, (2) (carboplatin or cisplatin)
- (1) gemcitabine, (2) (carboplatin or cisplatin)
- Cohort B (PD-L1 all comers): (1) atezolizumab, (2) tiragolumab

Atezolizumab and Tiragolumab Atezolizumab is administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. The dose of atezolizumab is fixed and independent of body weight. No dose reduction is allowed.

After administration of atezolizumab and an observation period, patients receive 600 mg of tiragolumab administered by IV infusion on Day 1 of each 21-day cycle. The tiragolumab dose is fixed and independent of body weight. No dose reduction is allowed.

Administration of study treatment will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions. Infusion of atezolizumab and tiragolumab

Administered according to the instructions outlined in Table 58.

Atezolizumab and Tiragolumab Dose Delays Unless atezolizumab or tiragolumab are permanently discontinued, the following rules apply:
• Treatment cycles generally begin with administration of atezolizumab and tiragolumab on Day 1 of each 21-day cycle. Because the safety profiles of atezolizumab and tiragolumab are similar if any study drug is delayed due to associated toxicity, it is recommended that the other study drug be delayed as well.
- If the administration of one study drug is delayed for drug-related toxicity and the other study drug is administered as planned, the delayed 21-day cycles) are recommended.

Chemotherapy centers should follow the information below and local prescribing information. In general, institutions should also follow institutional and local SOCs to determine dose adjustments in the event of patient weight change. If a treatment cycle is delayed or interrupted due to toxicity due to either component of the chemotherapy regimen, both chemotherapy components should be held and when restarted both remain synchronized should be reopened for

Paclitaxel Asian race/ethnicity patients receive a lower starting dose of paclitaxel at 175 mg/m ² IV over 3 hours. The lower starting dose of paclitaxel for patients of Asian race/ethnicity was based on the higher overall incidence of hematologic toxicity in patients from Asian countries compared with patients from non-Asian countries, which was supported by independent data monitoring. Observed during the safety review of the IMpower 150 and IMpower 131 trial results by the panel. The term "Asian race/ethnicity" refers to a pan-ethnic/ethnic group that includes diverse populations living in or having ancestral origins in East Asia, Southeast Asia, or South Asia. The applicability of this term in a particular patient is at the discretion of the treating investigator and should be based on the patient's clinical characteristics and country of origin.

Paclitaxel injections must be diluted prior to injection. Paclitaxel is diluted with 0.9% sodium chloride USP; 5% dextrose injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP, or 5% dextrose at a final concentration of 0.3-1. 2 mg/mL should be added to Ringer's Injection. The injection site must be closely monitored for possible infiltration during drug administration.

Contact of undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or equipment used to prepare infusion solutions is not recommended. Paclitaxel must be administered through an in-line filter with a microporous membrane of 0.22 μm or less. The use of filter devices such as the IVEX-2® filter incorporating short inlet and outlet PVC-clad tubes did not result in significant leakage of bis(2-ethylhexyl) phthalate.

Sites should follow institutional SOC guidelines to determine paclitaxel dose adjustments in the event of patient weight change. For paclitaxel infusions, an exception to the 3-hour infusion time is allowed for sites with institutional policies to infuse paclitaxel more quickly (over 90 minutes) or more slowly (up to 4 hours for the first infusion). .

Pemetrexed Institutions should follow standard administration procedures for pemetrexed. Administration of pemetrexed should be administered by IV infusion over at least 10 minutes. The pre-medication dose administered should comply with the prescribing information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with a long drug elimination half-life for at least 5 days before, on the day of, and at least 2 days after pemetrexed administration.

Gemcitabine Gemcitabine must 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 and before cisplatin (Table 57). Gemcitabine must be diluted prior to infusion.

The recommended diluent for reconstitution of gemcitabine is 0.9% preservative-free sodium chloride injection, USP. Gemcitabine should be administered according to local clinical practice and prescribing information.

Carboplatin Carboplatin was administered by IV infusion over 15-30 minutes immediately after completion of paclitaxel or pemetrexed administration and by local clinical practice to achieve a concentration-time curve (AUC) of 6 mg/mL/min (Calvert dosing). It should be administered with standard antiemetics according to guidelines.

A Carboplatin dose of AUC 6 mg/mL/min is calculated using the Calvert formula (Calvert et al., J Clin Oncol, 7:1748-1756, 1989):
Total Dose (mg) = (Target AUC) X (Glomerular Filtration Rate [GFR] + 25)

The GFR used in the Calvert formula to calculate AUC-based dose should not exceed 125 mL/min. For the purposes of this study, GFR is considered equivalent to creatinine clearance (CrCl). CrCl is calculated according to institutional guidelines or the following method.
Cockcroft and Gault (Nephron, 16:31-41, (1976)) using the following formula:
For females, CrCl = ((140-age)(weight)/(72XScr)) X 0.85
where: CrCl = creatinine clearance in mL/min; age = patient age; wt = patient weight in kg;
Scr = serum creatinine in g/dL

For patients with abnormally low serum creatinine levels, a minimum creatinine level of 0.8 mg/dL should be used to estimate GFR or limit estimated GFR at 125 mL/min. When a patient's GFR is estimated based on serum creatinine measurements by isotope dilution mass spectrometry, the FDA recommends that physicians use carboplatin for the desired exposure (AUC) to avoid potential toxicity from overdose. We recommend that you consider dose capping. Based on the Calvert formula described in the carboplatin label, the maximum dose can be calculated as follows.
Maximum Carboplatin Dose (mg) = Target AUC (mg min/mL) (GFRX 25 mL/min)

Maximum dose is based on GFR estimates capped at 125 mL/min for patients with normal renal function. Higher estimated GFR values should not be used. For target AUC=6, the maximum dose is 6×(125+25)=900 mg. For target AUC=5, the maximum dose is 5×(125+25)=750 mg. For target AUC=4, the maximum dose is 4×(125+25)=600 mg.

Cisplatin Cisplatin is administered by IV infusion at a dose of 75 mg/m ² over 1-2 hours or as per SOC at the center approximately 30 minutes after completion of the pemetrexed or gemcitabine infusion. Patients must receive adequate antiemetic treatment and adequate hydration prior to and after administration of cisplatin.

E. surgical planning

An attending physician with experience with early resectable NSCLC will evaluate the patient at screening to determine surgical suitability and eligibility for surgical excision. Patients must be eligible for curative R0 extraction at screening. No intent to downgrade to make the patient operable is permitted.

At screening, patients must be confirmed for surgical suitability based on pulmonary function testing (PFT) as outlined in the inclusion criteria. ppoFEV ₁ and ppoDL _CO are calculated using the following methodology (Brunelli et al., Chest, 143(5Suppl): e166S-e190S, 2013):
Perfusion method (lung ventilation/perfusion scan (VQ scan):
ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ or DL _CO X(1−x)
where x = percentage of total perfusion of the resected lung Anatomical method:
ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ or DLCOX (1 - (y/z))
where y = number of functional or non-obstructive lung segments to be removed; z = 19, total number of functional lung segments. It should be noted that the total number of functional lung segments (19) is 10 segments in the right lung (3 upper, 2 middle and 5 lower lobes) and 9 segments in the left lung (5 upper and 5 lower lobes). and four in the lower lobe).

Patients will be reassessed after completion of neoadjuvant treatment and prior to surgery by the surgeon and medical oncologist. Preoperative evaluations, including but not limited to blood tests, coagulation, cardiac tests or PFT (if specified), anesthesia evaluations, and other evaluation procedures should be performed for each local SOC.

Surgical procedures should be performed within 30 days of the preoperative visit whenever possible. If surgery cannot be performed within this time frame (eg, due to long-term adverse events), a medical monitor should be consulted. If surgery is planned more than 30 days from the preoperative visit, a repeat CT scan should be obtained prior to the planned surgery.

Extraction should be accomplished by an open or minimally invasive procedure (eg, thoracotomy, sternotomy, clamshell or hemiclamshell incision, or video-assisted thoracic surgery [VATS] or robot-assisted VATS).

Complete pathologic resection of the primary tumor and involved lymph nodes (R0) should be performed. Anatomical excision by segmentectomy, lobectomy, bilobectomy, or pneumonectomy is required. For all excisions, all anatomical segments (eg, arteries, bronchi, veins) must be included. Wedge resection is not permitted. Deep wedge resections, including areas that do not provide the aforementioned anatomical details (eg, wedge resections of the apical or superior areas), do not count as segmentectomy.

Hilar and mediastinal lymphadenectomy or sampling is mandatory. For right-sided resections, this includes at least the lymph nodes at levels 4R, 7, 10R and 11R.

Inclusion of level 2R lymph nodes is recommended. For left-sided resections, this includes at least the lymph nodes at levels 5/6, 7, 10L and 11L. For lower lobe extractions, inclusion of level 8 or 9 is recommended.

F. Postoperative Radiation Therapy Postoperative radiation therapy (PORT) is tolerated in patients with confirmed pathological N2+ disease (ypN2) or positive tumor margins (R1 or R2) present at the time of surgical excision, with adjuvant It must be administered before certain Atezo+Tira treatments or after adjuvant platinum-based chemotherapeutic agents.

Conformal 3D or intensity-modulated radiation therapy to recommended doses of 50-66 Grays (Gy) in fractions of 1.8-2 Gy should be administered according to institutional and/or international guidelines. Strongly recommended constraints include mean dose to lung < 20 Gy and V20 (percentage of lung volume receiving 20 Gy or more radiation dose) not exceeding 31% after lobectomy, or 8 Gy and V20 < 5 after pneumonectomy. % mean lung dose is included.

G. Combination therapy

Concomitant therapy includes any drug used by the patient (e.g., prescription drug, over-the-counter drug, vaccine, herbal or homeopathic remedies, dietary supplements).

Allowed Treatments Patients will be allowed to use the following treatments during the study.
● Oral contraceptives with <1% annual failure rate ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable-dose warfarin or low-molecular-weight heparin)
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
• Corticosteroids administered for COPD or asthma.
Low-dose corticosteroids given for orthostatic hypotension or adrenocortical insufficiency

Premedication with antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent atezolizumab infusions, at the discretion of the Investigator.

In general, investigators should manage patient care (including pre-existing symptoms) with supportive care other than those defined as attention or prohibitive care, as clinically indicated, and in accordance with local standard practice. be.

Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine) or equivalent drugs according to local standard practice. can be done. Serious infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, desaturation, or dyspnea should be treated with supportive care as clinically indicated (e.g., supplemental oxygen and β2- should be managed with adrenergic agonists).

Cautionary Therapy for Patients Treated with Atezolizumab and Tiragolumab Corticosteroids and TNFα Inhibitors Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab . Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines must be considered. If alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors can be administered at the investigator's discretion.

Systemic corticosteroids are recommended at the investigator's discretion for treatment of specific adverse events when associated with atezolizumab and/or tiragolumab therapy.

Prohibited Therapies The use of the following concomitant therapies is prohibited as described below:
• Combination therapies for the treatment of cancer (including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy), if approved by health authorities. Depending on the drug, whether experimental, it is prohibited for various periods of time before starting study treatment and during study treatment until disease progression is documented and the patient discontinues study treatment.
• Study treatment within 42 days prior to initiation of study treatment and during study treatment.
• Live attenuated vaccines (eg, FLUMIST®) are prohibited within 4 weeks prior to initiation of study treatment, during study treatment, 90 days after the last dose of tiragolumab, and 5 months after the last dose of atezolizumab. Patients being treated with chemotherapy (ie carboplatin, cisplatin, pemetrexed, paclitaxel or gemcitabine) should not receive live vaccines.
Due to the potential increased risk of autoimmune symptoms when administered in combination with atezolizumab and tiragolumab, no more than 4 weeks or 5 drug elimination half-lives (either within 4 weeks prior to initiation of study treatment and during study treatment) or longer) are prohibited (including but not limited to interferon and IL-2).
- Systemic immunosuppressants (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment (because drugs can potentially alter the efficacy and safety of study treatment)

H. Study Assessment Patients will be closely monitored for safety and tolerability throughout the study. Patients should be assessed for toxicity prior to each dose and doses administered only if clinical evaluation and local laboratory values are acceptable.

All treatment visits must occur ±3 days from the scheduled date unless otherwise specified. All assessments must be performed on the designated visits unless a time frame is designated. Patients should be assessed for toxicity prior to each dose and doses administered only if clinical evaluation and local laboratory values are acceptable. Assessments scheduled on the day of study treatment administration must be performed prior to dosing unless otherwise specified.

The following assessments can be performed ≤4 days prior to Day 1 of each cycle:
● limited physical examination ● local clinical examination

Screening assessments performed ≤4 days prior to Day 1 of Cycle 1 need not be repeated on Day 1 of Cycle 1, except for tumor screening.

If holidays, weekends, or other events interfere with scheduled dosing, dosing may be postponed to the next earliest day and subsequent dosing may continue on the 21-day schedule. If treatment is delayed for less than 3 days, the patient can resume their original schedule.

I. Follow-up Assessment of Tumor Response and Disease Status During the postoperative and adjuvant treatment phases, follow-up assessment of disease status will be performed from the day of surgery by chest CT (including liver and adrenal glands) with IV contrast for the first year. Every 4 months, then every 6 months for the second year, in all patients (both cohorts). If a CT scan with contrast is contraindicated (eg, in patients with impaired renal clearance), a non-contrast CT scan of the chest can be performed. Patients who have not experienced recurrence of disease have a follow-up assessment of disease status every 6 months by chest CT scan (including liver and adrenal glands) with IV contrast for 3-5 years afterward.

Follow-up assessments of disease status must occur within the acceptable timeframe for scheduled follow-up assessments. The timeframes allowed for disease status follow-up assessment are ±7 days at year 1, ±14 days at years 2-3, and ±4 weeks thereafter.

Disease recurrence after surgery must be confirmed pathologically and/or by clear radiological evidence. If the scan shows clear findings (e.g., mediastinal nodes measure <1.5 cm on the short axis and pulmonary parenchymal or visceral lesions measure <1 cm on the longest diameter), the patient is considered alive. should be examined. If biopsy is not feasible or safe, confirmatory scans should be repeated in 4-8 weeks. If a confirmatory scan confirms disease recurrence, the event must be documented on the date of the previous confirmatory examination that showed an equivocal event.

A biopsy must be performed before starting the next anticancer therapy. If the biopsy shows no evidence of disease recurrence (eg, non-malignant infiltrates), the patient may continue with scheduled study treatment, evaluation and/or follow-up.

Follow-up assessment of tumor or disease status should continue in patients who discontinue treatment prematurely for reasons other than disease progression or recurrence (eg, due to toxicity). In the absence of disease progression or recurrence, follow-up assessment of tumor or disease status should include disease progression or recurrence, withdrawal of consent, and death in all patients, whether or not new anticancer therapy is initiated. , loss of follow-up, or termination of the study by the sponsor, whichever occurs first.

J. Discontinuation of Study Treatment Patients must permanently discontinue study treatment if they experience any of the following:
- Unacceptable toxicities associated with atezolizumab or tiragolumab, including the occurrence of immune-mediated adverse events that the investigator judged to be unacceptable given the individual patient's potential response to treatment and severity of events Neoadjuvant treatment Chemotherapy may be continued if atezolizumab and tiragolumab are discontinued during the phase.
• Unacceptable toxicity associated with other components of the study treatment. If any or all chemotherapy agents are discontinued due to chemotherapy-related toxicity during the neoadjuvant treatment phase, Atezo+Tira should still be administered.
• Any medical condition that may jeopardize patient safety if the patient continues study treatment.
• Investigator's or sponsor's judgment that discontinuation of treatment would be most beneficial to the patient • Use of another non-protocol prescribed anti-cancer therapy.
● Pregnancy.
• Heterogeneous radiographic disease progression by RECIST v1.1 during the neoadjuvant treatment phase.
• Pathologically confirmed or clear radiological evidence of disease recurrence during the adjuvant treatment phase.

Patients who receive at least 2 cycles of neoadjuvant treatment and discontinue study treatment prematurely are not replaced. Patients receiving less than 2 cycles of neoadjuvant treatment can be replaced if the reason for early treatment discontinuation is not a particularly notable adverse event or disease progression.

Patients who discontinue neoadjuvant study treatment before receiving 4 cycles (e.g., due to treatment intolerance or lack of response) may undergo surgical excision or non-surgical standard-of-care treatment regimens (if not suitable for surgery). It will be assessed by the treating oncologist and attending physician. Patients who proceed with surgery as specified in the planned protocol remain eligible for all post-operative study treatments and procedures.

Patients return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study treatment. Visits where disease assessment indicates progressive disease or confirms disease recurrence may be used as discontinuation visits. Patients who discontinue study treatment for any reason other than progressive disease or recurrence continue to undergo tumor or disease status assessments.

Example 11. SAFETY ASSESSMENT OF THE GO42501 STUDY A. safety plan

The patient safety plan for this study includes the expected mechanism of action, results of nonclinical studies, published data on similar molecules, and clinical experience with tiragolumab alone and in combination with atezolizumab in phase I and II trials. , as well as the clinical safety profile of atezolizumab.

Measures are taken to ensure the safety of patients entering this study, including the use of strict inclusion and exclusion criteria, and close monitoring of patients during the study. Atezolizumab and tiragolumab are administered in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

B. Management of Adverse Events Dose Modifications There were no dose modifications, including dose reductions, for atezolizumab or tiragolumab in the study.

Treatment Interruption Study treatment may be temporarily withheld as necessary to manage toxicity. Based on available characterization of mechanism of action, tiragolumab may cause similar but unrelated adverse events to atezolizumab and may exacerbate the frequency or severity of atezolizumab-related adverse events. , or may have toxicities that do not overlap with atezolizumab. Because these scenarios may be indistinguishable from one another in clinical practice, immune-mediated adverse events can generally be attributed to both study drugs, and dose interruptions or treatment discontinuations in response to immune-mediated adverse events are atezolizumab and Should apply to both tiragolumab.

In the adjuvant setting, atezolizumab and tiragolumab may be maintained for up to 12 weeks. If tiragolumab is discontinued for >12 weeks for any reason, patients must permanently discontinue tiragolumab treatment, but without contraindications, to determine if toxicity is considered related to tiragolumab and/or the combination. After discussion, atezolizumab can be continued. Exceptions can be made if, at the investigator's discretion, the patient is likely to gain clinical benefit from resuming tiragolumab after >12 weeks of hold. In this case, tiragolumab may be restarted. If atezolizumab is discontinued for >12 weeks, patients must permanently discontinue atezolizumab.

However, atezolizumab may be restarted if, at the investigator's discretion, the patient is likely to gain clinical benefit from atezolizumab after >12 weeks of hold. All other study eligibility criteria must continue to be met for patients to continue receiving single-agent atezolizumab.

Continuation of single-agent tiragolumab after permanent discontinuation of atezolizumab is not permitted.

Atezolizumab and/or tiragolumab may be held longer than >12 weeks from the last dose if the patient must be tapered off steroids used to treat the adverse event, and tiragolumab is It may be held longer than ≧12 weeks from the last dose until the steroid is discontinued or the steroid is reduced to a prednisone dose (or dose equivalent) ≦10 mg/day. Dose interruptions for reason(s) other than toxicity may be tolerated. After discontinuing both study treatments, patients are monitored for safety and efficacy.

C. Safety parameters and definitions

Safety assessment includes monitoring and recording of adverse events (including serious adverse events and adverse events of particular interest), conducting protocol-specified safety laboratory evaluations, and protocol-specified vital signs. and other protocol-specified studies considered important to the safety evaluation of the study.

Adverse Event According to the ICH Guidelines for Good Clinical Practice, an adverse event is any untoward medical occurrence in a clinical trial subject administered a drug, regardless of the causal attribute. Adverse events can therefore be any of the following:
any unfavorable and unintended signs (including abnormal laboratory findings), symptoms or diseases temporally related to the use of the drug, whether or not considered drug-related, new disease or exacerbation of an existing disease ( exacerbation of known symptom characteristics, frequency, or severity)
• Intermittent recurrence of medical symptoms (e.g., headache) not present at baseline • Laboratory values or other laboratory tests related to symptoms or leading to change in study treatment or concomitant therapy, or discontinuation from study treatment (e.g., ECG, X-ray) Protocol-specified intervention-related adverse events, e.g., occurring prior to study treatment assignment (e.g., screening for invasive procedures such as biopsies)

Serious Adverse Event A serious adverse event is any adverse event that meets any of the following criteria:
• Fatal (ie, the adverse event actually causes or leads to death).
• Life-threatening (ie, the adverse event puts the patient at immediate risk of death from the investigator's perspective). This does not include adverse events that may have caused death if they occurred or continued in more severe forms.
• Require or prolong hospitalization of inpatients.
• Result in persistent or significant disability/incapacity (ie, the adverse event results in substantial disruption of the patient's ability to perform normal life functions).
• Congenital anomalies/birth defects in neonates/infants born to mothers exposed to the study treatment.
Is a significant medical event in the investigator's judgment (e.g., may endanger the patient or require medical/surgical intervention to prevent one of the consequences listed above) there's a possibility that).

The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe, or according to the NCI CTCAE) and the event itself may be relatively medically insignificant (further findings severe headache without pain, etc.).

Adverse Events of Special Note Adverse events of particular note for this study were:
• Cases of potential drug-induced liver injury, including elevated ALT or AST in combination with either elevated bilirubin or clinical jaundice, as defined by Hy's law.
Suspected transmission of infectious agents by study procedures defined below:

Any pathogenic or non-pathogenic organism, virus or infectious particle (eg, the prion protein that transmits infectious spongiform encephalopathy) is considered an infectious agent. Transmission of infectious agents can be suspected from clinical symptoms or laboratory findings indicative of infection in patients exposed to the drug. This term applies only when contamination of the study procedure is suspected.
● interstitial pneumonia ● colitis ● endocrine insufficiency: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and hypophysitis.
- Hepatitis with AST or ALT>10XULN.
● Systemic lupus erythematosus.
• Neuropathy: Guillain-Barré syndrome, myasthenia syndrome or myasthenia gravis, and meningoencephalitis.
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome.
- Nephritis.
o ocular toxicity (eg uveitis, retinitis, optic neuritis);
●Myositis.
• Myopathy, including rhabdomyolysis.
• Cardiac disorders of grade ≧2 (eg, atrial fibrillation, myocarditis, pericarditis).
• Vasculitis.
● Autoimmune hemolytic anemia.
• Severe skin reactions (eg Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrolysis).

Adverse Event Severity Rating The NCI CTCAE (v5.0) Adverse Event Severity Rating Scale is used to rate adverse event severity. The American Society for Transplantation and Cell Therapy (ASTCT) CRS consensus grading scale should be used in addition to the NCI CTCAE v5.0 when reporting the severity of CRS.

Example 12. Statistical Considerations and Analytical Plan for the GO42501 Study Efficacy and safety analyzes will be performed in all patients enrolled in the GO42501 study who received at least one dose of study drug for each cohort.

Determination of sample size The primary efficacy objective of this study is to assess the significant pathological response (MPR) rate. Approximately 41 patients will be enrolled in each cohort of the trial. Assuming an observed MPR rate of 61%, this sample size provides sufficient precision for point estimates of the MPR rate in each cohort with a lower bound of 46% for the two-sided 95% CI, and this ratio is Further investigation of combination therapy in this setting may be warranted.

Summary of study conduct Summarize the number of patients entering, withdrawing from, or completing the study. List and summarize reasons for early study termination. Enrollment and major protocol deviations are listed for each treatment cohort.

A. Summarize demographic and baseline characteristics.
Aggregate demographic information such as age and race. Descriptive statistics including mean, standard deviation, and range for continuous parameters and percentages and frequencies for categorical parameters are presented. Summaries are presented for the overall population and each treatment cohort. Baseline measurements are the last available data obtained before the patient received their first dose of any component of study drug, unless otherwise stated.

B. Safety analysis

For each cohort, safety analyzes include all enrolled patients who receive at least one dose of study treatment.

Summarize study treatment exposure, including duration of treatment, dosage and dose intensity.

The incidence and length of surgical delays associated with study treatment, the incidence of surgical and postoperative complications, and/or the number of surgical cancellations will be assessed for each cohort.

Verbal descriptions of adverse events are mapped to MedDRA thesaurus terms. The severity of all adverse events will be graded by the investigator according to the NCI CTCAE v5.0, and the severity of CRS will also be graded by the investigator according to the ASTCT consensus grading scale. These summaries are presented by treatment group. All adverse events will be summarized by treatment group and NCI CTCAE grade. CRS is also summarized by treatment group and ASTCT consensus grade. In addition, treatment-emergent adverse events related to study treatment, severe (i.e., grade ≥ 3 adverse events), fatal adverse events (i.e., Grade 5), and serious adverse events and adverse events of particular interest are also summarized. Multiple occurrences of the same event are counted once at maximum severity. Experimental data with values outside the normal range are identified. In addition, selected experimental data, including ADA results, and changes in vital signs are summarized by treatment arm. Summarize deaths and causes of death.

C. Effectiveness analysis

The efficacy analysis population includes all enrolled patients who received at least one dose of study treatment.

Primary Efficacy Endpoints MPR rate, defined as the proportion of patients achieving MPR, is estimated for each treatment cohort in the efficacy analysis population. MPR is defined as ≤10% residual viable tumor at surgical excision in the primary tumor, as assessed by the Central Pathology Laboratory. Patients who do not proceed to surgery are considered non-responders to MPR. Two-sided 95% CIs for MPR rates calculated using the Clopper-Pearson method are reported.

Secondary Efficacy Endpoints Pathologic complete response (pCR) rate is defined as the proportion of patients achieving pCR. pCR is defined as the absence of a viable primary tumor at the time of surgical excision, as assessed by a central pathology laboratory. pCR rates are analyzed using the same statistical methods as MPR rates for each treatment cohort for the efficacy analysis population.

Symptom-free survival (EFS) is defined as the time from the first dose of study drug to the first occurrence (whichever occurs first) of any of the following: Investigator according to RECIST v 1.1 Physician-assessed disease progression precluding surgery; local or distant disease recurrence (including new primary NSCLC development); or death from any cause. Patients who have not experienced disease progression precluding surgery, local or distant disease recurrence, or who die at the time of analysis will be censored at the last tumor or disease follow-up assessment. Patients with no post-baseline tumor assessment will be censored on the date of the first dose of study drug. EFS will be assessed using the Kaplan-Meier method for each treatment cohort in the efficacy analysis population.

D. Pharmacokinetic analysis

Samples are collected for PK analysis and exposures in this study are compared to exposures obtained in previous studies. Serum concentrations of tiatezolizumab and tiragolumab are reported as individual values and summarized by cohort and cycle where appropriate and data permit (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean). mean coefficient of variation).

Individual serum and median serum concentrations of atezolizumab and tiragolumab are plotted by cohort and day. Atezolizumab and tiragolumab concentration data can be pooled with data from other studies using established population PK models to derive data-assured PK parameters such as clearance, volume of distribution and AUC. . Potential correlations between relevant PK parameters and safety, efficacy or biomarker outcomes can be examined.

E. Immunogenicity analysis

Immunogenicity analyzes include patients who have received any anti-drug antibody (ADA) assessment and group patients according to the treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients for both atezolizumab and tiragolumab are summarized by cohort. Relationships between ADA status and safety, efficacy and PK endpoints can be analyzed and reported by descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analyzes are conducted to investigate the relationship between multiple pathological, immunological, and genomic characteristics of cancer and clinical outcome in these patients. These analyzes 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, will be analyzed in biomarker subgroups (eg, based on PD-L1 and TIGIT status) to assess treatment benefit, if feasible.

Example 13. Efficacy of Anti-TIGIT Antagonist Antibodies in Combination with PD-1 Axis Binding Antagonists in Patients With Cervical Cancer Metastatic and/or relapse after progression or relapse from at least one platinum-based but no more than two prior systemic treatments PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atezolizumab) in patients with cervical cancer that are PD-L1-positive (tumor cells and tumor-associated immune cells [TIC] >5%) to assess the efficacy and safety of treatment with an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antibody disclosed herein, eg, tiragolumab) in combination with ) and atezolizumab monotherapy. To be eligible, patients must have an East Coast Cancer Trials Group (ECOG) performance status of 0 or 1 and 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.

Randomization In this trial, approximately 160 patients will be enrolled and assigned to one of two treatment arms of atezolizumab or tiragolumab in combination with atezolizumab monotherapy. Randomization is performed in a 3:1 ratio by using a permuted block randomization method to ensure balanced allocation to each treatment group. Randomization is stratified according to ECOG performance status (0 vs. 1), previous use of chemoradiation or radiotherapy (yes vs. no), and treatment history (persistent vs. recurrent disease).

Eligibility This study enrolls female patients with a minimum age of 18 years according to the following entry criteria:
- Tissues of the cervix (neuroendocrine, clear cell and sarcoma tissues are not allowed) after 1-2 prior systemic chemotherapy not amenable to curative treatment with systemic chemotherapy, surgery and/or radiotherapy Clinically confirmed recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.
- At least one prior platinum-based systemic chemotherapy - Cisplatin radiosensitization administered with radiotherapy is not considered a line of systemic chemotherapy.
- radiomeasurable disease - East Coast Cancer Trials Group (ECOG) performance status of 0 or 1 - cervical cancer tissue for study analysis (archived or fresh biopsy specimen)
- Life expectancy of at least 12 weeks - Adequate hematologic and organ function - Women of childbearing potential must be willing to adhere to adequate contraception

Patients are excluded from enrollment based on the following criteria:
- Treatment with a therapeutic investigational therapy within 28 days prior to randomization and during study treatment - Any central nervous system (CNS) or brain metastasis - Active or history of autoimmune disease or immunodeficiency - Active tuberculosis - Known of clinically significant liver disease - Investigator-determined severe infection at randomization - CD 137 agonist or immune checkpoint blockade therapy, anti-CTLA-4, anti-TIGIT, anti-PD-1 and anti-PD-L1 therapeutic antibodies Prior treatment - Treatment with systemic immunostimulants within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to randomization - Treatment with systemic immunosuppressants within 1 week prior to randomization, or study Prediction of need for systemic immunosuppressants during pregnancy - women who are pregnant or breastfeeding.
- Known hypersensitivity to any component of the tiragolumab or atezolizumab formulations

A. Study Treatment Dosage and Administration During treatment, patients receive a fixed dose of 1200 mg atezolizumab or a fixed dose of 1200 mg atezolizumab and a fixed dose of 600 mg tiragolumab. Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 21-day cycle). Tiragolumab in combination with atezolizumab will be administered to all patients in the experimental arm at a fixed dose of 600 mg IV Q3W on Day 1 of each 21-day cycle.

In another study, on dosing days, atezolizumab is administered as monotherapy according to the instructions outlined in Table 59. Prior to the first infusion, the patient's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) are recorded within 60 minutes of starting the infusion. The first infusion of atezolizumab is administered over 60 (±15) minutes, during which patient vital signs are 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 events are experienced during the first infusion. Pre-infusion recording of vital signs shall be maintained within 60 minutes prior to initiation of atezolizumab infusion.

In another study, on dosing days, atezolizumab is administered prior to tiragolumab according to the instructions outlined in Table 60. Prior to the first infusion, the patient's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) are recorded within 60 minutes of starting the infusion. The first infusion of atezolizumab is administered over 60 (±15) minutes, during which patient vital signs are recorded every 15 (±5) minutes during the infusion and 30 (±10) minutes after the infusion. The first infusion of an anti-TIGIT antibody (e.g., an anti-TIGIT antibody disclosed herein, e.g., tiragolumab) is administered over 60 (±10) minutes, during which the patient's vital signs are 15 ( Recorded every ±5) minutes and 30 (±10) minutes after injection. Subsequent infusions can be administered over 30 (±10) minutes if no infusion-related adverse events are experienced during the first infusion. Pre-infusion recording of vital signs shall be maintained within 60 minutes prior to initiation of atezolizumab infusion.

Treatment may be continued as long as the patient is experiencing clinical benefit in the absence of unacceptable toxicity or exacerbation due to disease progression after integrated assessment of radiographic data, biopsy results, and clinical status. Patients who meet criteria for equivocal disease progression according to RECIST v1.1 as determined by an Independent Review Committee (IRC) will continue treatment (atezolizumab or tiragolumab in combination with atezolizumab alone) if all specified criteria are met. is allowed.

B. Concomitant Therapies Certain combination therapies are permissible. Concomitant therapy includes protocol-defined study treatment from 7 days prior to the start of study treatment until the discontinuation visit, plus any medications the patient has used (e.g., oral contraceptives, hormone replacement therapy, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, dietary supplements). Patients are allowed to use the following concomitant therapies during the study.

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines must be considered. If alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors can be administered at the investigator's discretion.

Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent study treatment infusions, at the discretion of the Investigator.

C. Efficacy Endpoints Complete randomization on two consecutive occasions (investigator determined according to RECIST v 1.1) ≥4 weeks apart to assess the efficacy of tiragolumab in combination with atezolizumab compared to atezolizumab monotherapy. Objective response rate (ORR) with ORR defined as the proportion of patients experiencing a response (CR) or partial response (PR) is measured as the primary endpoint. The primary efficacy analysis will be performed after all patients have been enrolled and a minimum follow-up of approximately 6 months has been achieved among patients with ongoing ORR assessment follow-up. In the primary analysis, patients with missing ORR ratings are counted as not achieving a response. The ORR of tiragolumab in combination with the atezolizumab group is compared to historical references using a one-sample z-test for proportions. Estimates of the ORR and its 95% CI (Clopper-Pearson; Clopper and Pearson 1934) are calculated for each treatment group. The low end of the 95% CI for ORR in the combination group (Table 61) and the observed ORR in the monotherapy group (Table 62) are expected to be beyond the reference point.

The secondary efficacy objectives of this study were based on duration of response (DOR), disease control rate (DCR), best clinical response (BCR), progression-free survival (PFS), and overall survival (OS). To evaluate the efficacy of tiragolumab and atezolizumab monotherapy in combination with DOR is the date of disease progression from the first occurrence of a documented objective response (CR or PR) or any Defined as the time to date of death from cause (whichever occurs first). DCR is defined as the proportion of patients with CR, PR or SD as determined by IRC according to RECIST v1.1. BCR is defined as the proportion of patients with an investigator-determined CR, PR or SD. PFS is defined as the time from randomization to first occurrence of disease progression or death from any cause (whichever occurs first) as determined by IRC according to RECIST v1.1. OS is defined as the time from randomization to death from any cause.

Additional exploratory efficacy endpoints may further include investigator-determined disease control (defined as SD or CR or PR over ≧6 weeks) according to RECIST v1.1.

Adverse events (AEs) (e.g., the National Cancer Institute Common Terminology Criteria for Adverse Events) version 5.0 (AEs graded according to the NCI CTCAE v 5.0)) to measure the incidence, nature and severity of adverse events not specifically listed in the NCI CTCAE according to Table 63 Measure). The severity of cytokine release syndrome (CRS) is also determined according to the American Society for Transplantation and Cell Therapy CRS consensus grading scale. In addition, clinically significant changes in vital signs, physical examinations, and laboratory test results from baseline during and after administration of tiragolumab in combination with atezolizumab compared to atezolizumab monotherapy will also be measured.

The primary endpoint measure, objective response rate (ORR), is defined as the time frame from documented objective response to the date of disease progression or death from any cause (whichever occurs first) (up to 36 months). ). Timeframes for secondary outcome measurements are shown in Table 64.

D. Biomarkers Patient samples, including archived tumor tissue, as well as serum, plasma, whole blood and stool, will be collected for exploratory biomarker assessment of all patients in the randomized trial. In addition to assessment of PD-L1 status, biomarkers associated with tiragolumab and/or atezolizumab resistance, disease progression, and clinical benefit will be analyzed. For example, potential predictive and prognostic biomarkers associated with clinical benefit and safety of tiragolumab and/or atezolizumab are analyzed.

Tumor tissue and blood samples collected at baseline (or tumor tissue collected at disease progression, if deemed clinically feasible by the investigator) will be subjected to whole exome sequencing (WES) and/or next-generation sequencing. predicts response to a study treatment, is associated with progression to a more severe disease state, is associated with acquired resistance to a study treatment, is associated with susceptibility to the occurrence of adverse events, or Identify somatic mutations that can enhance our knowledge and understanding of disease biology.

Biomarkers include, but are not limited to, PD-L1 and/or TIGIT expression on tumor tissue, circulating tumor DNA in tumor tissue and/or blood identified by WGS and/or NGS (including but not limited to mutations). Germline and somatic mutations (including burden, MSI and MMR defects), analyzes of genes (e.g. CD274) or gene signatures associated with tumor immunobiology, e.g. _{T effector} genes, PD-L1, TIGIT, HPV Included are alterations, lymphocyte subpopulations, T cell receptor repertoire, cytokines associated with 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 primary patient populations, efficacy, safety, PK, immunogenicity, and patient-reported outcomes (PRO ) can be assessed between protein, RNA, DNA, tumor mutational burden, and other exploratory biomarkers in tumor tissue and/or blood. In addition, to assess the effect of the TIGIT pathway on ORR, PFS, DOR and/or OS in primary populations, ORR, DOR, PFS and OS were measured using tumors with TIGIT expression defined by protein and/or RNA expression. It can be evaluated in a patient population.

Exploratory biomarker analyzes can be performed in an attempt to understand the association between these markers (eg, TIGIT IHC status) and efficacy of study treatments. Efficacy outcomes can be investigated in a population of patients whose tumors have high TIGIT expression as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data will be conducted in the context of this trial and can be explored together with data from other trials to enhance researchers' understanding of disease pathobiology and guide the development of new therapeutic approaches. .

E. Immunogenicity Analysis To assess immune responses to tiragolumab and atezolizumab, the incidence of treatment-developed anti-drug antibodies (ADAs) and their potential impact on safety, efficacy and pharmacokinetics (PK) was evaluated. evaluate.

As of December 2019 in the Phase Ia portion of the GO30103 study, no treatment-developed anti-drug antibodies (ADA) to tiragolumab were detected. In the Phase Ib portion of the GO30103 trial, 3 of 154 (1.9%) evaluable patients were positive for treatment-emergent ADAs for tiragolumab. As of October 2019 in the GO40290 study, 1 of 66 (1.5%) patients evaluated were positive for emergent ADA on treatment for tiragolumab. As of October 2019 in the GO40290 study, 1 of 66 (1.5%) patients evaluated were positive for treatment-emergent ADAs for tiragolumab, and patients were positive at only one time point .

F. Pharmacokinetic Analysis To characterize the pharmacokinetics of tiragolumab when administered in combination with atezolizumab, serum concentrations of tiragolumab are determined from subjects at different time points. Additionally, plasma concentrations of atezolizumab are obtained from subjects at different time points during the study to characterize the pharmacokinetics of atezolizumab when atezolizumab is administered in combination with tiragolumab or as monotherapy.

Example 14. Phase 1b, open-label, multicenter study of the safety, efficacy, and pharmacokinetics of atezolizumab and tiragolumab in combination with chemotherapy in patients with triple-negative breast cancer. A Phase Ib, open-label, multi-center study designed to evaluate the safety, efficacy and pharmacokinetics of tiragolumab in combination with chemotherapy is described. This trial will consist of the following cohorts:
• Cohort B enrolls patients with clinically assessed T2-4d TNBC who are eligible for surgery (PD-L1 all-commr population). Patients are randomized in a 1:1 ratio to one of the following two treatment groups.
- Group A: tiragolumab in combination with atezolizumab, nab-paclitaxel, and carboplatin, followed by tiragolumab in combination with atezolizumab, doxorubicin, and cyclophosphamide (termed tiragolumab and atezolizumab + nab-pac-carbo-AC)
- Arm B: atezolizumab, tiragolumab in combination with nab-paclitaxel, followed by atezolizumab, doxorubicin, and tiragolumab in combination with cyclophosphamide (termed tiragolumab and atezolizumab + nab-pac-AC)

In addition, AC and G-CSF (eg, filgrastim or pegfilgrastim) or GM-CSF are administered to patients in Cohort B as background treatment after nab-paclitaxel.

This study initially evaluated the neoadjuvant tiragolumab in combination with atezolizumab, nab-paclitaxel, and carboplatin, followed by atezolizumab, in combination with nab-paclitaxel, in patients eligible for surgery with clinically assessed T2-4d TNBC. It is designed to allow assessment of the safety and tolerability, preliminary efficacy, and pharmacokinetics of AC or the neoadjuvant tiragolumab followed by AC.

A. Study Design This Phase Ib, multicenter, open-label, multicenter global study will investigate atezolizumab, nab-paclitaxel in patients eligible for surgery with first clinically assessed T2-4d TNBC (PD-L1 all comer population). , and the neoadjuvant tiragolumab in combination with carboplatin, followed by doxorubicin and cyclophosphamide (AC), or atezolizumab, safety and tolerability with the neoadjuvant tiragolumab in combination with nab-paclitaxel, followed by AC, It is designed to investigate preliminary efficacy and pharmacokinetics. FIG. 22 shows the Cohort B study plan.

Consent and eligible patients will be randomized in a 1:1 ratio to one of the following two treatment groups:
- Group A (up to approximately 20 patients): tiragolumab (420 mg) and atezolizumab (840 mg) administered QW by IV infusion and nab-paclitaxel (125 mg/m ² ) administered Q3W by intravenous infusion administered Q2W for 4 cycles by IV infusion in combination with carboplatin (area under the concentration-time curve [AUC]: 5 mg/mL/min]), followed by granulocyte colony-stimulating factor (G-CSF; e.g., filgrastim) or pegfilgrastim) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with doxorubicin (60 mg/m ² ) and cyclophosphamide (600 mg/m ² ) by intravenous infusion with tiragolumab ( 420 mg) and atezolizumab (840 mg) are administered Q2W over 4 doses.
Arm B (up to approximately 20 patients): tiragolumab (420 mg) and atezolizumab (840 mg) administered by IV infusion Q2W in combination with nab-paclitaxel (125 mg/m ² ) administered by IV infusion QW for 12 weeks followed by doxorubicin (60 mg/m ² ) and cyclophosphamide (600 mg/m2) administered Q2W by IV infusion with G-CSF (eg, filgrastim or pegfilgrastim) or GM-CSF support. Tiragolumab (420 mg) and atezolizumab (840 mg) in combination with m ² ) are administered over 4 doses.

Exploratory endpoints (pathologic complete response (pCR); eradication of invasive tumor from both breast and lymph nodes (ypT0/is ypN0)) were evaluated in local recurrence after completion of neoadjuvant treatment and surgery. Established by review. Surgery should be performed no later than 14 days and no later than 6 weeks after the last dose of neoadjuvant therapy. Platelet counts should be confirmed prior to surgery and should be greater than or equal to 75,000 cells/μL.

Postoperative patient management may include radiotherapy if clinically indicated, and management of patients who do not achieve pCR should follow current standard of care guidelines.

Patients with clinically positive axillary lymph nodes as assessed by physical examination or any radiographic imaging at baseline will undergo fine-needle aspiration or core needle biopsy and lymphadenectomy prior to randomization. (ALND) or at least sentinel lymph node biopsy (SLNB) is recommended at the time of definitive surgery. Baseline fine needle aspiration or core needle biopsy results were used to determine lymph node staging (according to the Anatomic Stage Groups of the Union for International Cancer Control/American Joint Committee on Cancer [UICC/AJCC] 8th edition). , patients with positive biopsies should be staged as node-positive (N1-N3c), and patients with negative or equivocal biopsies should be node-negative (N0 ).

For patients with clinical or fine- or core-needle biopsy-proven negative axillary lymph nodes at baseline, axillary surgical management after completion of neoadjuvant therapy may include SLNB or ALND. If SLNB is performed, all patients with 2 or more lymph nodes (minimum 2-3) removed and sentinel node-positive bulky metastases should receive ALND regardless of the number of positive nodes is strongly recommended.

Patients undergo both clinical and radiological tumor assessments at scheduled intervals during the study.

To assess the mechanism of action and possible resistance mechanisms of the drug combination in the tumor microenvironment, tumor tissue may be collected on Day 1 of Cycle 2 prior to dosing.

Tumor tissue will be collected by biopsy as assessed and documented by the investigator and at the first evidence of disease progression (prior to initiation of new anticancer treatment) unless clinically infeasible. be. Samples are used to allow analysis of tumor tissue biomarkers associated with resistance or disease progression and clinical benefit of tiragolumab in combination with atezolizumab.

B. Dosing and Administration

The treatment regimen is summarized in FIG.

On the day of the scheduled infusion of atezolizumab, tiragolumab and chemotherapy, chemotherapy is administered after infusion of atezolizumab and tiragolumab.

After atezolizumab infusion (840 mg), patients receive 420 mg of tiragolumab.

Administration of atezolizumab, tiragolumab, and chemotherapy will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Refer to the Investigational Product Control Procedures for detailed instructions regarding formulation, storage, and administration.
Tiragolumab and atezolizumab

Patients in Cohort B received a fixed dose of 840 mg atezolizumab administered by IV infusion Q2W on days 1 and 15 of each 28-day cycle, followed by days 1 and 15 of each 28-day cycle. also received a fixed dose of 420 mg tiragolumab administered by IV infusion Q2W (see Figure 22). The doses of tiragolumab and atezolizumab are fixed and independent of body weight. Tiragolumab and atezolizumab infusions (including the observation period) will be administered according to the instructions outlined in Table 65.

Nab-paclitaxel Nab-paclitaxel is administered to patients as an IV infusion administered over 30 minutes.

Nab-paclitaxel should be administered after atezolizumab and tiragolumab. The dose of nab-paclitaxel is 125 mg/m ² and is administered to patients by IV infusion QW for 12 weeks. Doses of nab-paclitaxel should not be administered more frequently than every 7 days.

Sites must follow institutional standard of care for determining dose adjustments of nab-paclitaxel if patient weight changes. The injection site must be closely monitored for possible infiltration during study drug administration.

Refer to your local prescribing information for additional details regarding the preparation and administration of nab-paclitaxel.

Carboplatin Carboplatin will be administered after completion of nab-paclitaxel administration by brief IV infusion over 15-60 minutes to target an AUC of 5 mg/mL/min every 3 weeks for 4 doses.

There is no known antidote for carboplatin overdose. If necessary, patients may require supportive treatment for myelosuppression and impaired renal, hepatic and hearing function. Doses up to 1600 mg/m2 have been associated with extremely ill patients with diarrhea and alopecia. Use of carboplatin at doses higher than recommended has also been associated with vision loss. Refer to your local prescribing information for carboplatin for additional details.

Cyclophosphamide Cyclophosphamide should be given as an IV bolus over 3-5 minutes or as an IV infusion according to local standard of care. AC must be administered after atezolizumab and tiragolumab. The dose of cyclophosphamide is 600 mg/ ^m2 administered intravenously. Dose delays and dose reductions for toxicity are acceptable. Cyclophosphamide is administered in 4 doses (Dose Density AC) Q2W with either G-CSF or GM-CSF as indicated. Note: Oral cyclophosphamide is not allowed.

Prevention and treatment of chemotherapy-induced nausea and vomiting should be administered when clinically indicated. Because systemic corticosteroids may attenuate the potentially beneficial immunological effects of treatment with atezolizumab and tiragolumab, alternative agents should be considered when clinically feasible.

Refer to your local prescribing information for details regarding the preparation and administration of cyclophosphamide.

Doxorubicin Doxorubicin should be administered as an IV bolus over 3-5 minutes or as an IV infusion over 15-30 minutes according to local standard of care. AC must be administered after atezolizumab and tiragolumab. The dose of doxorubicin is 60 mg/ ^m2 administered to the patient by IV infusion. Dose delays and reduced toxicity are acceptable. Doxorubicin is administered Q2W for 4 doses (dose density AC) with G-CSF or GM-CSF support.

Refer to your local prescribing information for details regarding the preparation and administration of doxorubicin.

Premedication and Supportive Care In general, chemotherapy supportive care should be administered according to American Society of Clinical Oncology (ASCO), European Organization for Research and Treatment of Cancer (EORTC), or ESMO guidelines, or local standards of care.

Prevention and treatment of chemotherapy-induced nausea and vomiting should be administered when clinically indicated. Systemic corticosteroids may attenuate the potentially beneficial immunological effects of treatment with atezolizumab and tiragolumab, so unless clinically feasible, except for guidance provided in the protocol should consider alternative agents.

Prophylactic G-CSF or GM-CSF may be used to reduce the risk of hematologic toxicity according to local policy and is required during the AC portion of chemotherapy. Treatment of neutropenia with G-CSF or GM-CSF is permitted according to local policy.

Dose Modifications There were no dose modifications of atezolizumab or tiragolumab in this study. See Table 25 for administration of nab-paclitaxel (ie dose modification and treatment interruption rules). Refer to each agent's respective local prescribing information for guidelines regarding the management of carboplatin-, doxorubicin-, or cyclophosphamide-related toxicities (ie, dose modification and treatment interruption rules).

C. Combination therapy

Concomitant therapy includes any drug used by the patient (e.g., prescription drug, over-the-counter drug, vaccine, herbal or homeopathic remedies, dietary supplements).

Allowed Treatments Patients are allowed to use the following treatments during the study:
● Oral contraceptives with an annual failure rate of less than 1% ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable-dose warfarin or low molecular weight heparin)
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
o Corticosteroids given for chronic obstructive pulmonary disease or asthma o Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency o Bisphosphonates for the prevention of skeletal events o For the following: Palliative radiotherapy outlined (e.g. treatment of known bone metastases or symptomatic relief of pain):
Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with tiragolumab and atezolizumab may be continued during palliative radiotherapy. Treatment with nab-paclitaxel must be discontinued according to institutional standard of care.
- G-CSF (eg, filgrastim or pegfilgrastim) or GM-CSF treatment permitted for patients receiving chemotherapy (nab-paclitaxel) and required during the AC portion of chemotherapy

Primary prophylaxis should be administered to patients according to ASCO, EORTC, or ESMO guidelines or according to local standard practice (i.e., in patients ≥60 years and/or with comorbidities) (Smith et al. 2006 Crawford et al. 2010; Aapro et al. 2011).

Evidence supporting the use of long-acting (pegylated) forms of G-CSF in patients receiving weekly nab-paclitaxel is limited and investigators prefer conventional formulations of G-CSF should be considered.

Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent atezolizumab and tiragolumab infusions at the investigator's discretion.
Sensitive treatment

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines are considered. If alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors can be administered at the investigator's discretion.

Systemic corticosteroids are recommended at the investigator's discretion for treatment of specific adverse events when associated with atezolizumab therapy.

Prohibited Therapies The use of the following concomitant therapies is prohibited as described below:
Any health authority-approved or experimental combination therapy for the treatment of cancer (including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy). Concomitant therapy for various periods prior to initiation of study treatment, depending on drug, and during study treatment until disease progression is documented and patient discontinues study treatment, excluding palliative radiation therapy, regardless of - Study treatment within 28 days prior to initiation of study treatment and during study treatment - Live attenuated vaccine (e.g., FLUMIST®) within 4 weeks prior to initiation of study treatment, during atezolizumab treatment and 5 months after the last dose of study treatment ))
Due to the potential increased risk of autoimmune symptoms when administered in combination with atezolizumab and tiragolumab, no drug elimination half-lives (either within 4 weeks or 5 during study treatment) or longer), systemic immunostimulants (including but not limited to interferon and IL-2)
- Systemic immunosuppressants (including but not limited to azathioprine, methotrexate, and thalidomide) during study treatment (because these agents can potentially alter the efficacy and safety of atezolizumab and tiragolumab)

Additional Restrictions Related to Carboplatin Chemotherapy • Concomitant use of yellow fever vaccine is prohibited and vaccination with other live attenuated vaccines should be avoided.
• Killed or inactivated vaccines may be administered, but responses to such vaccines may be diminished.
• Concomitant use of phenytoin or fosphenytoin is not recommended due to the risk of exacerbation of convulsions, risk of increased toxicity, or loss of efficacy of cytotoxic drugs.
Caution should be exercised in concomitant use of the following drugs: cyclosporine, nephrotoxic or ototoxic agents (e.g. aminoglycosides, vancomycin, capreomycin and diuretics, e.g. loop diuretics [increased toxicity, exacerbated toxicity, or risk of cumulative toxicity]).
• Concurrent radiotherapy (given together or <7 days apart) should be avoided.

D. Inclusion Criteria Patients must meet the following general criteria for study entry:
A signed informed consent form Females and males ≥18 years of age at the time of signing the informed consent form Ability to comply with the study protocol ECOG performance status of 0 or 1 (see Appendix 5)
Adequate hematologic and end-organ function, defined as the following laboratory results obtained within 14 days prior to the start of study treatment (Day 1 of Cycle 1) - Prior to Day 1 of Cycle 12 ANC ≧1.5×109/L (1500/μL) without G-CSF support within weeks
- Lymphocyte count ≥0.5 X 109/L (≥500/μL)
- Platelet count ≥100 X 109/L (≥100,000/μL) without transfusion within 2 weeks prior to Cycle 1 Day 1
- Hemoglobin ≧90 g/L (≧9 g/dL).

Patients can receive blood transfusions or erythropoietic procedures to meet this criterion - AST, ALT, ALP ≤ 2.5X upper limit of normal (ULN)
- Serum bilirubin ≤ 1.5 XULN, except:
Known Gilbert's disease patients with serum bilirubin levels < 3XULN can be enrolled.
-INR and aPTT≤1.5XULN
This applies only to patients who have not received therapeutic anticoagulation therapy; patients receiving therapeutic anticoagulation therapy should be on a stable dose.
- Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula)
- serum albumin ≥25 g/L (≥2.5 g/dL)
• Negative HIV test at screening.
- Negative hepatitis B surface antigen (HBsAg) test at screening - Positive hepatitis B surface antibody (HBsAb) test at screening or negative HBsAb at screening with any of the following:
- total hepatitis B core antibody (HBcAb) negative - positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA <500 IU/mL

HBV DNA testing is performed only for patients with negative HBsAg, negative HBsAb, and positive total HBcAb tests.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening.

HCV RNA testing is performed only for patients who test positive for HCV antibodies.
For women of childbearing potential: Consent to abstinence (abstinence from heterosexual intercourse) or use of contraceptive methods, and consent to abstain from donating eggs, as defined below:

Women should be treated during treatment and for at least 5 months after the last dose of atezolizumab, 90 days after the last dose of tiragolumab, 1 month after the last dose of nab-paclitaxel, 6 months after the last dose of carboplatin or doxorubicin, or For 12 months after the last dose of Famide, whichever is later, must maintain abstinence or use a contraceptive method that results in a failure rate of <1% per year. Females should refrain from donating eggs during this same period.

Females are post-menopausal, have not reached a post-menopausal state (>12 consecutive months of amenorrhea, no other cause identified), and are surgically infertile (removal of ovaries and/or uterus). ) is considered to be of possible gestation.

Examples of methods of contraception with an annual failure rate of <1% include combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation, progestogens associated with inhibition of ovulation when used consistently and correctly. hormonal contraception alone, bilateral fallopian tube obstruction, male infertility; intrauterine devices; intrauterine hormone releasing systems; and sexual abstinence.

The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and normal lifestyle.

Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.

Women who wish to become pregnant after discontinuation of study treatment should seek advice regarding oocyte storage prior to initiation of study treatment due to the potential for irreversible infertility resulting from treatment with chemotherapy. .
For men: agreeing to maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and to abstain from donating sperm, as defined below:

For female partners of childbearing potential or pregnant, either during the treatment period and for 90 days after the last dose of tiragolumab or 6 months after the last dose of nab-paclitaxel, carboplatin, doxorubicin, or cyclophosphamide Later, men must maintain abstinence or use additional methods of contraception in conjunction with condoms that result in failure rates of <1% per year. Men must stop donating sperm during the same period.

The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle.

Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not acceptable methods of contraception.

Men who wish to have children after initiation of study treatment should seek advice on sperm storage prior to initiation of study treatment due to the potential for irreversible infertility resulting from treatment with chemotherapy.
• Females who are not postmenopausal (≥12 months of non-treatment-induced amenorrhea) or who have undergone surgical sterilization must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Patients must meet the following cancer-specific eligibility criteria for enrollment:
- Histologically documented TNBC (negative status for HER2, ER and PR as assessed by local laboratory)
HER2-negative is defined as either of the following (Wolff et al. 2018) by local laboratory assessment:
ISH unamplified (HER2 to CEP 17 ratio <2.0, or single-probe average HER2 gene copy number <4 signals/cell, or IHC 0 or IHC 1+ ER, and PgR-negative cells expressing hormone receptors in IHC analysis) is defined as <1% of

Patients with multifocal tumors (two or more separate tumors confined to the same quadrant as the primary tumor) are eligible if at least one focus is sampled as TNBC, confirmed locally, and documented. be.

Patients with multicentric tumors (multiple tumors involving two or more separate quadrants) are eligible if all individual lesions are sampled, confirmed locally, and documented as TNBC .
- Confirmed tumor PD-L1 assessment documented through central examination of representative FFPE tumor tissue specimens on paraffin blocks (preferred) or at least 20 unstained slides

Tumor tissue must be of good quality based on total tumor content and viable tumor content and assessed for PD-L1 expression as determined using the Ventana (SP142) PD-L1 IHC assay prior to enrollment. Positivity is defined as ≧1% of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells of any intensity as determined by a central laboratory. Patients whose tumor tissue was not evaluable for PD-L1 expression were not eligible.

If multiple tumor specimens are submitted, patients may be eligible if at least one specimen is evaluable for PD-L1. Acceptable samples include core needle biopsies (minimum of 3 cores) for deep tumor tissue, or excision, incision, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspirations, brushings, cell pellets from pleural effusions, bone metastases, and lavage fluid samples are not permitted.
- Primary breast tumor size >2 cm by at least one radiographic or clinical measurement - Stage at presentation: cT2-cT4, cN0-cN3, and cM0
Patient consent to undergo appropriate surgical management (e.g., including axillary lymph node surgery and partial or total mastectomy) after completion of neoadjuvant treatment Echocardiogram (ECHO) or multigated acquisition (MUGA) ) baseline left ventricular ejection fraction (LVEF) ≥53% as measured by scan

E. Exclusion Criteria Patients meeting any of the following criteria will be excluded from the study:
Pregnancy during study treatment, within 90 days after tiragolumab treatment, within 5 months after atezolizumab treatment, within 6 months after nab-paclitaxel, carboplatin or doxorubicin treatment, or within 12 months after cyclophosphamide treatment (whichever is longer) or breastfeeding, or intending to become pregnant

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
- Evidence of significant uncontrolled comorbidities that could affect interpretation of results, including protocol compliance or significant liver disease (e.g., cirrhosis, uncontrolled grand paroxysmal disorder, or superior vena cava syndrome) - Significant cardiovascular disease within 3 months prior to initiation of study treatment, e.g. New York heart disease (class II or greater), myocardial infarction, unstable arrhythmia or unstable angina pectoris

Patients with known LVEF <53% are excluded.

Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.
- Severe infection within 4 weeks prior to initiation of study treatment (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia)
- Treatment with oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving routine antibiotic prophylaxis (eg, to prevent exacerbation of chronic obstructive pulmonary disease or for tooth extraction) are eligible.
- Anticipation of need for major surgery within 28 days prior to initiation of study procedure or non-diagnostic major surgery during study

Placement of a central venous access catheter(s) (eg, ports, etc.) is not considered a major surgical procedure and is therefore acceptable.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, or fusion proteins.
Known hypersensitivity or allergy to any component of CHO cell-produced biologics or tiragolumab or atezolizumab preparations Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Active autoimmune disease including, but not limited to, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; or its medical history

Patients with a history of autoimmune-mediated hypothyroidism on stable doses of thyroid replacement hormone are eligible for this trial.

Patients with type 1 diabetes controlled on a stable insulin dosing regimen are eligible for this study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin symptoms only (e.g., no psoriatic arthritis) are allowed if they meet the following conditions:
- Rash must cover <10% body surface area - Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UV within the last 12 months No occurrence of acute exacerbation of underlying symptoms requiring A-irradiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids Prior allogeneic stem cell or solid organ transplantation Idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (ie, bronchiolitis obliterans, subclinical organizing pneumonia) on screening chest computed tomography (CT) scan History or evidence of active pneumonitis

A history of radiation pneumonitis (fibrosis) in the radiology area is acceptable.
●Positive EBV viral capsid antigen (VCA) IgM test at screening

To screen for active or suspected chronic active infection, an EBV polymerase chain reaction (PCR) test should be performed when clinically indicated.

Patients with a positive EBV PCR test are excluded.
- Active tuberculosis - Receiving a live-attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipating that such a live-attenuated vaccine will be needed during the study

Patients must agree not to receive a live attenuated vaccine (eg, FluMist®) within 28 days prior to initiation of study treatment, during treatment, or within 5 months after the final dose of study treatment.
- Pretreatment with a CD 137 agonist or immune checkpoint blockade therapy, including anti-CTLA-4, excluding anti-PD-1 or anti-PD-L1 therapeutic antibodies - Within 4 weeks prior to initiation of study treatment or 5 drug withdrawals of drug Treatment with systemic immunostimulants (including but not limited to interferon or IL-2) within half-life (whichever is longer) Systemic immunosuppressants (including but not limited to, Treatment with prednisone, dexamethasone, azathioprine, methotrexate, thalidomide and anti-tumor necrosis factor [anti-TNF] agents) or investigational systemic immunosuppressants expected to be required

Patients receiving acute low-dose systemic immunosuppressants (eg, a single dose of dexamethasone for nausea) may be enrolled in the study.

The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency is permissible. be.
● History of invasive breast cancer ● Stage IV (metastatic) breast cancer ● Prior systemic therapy for the treatment and prevention of breast cancer ● Previous treatment with anthracyclines, platinum or taxanes for any malignancy Note: non-pleomorphic LCIS ( Patients with no treatment or surgically treated) are eligible.
Synchronous bilateral invasive breast cancer Prior incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes Axillary lymph node dissection prior to initiation of neoadjuvant therapy Appropriately prepared cervix Carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, or stage I uterine cancer, unless the risk of metastasis or death is not negligible (e.g., >90% 5-year OS) history of other malignancies within 5 years prior to Screening history of cerebrovascular disease within 12 months prior to initiation of study treatment cardiopulmonary insufficiency defined as any of the following prior to initiation of study treatment:
- History of NCI CTCAE v 5.0 grade ≥ 3 symptomatic congestive heart failure or New York Heart Association class II or greater heart disease - Angina pectoris requiring antianginal medication, severe not controlled by appropriate medication cardiac arrhythmias, severe conduction abnormalities, or clinically significant valvular disease ventricular tachycardia], high-grade atrioventricular [AV] block [second-degree AV block type 2 [Mobitz 2], or third-degree AV block])
- Significant symptoms (grade ≥2) related to left ventricular dysfunction, arrhythmias or cardiac ischemia
- Myocardial infarction within 12 months prior to initiation of study treatment - Uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg)
- evidence of transmural infarction on ECG - requirement for oxygen therapy known allergy or hypersensitivity to components of nab-paclitaxel, cyclophosphamide, doxorubicin or carboplatin preparations known allergy to G-CSF or GM-CSF preparations or hypersensitivity

F. Analyzes Safety Analysis Patients will be randomized in a 1:1 ratio to one of two groups in Cohort B to assess the safety profile of atezolizumab + nab-pac-carbo-AC versus tiragolumab and atezolizumab + nab-pac + AC. . No formal statistical comparisons were made for the primary safety endpoints, and safety analyzes are descriptive. Therefore, no formal power calculation was performed. The sample size is considered sufficient to provide a descriptive safety analysis to assess the tolerability of atezolizumab+nab-pac-carbo-AC versus tiragolumab and atezolizumab+nab-pac-AC. The planned sample size allows the observation of adverse events with a true incidence of ≧10% with acceptable probabilities across each treatment group and both groups combined (see Table 66).

Safety assessment should include the incidence, nature and severity of adverse events, protocol-specified vital signs, laboratory abnormalities, and other protocol considerations considered important to the safety assessment of the study. including tests specified in the Adverse events are graded according to NCI CTCAE v5.0.

Safety is measured by the ADA and assessed by summaries of adverse events, laboratory test changes, vital sign changes, study treatment exposure and immunogenicity presented by treatment group.

Verbal descriptions of adverse events are mapped to MedDRA terminology.

A treatment-emergent event (defined as an event occurring at or after the first dose of study treatment), regardless of relationship to study drug as assessed by the Investigator, is a MedDRA term, an appropriate MedDRA level, and summarized by the NCI CTCAE v5.0 grade. For each patient, if multiple occurrences of the same adverse event occur, the maximum severity reported will be used for summaries.

The following treatment-emergent adverse events will be summarized separately: adverse events leading to discontinuation of study drug, adverse events leading to dose reduction or interruption, grade ≥3 adverse events, grade 5 adverse events, serious Adverse Events and Adverse Events of Special Interest.

Summarize all deaths and causes of death.

Relevant laboratory values are summarized by time point and NCI CTCAE Grade 3 and Grade 4 values are identified as appropriate. Changes in NCI CTCAE grades will be summarized by treatment group.
Analysis of exposure, adverse events, laboratory and vital signs data

Safety will be assessed through summaries of exposure to study treatment, adverse events, laboratory changes, and changes in vital signs and ECG.

Study treatment exposure (eg, duration of treatment, total dose received, and number of cycles and dose modifications) will be summarized by descriptive statistics.

All verbatim adverse event terms are mapped to MedDRA thesaurus terms and adverse event severity is graded according to the NCI CTCAE v5.0. All adverse events occurring at or after the first dose of study treatment (i.e., treatment-emergent adverse events), serious adverse events, adverse events leading to death, adverse events of special interest, and study treatment Adverse events leading to discontinuation of study will be summarized by mapped terms, appropriate synonym levels, and severity. For events of varying severity, the highest grade is used for summaries. Summarize deaths and causes of death.

Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data are displayed by time with grades identified as appropriate. In addition, baseline and post-baseline maximum severity grades will be summarized using a shift table of selected laboratory tests. Summarize changes in vital signs and ECG.

Efficacy Analysis The efficacy analysis used an ITT approach, enrolled patients were included in the analysis whether or not they received their assigned study drug, patients in Cohort B were assigned at randomization Grouped in a 1:1 ratio according to treatment. Analysis based on subsets of the ITT population can also be performed. Hypothesis tests are two-sided unless otherwise indicated.

The study efficacy objective for Cohort B is to investigate the efficacy of tiragolumab and atezolizumab + nab-pac-AC versus tiragolumab and atezolizumab + nab-pac-carbo-AC based on the following endpoints.
• pCR, defined as tumor eradication from both breast and lymph nodes (ypT0/ is ypN0).

This efficacy endpoint is established after completion of neoadjuvant treatment and surgery. Patients with missing pCR scores are counted as not achieving pCR.
• EFS, defined as the time from randomization to documented disease recurrence, progression, or death from any cause.

Patients who are asymptomatic at the time of analysis are censored on the last known alive and asymptomatic day.

Patients with no post-baseline information will be censored on the day of randomization.
• OS, defined as the time from randomization to the date of death from any cause.

Patients not reported dead at the time of analysis are censored on the date they were last known alive. Patients with no information after baseline will be censored at the date of randomization.

Pharmacokinetic Analysis Samples are collected for PK analysis and exposures in this study are compared to those obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab and plasma concentrations of nab-paclitaxel, carboplatin, doxorubicin and cyclophosphamide, where appropriate and data permitting, are reported as individual values by treatment arm and cycle and summarized (mean , standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Median individual and serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be pooled with data from other studies using established population PK models to derive data-assured PK parameters such as clearance, volume of distribution and AUC. . Potential correlations between relevant PK parameters and dose, safety, efficacy or biomarker outcomes can be examined.

Immunogenicity Analysis The immunogenicity analysis includes patients with any ADA assessment and groups the patients according to the treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients during treatment and the follow-up period are summarized by treatment group.

Relationships between ADA status and safety, efficacy and PK endpoints can be analyzed and reported using descriptive statistics.

Biomarker Analysis Although no formal statistical analysis of the exploratory biomarkers has been performed, the data can be analyzed in the context of this study and together with data from other studies.

Example 15. A phase II randomized, double-blind study of atezolizumab plus tiragolumab and atezolizumab plus placebo as first-line treatment in patients with recurrent/metastatic PD-L1-positive squamous cell carcinoma of the head and neck. A phase II randomization designed to evaluate the efficacy and safety of atezolizumab + tiragolumab and atezolizumab + placebo as first-line (1L) treatment in recurrent/metastatic PD-L1-positive squamous cell carcinoma (SCCHN) A double-blind global study is described. This study consists of the following groups:
Group A: Patients received a fixed dose of 1200 mg of atezolizumab administered by IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by IV infusion of Q3W. 600 mg fixed dose tiragolumab on Day 1 of each 21-day cycle.
Group B: Patients received 1200 mg fixed dose atezolizumab administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by placebo administered by IV infusion Q3W on each 21-day cycle. Received on the first day.

A. Study Design This Phase II, randomized, double-blind, global study is designed to evaluate the efficacy and safety of atezolizumab + tiragolumab and atezolizumab + placebo as 1L treatment in recurrent/metastatic PD-L1-positive SCCHN It is Eligible patients must have recurrent disease and/or metastatic PD-L1-positive SCCHN (tumor-associated immune cells (TIC) ≥5%) not amenable to local therapy with curative intent, and no recurrent/metastatic disease. Male and female patients aged 18 years and older with US East Coast Cancer Clinical Trials Group (ECOG) performance status of 0 or 1 who have not received prior systemic therapy are included.

During screening, tumor specimens from each potentially eligible patient were tested for PD-L1 as assessed by a central laboratory using the investigational VENTANA PD-L1 (SP 263) Companion Diagnostics (CDx) assay. Test prospectively for expression. Only PD-L1 positive patients with a centrally assessed TIC of ≥5% are eligible. PD-L1 expression is defined as PD-L1 low with TICs between 5% and 19% and PD-L1 high with TICs greater than or equal to 20%.

Eligible patients will be stratified by human papillomavirus (HPV) status for oropharyngeal cancer (HPV-positive oropharyngeal cancer: present vs. absent) and PD-L1 status (PD-L1: low vs. high). Enrollment in each PD-L1 subgroup (PD-L1 low [TIC 5%-19%] and PD-L1 high [TIC ≥ 20%]) is limited to approximately 55% of all planned enrollments (i.e. , about 66 patients).

Eligible patients are randomized in a 2:1 ratio to receive either atezolizumab plus tiragolumab (Arm A) or atezolizumab plus placebo (Arm B).

Group A: Patients received a fixed dose of 1200 mg of atezolizumab administered by IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by IV infusion of Q3W. 600 mg fixed dose tiragolumab on Day 1 of each 21-day cycle.

Group B: Patients received 1200 mg fixed dose atezolizumab administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by placebo administered by IV infusion Q3W on each 21-day cycle. Received on the first day.

Patients will have tumor assessments at baseline, every 6 weeks (±7 days) for the first 30 weeks after Day 1 of Cycle 1, and every 9 weeks (±7 days) after completion of the Week 30 tumor assessments. receive. Tumor assessment was based on radiological disease progression by RECIST v1.1 or loss of clinical benefit for patients continuing study treatment after radiographic disease progression by RECIST v1.1, withdrawal of consent, death or sponsor Continue as per schedule, regardless of treatment delays, until termination of the study by D, whichever occurs first. At the investigator's discretion, scans should be performed whenever progressive disease or loss of clinical benefit is suspected.

Patients who discontinue study treatment (for any reason, including but not limited to clinical decline or toxicity) in the absence of radiographic disease progression by RECIST v1.1 will have radiographic disease progression by RECIST v1.1. , scheduled tumor assessments will continue at the above frequency until withdrawal of consent, death, or sponsor termination of the study, whichever occurs first. In the absence of radiographic disease progression by RECIST v1.1, tumor assessment should continue regardless of whether the patient begins new anticancer therapy. Objective response at a single time point will be determined by the investigator according to RECIST v1.1.

Serum samples are collected to monitor atezolizumab and tiragolumab PK and to detect the presence of antibodies to atezolizumab and tiragolumab. Patient samples, including archival and fresh tumor tissue, plasma, and blood samples, are collected for exploratory biomarker assessment.

Safety assessments include other protocol-specified studies such as the incidence, nature and severity of adverse events, and laboratory abnormalities considered important to the study's safety assessment.

After discontinuation of study treatment, survival follow-up information will be obtained by telephone, patient medical records, and/or clinic visit approximately every 3 months until death, loss of follow-up, or termination of the study by the sponsor, whichever occurs first. Collected by hospital visit. All patients will be discontinued for survival and new anticancer therapy information unless the patient requests withdrawal from survival follow-up (this request must be documented in the source document and signed by the investigator). You will be contacted regularly. If a patient is withdrawn from survival follow-up, study staff can obtain information on survival status using publicly available sources (eg, county records).

Treatment will be clinically assessed by the investigator if there is no unacceptable toxicity or exacerbation due to disease progression after integrated assessment of radiographic data, biopsy results (if available), and clinical status. It can be continued as long as the patient experiences the benefits. Patients who meet criteria for disease progression by RECIST v 1.1 but continue to have clinical benefit will be treated (atezolizumab + tiragolumab or atezolizumab + placebo) if they meet all outlined criteria and provide written informed consent. is allowed to continue.

B. Dosing and Administration The treatment regimen is summarized in FIG.

Atezolizumab All patients will receive 1200 mg atezolizumab administered by IV infusion on Day 1 of each 21-day cycle. Atezolizumab dose is fixed and independent of body weight. Atezolizumab infusions will be administered according to the instructions outlined in Table 67.

Tiragolumab and Placebo After the administration of atezolizumab and an observation period (see Table 67), patients receive 600 mg tiragolumab/placebo administered by IV infusion on Day 1 of each 21-day cycle. The tiragolumab/placebo dose is fixed and independent of body weight. Tiragolumab/placebo infusions will be administered according to the instructions outlined in Table 68.

Atezolizumab and Tiragolumab/Placebo Unless atezolizumab or tiragolumab/placebo are permanently discontinued, the following rules apply:
• Treatment cycles generally begin with administration of atezolizumab and tiragolumab/placebo on Day 1 of each 21-day cycle. Because the safety profiles of atezolizumab and tiragolumab are similar when either study drug is delayed due to drug-related toxicity, it is recommended that the other study drug be delayed as well. However, cycles may begin with administration of other study medications as deemed appropriate at the discretion of the Investigator.
- If the administration of one study drug is delayed for drug-related toxicity and the other study drug is 21-day cycles) are recommended.

Dose Modifications There are no dose modifications, including dose reductions, for atezolizumab or tiragolumab/placebo in this study.

C. Concomitant Therapy Concomitant therapy is any medication used by the patient (e.g., prescription, over-the-counter, vaccines, herbal or homeopathic remedies, dietary supplements).

Allowed Treatments Patients will be allowed to use the following treatments during the study.
● Oral contraceptives with <1% annual failure rate ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable-dose warfarin or low-molecular-weight heparin)
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
Inhaled or low-dose corticosteroids given for COPD or asthma Low-dose corticosteroids given for orthostatic hypotension or adrenocortical insufficiency Palliative radiotherapy as outlined below (e.g., Treatment of known bone metastases or symptomatic relief of pain):

In patients without documented radiographic disease progression by RECIST v1.1, maximizing supportive care for symptomatic treatment and avoiding radiation therapy that interferes with assessment of tumor target lesions is strongly encouraged.

Treatment with atezolizumab and tiragolumab/placebo may be continued during palliative radiotherapy.

Premedication with antihistamines, antipyretics, and/or analgesics may only be administered for the second and subsequent atezolizumab and tiragolumab/placebo infusions at the investigator's discretion.

In general, investigators should manage patient care (including pre-existing symptoms) with supportive care other than those defined as attention or prohibitive care, as clinically indicated, and in accordance with local standard practice. be. Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine) or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and ββ2-adrenergic agonist).

Treatments requiring caution Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab and/or tiragolumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines are considered. If alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors can be administered at the investigator's discretion.

Systemic corticosteroids are recommended at the investigator's discretion for treatment of specific adverse events when associated with atezolizumab and/or tiragolumab therapy.

Prohibited Therapies The use of the following concomitant therapies is prohibited as described below:
Any combination therapy for the treatment of cancer (including, but not limited to, surgery, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy) is approved by health authorities. Depending on the drug, whether experimental or experimental, for various periods prior to initiation of study treatment, and during study treatment, until disease progression is documented and the patient discontinues study treatment, a specific Prohibited except for palliative radiotherapy and local therapy under certain circumstances.
• Study treatment is prohibited within 28 days prior to initiation of study treatment and during study treatment.
- Live attenuated vaccines (e.g., FLUMIST®) are prohibited within 4 weeks prior to initiation of study treatment, during study treatment, and for 5 months after final dose of atezolizumab and 90 days after final dose of tiragolumab/placebo do.
o Within 4 weeks or 5 drug elimination half-lives (either within 4 weeks prior to initiation of study treatment and during study treatment due to potential increased risk of autoimmune symptoms when administered in combination with study treatment) Systemic immunostimulants (including but not limited to interferon and IL-2) within the longer term) are prohibited.
- Systemic immunosuppressants (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) should not be used in studies because these agents can potentially alter the efficacy and safety of study treatments. Prohibited during treatment.

D. Inclusion Criteria Patients must meet the following study entry criteria:
- Signed informed consent form - Age ≥18 years at the time of signing the informed consent document - Ability to comply with the study protocol - Histologically or cytologically confirmed oropharynx, oral cavity, larynx or recurrent/metastatic SCCHN involving the hypopharynx, considered incurable by local therapy

Patients with a primary site of tumor in the nasopharynx or parotid gland of any histology are not eligible.
• Known results from testing for HPV status in oropharyngeal carcinoma locally determined by p16 immunohistochemistry (IHC), in situ hybridization or polymerase chain-based assays Note: oral cavity cancer, laryngeal cancer and hypopharyngeal cancer HPV testing for cancer is not required.
- No prior systemic therapy for metastatic and/or recurrent SCCHN

Patients who received systemic therapy given as part of multimodal treatment (eg, concurrent chemoradiation) for locally advanced disease and whose last dose of systemic therapy was ≧6 months prior to randomization are permitted.
●Measurable disease according to RECIST v1.1

Previously irradiated lesions can be considered measurable disease only if progressive disease is clearly documented at the site after irradiation.
- median of representative tumor tissue specimens, as determined by the investigational VENTANA PD-L1 (SP263) CDx assay, either in previously obtained archival tumor tissue or in tissue obtained from prescreening/screening biopsies; Tumor PD-L1 expression with TIC > 5% documented by laboratory. Approximately 66 patients (55% of all planned enrollments) were enrolled in one of the PD-L1 subgroups (PD-L1 low (TIC 5%-19%) and PD-L1 high (TIC ≥20%)). No additional patients will be enrolled in the PD-L1 subgroup thereafter.

Confirmed availability of representative tumor specimens in formalin-fixed paraffin-embedded (FFPE) blocks (preferred) or at least 20 slides containing unstained freshly cut serial sections with relevant pathology reports. If only 19 slides are available, the patient may still be eligible for the study after obtaining medical monitor confirmation.

If archival tumor tissue is unavailable or determined to be unsuitable for the required testing, tumor tissue must be obtained from a biopsy performed at prescreening/screening. A biopsy may also be performed at pre-screening/screening if the patient's archival tissue test results do not meet eligibility criteria.
● ECOG performance status 0 or 1
- Life expectancy ≥ 12 weeks - Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to randomization:
- ANC ≧1.5×109/L (1500/μL) without granulocyte colony stimulating factor support
- Lymphocyte count ≧0.5×109/L (500/μL)
- Platelet count ≥100 X 109/L (100,000/μL) without transfusion
- Hemoglobin > 90 g/L (9 g/dL).

Patients may receive blood transfusions or erythropoietic procedures according to local SOC to meet this criterion.
- AST, ALT and alkaline phosphatase (ALP) < 2.5X upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases: AST and ALT ≤ 5XULN
Patients with documented liver or bone metastases: ALP ≤ 5XULN
- total bilirubin ≤ 1.5 XULN, except:
Patients with known Gilbert's disease: total bilirubin < 3XULN
- creatinine ≤ 1.5 XULN
- albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5XULN
Patients receiving therapeutic anticoagulants: stable anticoagulants Negative HIV test at screening Negative hepatitis B surface antigen (HBsAg) test at screening Hepatitis B surface antibody (HBsAb) at screening ) positive test or negative for HBsAb at screening with any of the following:
- total hepatitis B core antibody (HBcAb) negative - positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA <500 IU/mL

HBV DNA tests must be performed on patients with negative HBsAg tests, negative HBsAb tests, and positive total HBcAb tests.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening.
- HCV RNA testing should be performed for patients with a positive HCV antibody test.
For women of childbearing potential: consent to remain abstinent (abstain from heterosexual intercourse) or to use contraception, as defined below:

Women must remain abstinent or use a contraceptive method with an annual failure rate of <1% during the treatment period and for 5 months after the last dose of atezolizumab and 90 days after the last dose of tiragolumab/placebo. .

Females are postmenopausal, have not achieved postmenopausal status (amenorrhea with no identified cause other than menopause for ≧12 consecutive months), and have had surgery (i.e., ovarian, fallopian tube, and/or uterine Ablation) or another cause determined by the Investigator (eg, Müllerian agenesis) is considered fertile if not permanently infertile. Fertility definitions can be adapted to match local guidelines or regulations.

Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, hormonal devices that inhibit ovulation, hormone-releasing intrauterine devices, and copper-added intrauterine devices. .

The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Cyclic abstinence (eg, calendar, ovulatory, symptomothermic, or postovulatory) and abstinence are not suitable methods of contraception. When required according to local guidelines or regulations, information regarding the reliability of locally accepted methods of appropriate contraception and abstinence is provided on the local informed consent form.
For men: Consent to abstinence (abstinence from heterosexual intercourse) or condom use, and consent to refrain from donating sperm, as defined below.

For female partners of childbearing potential or pregnant, males should remain abstinent or use a condom during treatment with tiragolumab/placebo and for 90 days after the last dose of tiragolumab/placebo to avoid exposing the embryos. must be used. Men must stop donating sperm during the same period.

The reliability of sexual abstinence must be evaluated in relation to the duration of the clinical trial and the patient's preferred and usual lifestyle. Cyclic abstinence (eg, calendar, ovulatory, symptomatic, or postovulatory) and abortive intercourse are not adequate methods to prevent drug exposure. If required according to local guidelines or regulations, information regarding the reliability of abstinence will be provided on the local informed consent form.

E. Exclusion Criteria Patients meeting any of the following criteria will be excluded from the study:
- Disease amenable to local therapy with curative intent - Progressive or recurrent disease within 6 months of last dose of systemic treatment with curative intent for locally advanced SCCHN - Grade ≥ related to surgery or other prior therapy Patients with 2 unresolved toxicities < Grade 2 alopecia or neuropathy are permitted.

Patients undergoing major surgery should be well recovered, including recovery from any complications associated with the intervention.

Patients with irreversible toxicities that are controlled and not expected to be exacerbated by study drug treatment can be included after consulting a medical monitor.
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:
- Measurable disease by RECIST v1.1 must be present outside the CNS - Patient has no history of intracranial or spinal cord hemorrhage.
- Patient has not received stereotactic radiotherapy within 7 days prior to randomization, has not received whole-brain radiotherapy within 14 days prior to randomization, or received neurosurgical therapy within 28 days prior to randomization I have never had a surgical resection.
- Patient has no ongoing need for corticosteroids as treatment for CNS disease. Anticonvulsant therapy at stable doses is acceptable.
history of leptomeningeal disease uncontrolled tumor-related pain

Patients requiring analgesics must be on a stable regimen at study entry.

Symptomatic lesions amenable to palliative radiotherapy (eg bone metastases or metastases causing nerve impingement) must be treated prior to enrollment.

Patients must recover from the effects of radiation. There is no minimum recovery period required.

Asymptomatic metastatic lesions likely to cause functional impairment or intractable pain with further growth (e.g., epidural metastases not currently associated with spinal cord compression) should be treated with locoregional, if appropriate, prior to enrollment. Treatment should be considered.
● Uncontrolled or symptomatic hypercalcemia ● Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Active or history of autoimmune disease or immunodeficiency activity, including but not limited to Guillain-Barré syndrome, or multiple sclerosis, with the exception of:

Patients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormone are eligible for the study.

Patients with controlled type 1 diabetes on an insulin regimen are eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following conditions are met: is.
- Rash must cover <10% body surface area - Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UV within the last 12 months No acute exacerbation of underlying symptoms requiring A-irradiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids Idiopathic pulmonary fibrosis, organizing pneumonia (e.g. , bronchiolitis obliterans), drug-induced interstitial pneumonia, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scan.

A history of radiation pneumonitis (fibrosis) in the radiology area is acceptable.
● Active tuberculosis ● Significant cardiovascular disease (New York Heart Association Class II or higher heart disease, myocardial infarction, cerebrovascular accident, etc.), unstable arrhythmia or unstable angina pectoris within 3 months before the start of study treatment .
Major surgical procedure other than diagnosis within 4 weeks prior to initiation of study procedure, planned or anticipated need for major surgical procedure during study Additional malignancy other than SCCHN within 5 years prior to randomization malignancies with negligible risk of metastasis or death (e.g., 5-year OS >90%), e.g., appropriately treated cervical carcinoma in situ, non-melanoma skin cancer, Excludes localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.
- Severe infection within 4 weeks prior to initiation of study treatment (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia)
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving prophylactic antibiotics (e.g., to prevent exacerbations of urinary tract infections or chronic obstructive pulmonary disease) are eligible for the study;
- Prior allogeneic stem cell or solid organ transplantation - Any other disease, metabolic dysfunction, physical examination findings, or laboratory findings that contraindicate study drug use may affect interpretation of results or may put the patient at increased risk of treatment complications.
- Treatment with a live-attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipated need for such vaccine during study treatment, within 5 months after last dose of atezolizumab, or 90 after last dose of tiragolumab/placebo Treatment with live attenuated vaccine within days.
Current treatment with antiviral therapy for HBV or HCV Positive Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgM test at screening

To screen for suspected acute or chronic active infection, an EBV polymerase chain reaction (PCR) test should be performed when clinically indicated. Patients with a positive EBV PCR test are excluded.
- Treatment with study therapy within 28 days prior to initiation of study treatment.
- Pretreatment with a CD137 agonist or immune checkpoint blockade therapy, including anti-CTLA-4, anti-TIGIT, anti-PD-L1 and anti-PD-1 therapeutic antibodies - Within 4 weeks or 5 prior to initiation of study treatment Treatment with systemic immune stimulants (including but not limited to interferon and interleukin-2 [IL-2]) within the drug elimination half-life (whichever is longer).
- Treatment with systemic immunosuppressants (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, except for: , or prediction of need for systemic immunosuppressants during study treatment:
- Patients who received acute low-dose systemic immunosuppressants or single pulse-dose systemic immunosuppressants (e.g., 48-hour corticosteroids for contrast allergy) after obtaining medical monitor confirmation , are eligible for the test.
- Patients who received mineralocorticoids (eg fludrocortisone), inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for testing.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese Hamster Ovary Cell Products or any component of the atezolizumab or tiragolumab formulations.
- Pregnancy or lactation, or intention to become pregnant during study treatment, within 5 months after last dose of atezolizumab, or within 90 days after last dose of tiragolumab/placebo.

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

F. Grade

Patients will be closely monitored for safety and tolerability throughout the study. Patients will be assessed for toxicity prior to each dose; dosing will be administered only if clinical evaluation and local laboratory values are acceptable.

Medical history, baseline symptoms, concomitant medications and demographic data Clinically significant illness, surgery, history of cancer (including previous cancer treatments and treatments), reproductive status, smoking history, and use of alcohol and drugs of abuse Medical history including use will be recorded at baseline. In addition, all drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, dietary supplements) used by the patient within 7 days prior to initiation of study treatment are recorded. At each follow-up check-up, an interval medical history is obtained and changes in medications and allergies are recorded.

Demographic data includes age, gender, and self-reported race/ethnicity.

ECOG Performance Status Performance Status is measured using the ECOG Performance Status Scale.

Physical Examination A complete physical examination must be performed at Screening, which includes the head, eyes, ears, nose, and throat, as well as the cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, and urinary systems. Reproductive and nervous system evaluations should be included. Any abnormalities identified at baseline should be recorded.

Limited, physical examination should be performed at designated post-baseline visits and as clinically indicated, according to symptoms. Changes from baseline abnormalities should be recorded in patient notes. New or worsening clinically significant abnormalities should be recorded as adverse events.

Physical Examination Vital signs include measurement of respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is seated, and body temperature. Abnormalities observed at baseline and at subsequent visits, new or worsening clinically significant abnormalities are recorded.

Tumor and Response Assessment The screening evaluation and subsequent tumor evaluation included a CT scan of the chest and abdomen (with oral or IV contrast) or a CT scan of the head and neck (base of skull to clavicle) (with oral or IV contrast). (using contrast agents) or magnetic resonance imaging (MRI) (using contrast agents). Pelvic CT scan with contrast should be performed as clinically indicated or according to local SOC at screening and subsequent response assessment. If CT scans with contrast are contraindicated (e.g., in patients with impaired renal clearance), non-contrast CT scans of the chest can be performed, and contrast-enhanced CT scans of the head and neck, abdomen, and pelvis can be performed. A complete MRI scan (if applicable) must be performed. Further investigations such as bone scans should also be performed if clinically indicated at baseline and subsequent response assessments.

Clinically indicated for brain contrast CT scan or contrast MRI scan (if contrast CT is contraindicated) to assess CNS metastases at screening and subsequent response assessment should be done if there is If a contrast-enhanced CT scan is performed and the presence of brain metastases is considered ambiguous, an MRI scan of the head is required to confirm or rule out the diagnosis of CNS metastases at baseline. Patients with active or untreated CNS metastases are not eligible for this study. Patients with a history of brain metastases who were irradiated at screening do not need to undergo brain scans at subsequent response assessment unless clinically indicated.

If CT scans for tumor assessment are performed on a Positron Emission Tomography (PET)/CT scanner, the CT acquisition must conform to the standard for full contrast-enhanced diagnostic CT scans.

Tumor assessments performed as SOC prior to obtaining informed consent may be used without repeat testing if the scans are of diagnostic quality and are performed within 28 days of randomization.

The same radiation modality (eg, CT scan with contrast agent) and procedure (eg, same contrast protocol for CT scan) used in screening must be used for all subsequent tumor assessments. All known sites of disease, including measurable and/or non-measurable disease, must be documented at screening and reevaluated at each subsequent tumor evaluation.

Patients will have tumor assessments at baseline, every 6 weeks (±7 days) for the first 30 weeks after Day 1 of Cycle 1, and every 9 weeks (±7 days) after completion of the Week 30 tumor assessments. receive. Tumor assessment was based on radiological disease progression by RECIST v1.1 or loss of clinical benefit for patients continuing study treatment after radiographic disease progression by RECIST v1.1, withdrawal of consent, death or sponsor Continue as per schedule, regardless of treatment delays, until termination of the study by D, whichever occurs first. Also, at the investigator's discretion, scans should be performed whenever progressive disease or loss of clinical benefit is suspected.

RECIST v. 1. Patients who discontinue study treatment (for any reason, including but not limited to clinical Regardless, continue to undergo tumor response assessment according to the schedule above. Tumor assessment will continue until radiological disease progression, withdrawal of consent, death, or sponsor termination of the study by RECIST v1.1, whichever occurs first, and initial response will use RECIST v1.1. and assessed by the Investigator for the imaging modalities detailed above. Investigator assessment of overall tumor response at all time points should be based solely on RECIST v1.1. Ratings should be performed by the same rater if possible to ensure internal consistency between visits.

Investigator assessment of overall tumor response at all time points is based solely on RECIST 1.1. Tumor assessment must continue after disease progression by RECIST v1.1 for patients who received study treatment beyond progression. This includes continuous measurement of target lesions, evaluation of non-target lesions, and evaluation of newly identified lesions at all subsequent assessments.

Laboratory, Biomarkers, and Other Biological Samples Samples for the following clinical tests will be sent to the test facility's local laboratory for analysis:
• Hematology: WBC counts, RBC counts, hemoglobin, hematocrit, platelet counts and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes).
Chemistry panel (serum or plasma): bicarbonate or total carbon dioxide (if considered SOC for that area), 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 tests: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 is not performed), and free thyroxine (also known as T4)
o EBV serology including o EBV VCA IgM
o EBV VCA IgG or Epstein-Barr Virus Nuclear Antigen (EBNA) IgG
o If clinically indicated: EBV PCR
● HIV serology ● HBV serology consisting of:
o HBsAg, HBsAb and total HBcAb for all patients
o HBV DNA from patients with negative HBsAg and HBsAb tests and positive total HBcAb tests

Patients with positive quantitative HBV DNA at screening (must be <500 IU/mL per eligibility criteria) will undergo an additional HBV DNA test as outlined in the Activity Schedule.
• HCV serology: HCV antibody and (if HCV antibody test positive) HCV RNA.
For patients with SCCHN involving the oropharynx: HPV status of tumor tissue as determined by p16 IHC, in situ hybridization, or PCR-based assay Pregnancy test

All women of childbearing potential will have a serum pregnancy test at screening. During study treatment, a urine pregnancy test is performed on Day 1 of each cycle. A urine pregnancy test is also performed at the discontinuation visit. If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.

Females are postmenopausal, have not achieved postmenopausal status (amenorrhea with no identified cause other than menopause for ≧12 consecutive months), and have had surgery (i.e., ovarian, fallopian tube, and/or uterine Ablation) or another cause determined by the Investigator (eg, Müllerian agenesis) is considered fertile if not permanently infertile.
Urinalysis (pH, specific gravity, glucose, protein, ketones, blood); dipsticks allowed

The following samples are sent to one or more central laboratories or to the sponsor or designee for analysis.
• Serum samples for analysis of autoantibodies: antinuclear antibodies, anti-double-stranded DNA, circulating antineutrophil cytoplasmic antibodies, and perinuclear antineutrophil cytoplasmic antibodies • Serum samples for C-reactive protein • Validated Serum samples for atezolizumab and tiragolumab PK analysis using a validated assay Serum samples for assessment of ADAs for atezolizumab and tiragolumab using validated assays Blood and plasma samples for biomarker discovery studies

Blood samples can be processed to obtain peripheral blood mononuclear cells (PBMC) and other derivatives (eg, RNA, DNA, etc.).
Archived or freshly collected tumor tissue samples obtained at baseline for determination of PD-L1 expression and biomarker research studies

Representative FFPE tumor specimens in at least 20 slides containing paraffin blocks (preferred) or unstained freshly cut serial sections must be submitted with relevant pathology reports prior to study enrollment. If only 15-19 slides are available, patients may still be eligible for the study after obtaining medical monitor approval.

Tumor tissue must be of good quality based on total tumor content and viable tumor content.

Samples must contain a minimum of 50 viable TCs preserving cellular context and tissue architecture, regardless of needle gauge or collection method.

Specimens obtained by excision, core needle biopsy (at least 3 cores embedded in a single paraffin block), or excisional, incisional, punch, or forceps biopsy are acceptable. Fine-needle aspirations (defined as samples that do not preserve tissue architecture and yield cell suspensions and/or smears), brushings, cell pellets from pleural effusions, and lavage fluid samples are not permitted. Tumor tissue from demineralized bone metastases is not permitted.

A pretreatment tumor biopsy is required if archival tumor tissue is unavailable or determined to be unsuitable for the required testing. A pretreatment tumor biopsy may also be performed if the patient's archival tissue examination results do not meet eligibility criteria.
- Tumor tissue samples obtained at progression for biomarker exploratory studies (if considered clinically feasible)

A biopsy at progression should be performed within 40 days of progression or before the next anticancer therapy, whichever comes first.

Samples collected by excision, core needle biopsy (at least three cores are preferred), or excision, incision, punch or forceps biopsy are preferred.

NGS can be performed by Foundation Medicine. If performed by Foundation Medicine, the NGS report can be obtained via the Investigator, Foundation Medicine's web portal. Where permitted by local law, the investigator may share and discuss results with the patient unless the patient chooses otherwise. NGS reports are produced for research purposes and are not provided for the purpose of guiding future treatment decisions. No results are available for samples that do not meet the test criteria.

Exploratory biomarker studies may include analysis of tumor genetic alterations, HPV status or gene signatures associated with tumor immunobiology, PD-L1, TIGIT, lymphocyte subpopulations, and T cell receptor repertoires, It is not limited to these. Studies may include extraction of DNA, cell-free DNA or RNA; analysis of mutations and other tumor-specific genomic variants; and genomic profiling through the use of NGS of comprehensive gene panels. Somatic variants can be identified by comparing DNA extracted from blood to DNA extracted from tissue to distinguish germline variants from somatic variants. NGS methods may include WGS or WES of tissue and blood samples, but WGS or WES of blood samples are performed only at the site of interest.

Please refer to the laboratory manual for sampling procedures, storage conditions and transport instructions.

Unless the patient has given specific consent to have their leftover samples retained for any exploratory research, biological samples are not included in the final clinical study report completion, with the following exceptions: destroyed by time.
• Serum samples collected for PK or immunogenicity analysis may be required for further immunogenicity characterization and for the development and validation of PK or immunogenicity assays; shall be destroyed within 5 years after the completion of the final clinical study report.
- Blood, plasma and PBMC samples collected for biomarker studies, with the exception of tissue samples that underwent WGS or WES, will be destroyed within 5 years after the final clinical study report is completed and they are no longer needed. are stored until they are no longer needed or until they are exhausted. However, the retention period is subject to the IRB/EC approved informed consent form and applicable legislation (eg, requirements of health authorities).
• For enrolled patients, the remaining archival tissue blocks will be returned to the site upon request or within 18 months of the final clinical study report, whichever occurs first. For unenrolled patients, the remaining archival tissue blocks will be returned to the site within 6 weeks after eligibility determination.

If a patient withdraws from the study, samples collected prior to the withdrawal date may still be analyzed unless the patient specifically requests that the sample be destroyed or local law requires sample destruction. . However, if samples were tested prior to collection, those test results remain part of the overall study data.

Given the complexity and exploratory nature of exploratory biomarker analyzes, data derived from these analyzes are generally not provided to trial investigators or patients unless required by law (not obtained at disease progression). (except reports from Foundation Medicine, which are applicable only to biopsies). The overall results of the studies conducted are available in accordance with the sponsor's policy on publication of trial data in effect.

Electrocardiogram An ECG is required as clinically indicated at screening and at other times during the study. Each patient's ECG should be obtained from the same machine whenever possible. Lead placement should be as consistent as possible. ECG recordings must be taken after the patient has rested in the supine position for at least 10 minutes.

For safety monitoring purposes, the investigator must review, sign, and date all ECG records. A copy of the ECG recording is kept on site as part of the patient's permanent test file. Morphological waveform changes or other ECG abnormalities must be documented on the eCRF.

Clinical Outcome Assessment PRO scales will be completed to more fully characterize the clinical profiles of atezolizumab + tiragolumab and atezolizumab + placebo. In addition, the PRO scale allows capture of each patient's direct experience with atezolizumab + tiragolumab and atezolizumab + placebo.

PRO data will be collected using the following scales:
●PROMIS® Item Bank v2.0-Physical Functions-Short Form 10b
● PROMIS (registered trademark) Item Bank v1.0-fatigue-short form 4a
● PROMIS® Item Bank v1.1-Disturbed by Pain-Short Form 4a
● PROMIS® Numerical Rating Scale v1.0—Pain Intensity 1a
●Patient Global Impressions of Severity (PGI-S)
-Patient Global Impression of Change and its Importance (PGI-CI)
● Most important symptoms (MIS)
●PRO-CTCAE

PRO questionnaires (ie, PROMIS®, PGI-S/PGI-CI, MIS, and PRO-CTCAE) are completed during the treatment and at the treatment discontinuation visit.

Data Collection Methods for Clinical Outcome Assessment PRO scales used to characterize the clinical profile of atezolizumab + tiragolumab and atezolizumab + placebo were either self-administered at the clinic or interviewed at specific time points during the study. apply (if necessary). PRO data obtained through the use of PROMIS®, PGI-S/PGI-CI, MIS, and PRO-CTCAE questionnaires.

In the clinic, scales will be applied before patients receive information about disease status, before non-PRO assessments are performed, and before administration of study treatment, unless otherwise specified.

Written PRO questionnaires, translated into the local language as necessary and scheduled to be administered during the clinic visit, prior to other study assessments and prior to administration of study treatment, to avoid assessment bias as much as possible. must be completed by the patient at the study site at the beginning of the clinic visit. Patients complete a paper version of the questionnaire provided by the site staff. Interviewer ratings are permitted, but can only be done by clinic staff for patients who are unable to complete the measurements themselves.

Investigators should review all questionnaires for completeness before the patient leaves the study site.

During clinic visits, the PRO scale must be applied as outlined below:
• The patient's health status should not be discussed prior to application of the scale.
• Sites must maintain official versions of each sponsor-supplied scale. Scales should not be copied from the protocol.
• The site should allow sufficient time for the patient to complete the scale, estimated to be 15 minutes on day 1 of cycles 1 and 2, and less than 10 minutes for each subsequent cycle .
• The site should minimize distractions and distractions and apply the scale in a quiet area.
• Patients should be instructed to answer questions to the best of their ability; there are no right or wrong answers.
• Field staff should not interpret or explain questions and may read questions verbatim upon request.
• Patients should not seek advice or assistance from others (eg, family members or friends) in completing the scale.
• Site staff should review all completed scales and ask patients to correct responses that are not clearly marked in the appropriate location. If responses are missing, site staff should ask the patient to complete the item or confirm that the item was intentionally left blank.

Clinical Outcome Rating Scale Description PROMIS® Item Bank v2.0-Physical Function-Short Form 10b
PROMIS® Item Bank v2.0-Physical Functions-Short Form 10b measures upper extremity (dexterity), lower extremity (gait or mobility), and central area (neck, back) functions, as well as instrumental activities of daily living. It consists of 10 questions designed to measure the self-reported ability of physical activity, including All questions are scored on a scale of 1-5, with a score of 5 equaling the patient's best functional ability and a score of 1 equaling the patient's worst functional ability. The recall period is 7 days.

PROMIS® Item Bank v1.0 - Fatigue Short Form 4a
The PROMIS® Item Bank v1.0-Fatigue-Short Form 4a consists of four items designed to assess a self-reported spectrum of fatigue symptoms and the patient's ability to carry out daily activities. A questionnaire item asks the patient's degree of fatigue experienced in the past 7 days. Items are scored on a scale of 1-5, with a score of 5 equaling the highest level of fatigue experienced by the patient and a score of 1 equaling the lowest level of fatigue experienced by the patient. The recall period is 7 days.

PROMIS® Item Bank v1.1 - Disturbed by Pain - Short Form 4a
PROMIS® Item Bank v1.1-Pain Disturbance-Short Form 4a is a 4-question self-report scale designed to assess the impact/disturbance of pain on relevant aspects of a patient's life. consists of All questions are scored on a scale of 1-5, with a score of 5 equaling the highest level of pain disturbance and a score of 1 equaling the lowest level of pain disturbance experienced by the patient. The recall period is 7 days.

PROMIS® Numerical Rating Scale v 1.0—Pain Intensity 1a
The PROMIS® Numeric Rating Scale v1.0—Pain Intensity 1a consists of one question on a self-report scale designed to rate a patient's average pain level.

The questions are scored on a scale of 1-10, with a score of 10 corresponding to "worst possible pain" and a score of 1 corresponding to "no pain". The recall period is 7 days.

Patient Global Impression of Severity (PGI-S)
The Patient Global Impression of Severity (PGI-S) is a one-item self-report scale used to rate the patient's impression of the severity of his or her overall symptoms over the previous 7 days. . The PGI-S utilizes a 5-point response scale, with a score of 5 equating to "very severe" and a score of 1 equating to "none" (adapted from Guy et al. 1976).

Patient Global Impression of Change and its Significance (PGI-CI)
The Patient's Global Impression of Change is a one-item self-reported measure used to rate a patient's impression of a change in their symptoms compared to when they entered the study. It utilizes a 7-point response scale, with a score of 7 equating to 'very bad' and a score of 1 equating to 'much improved' (adapted from Guy et al. 1976). In the following question on the patient's global impression of change, the patient was asked to indicate whether the change experienced was significant to the patient, and if the patient did not experience the change, the response options were yes, No” or “Not Applicable”.

Most Important Symptoms (MIS)
The purpose of the Most Important Symptom Questionnaire is to identify which symptoms have been most troublesome to the patient in the past 7 days. The MIS is based on the University of Washington Quality of Life Questionnaire Scale 2.0 and later severity rating scales and adds several disease and/or treatment related symptoms (Rogers et al. 2002). Patients are asked to pick the 4 most troublesome symptoms in the past week.

PRO-CTCAE
PRO-CTCAE is a validated item bank used to characterize the presence, frequency, severity, and/or degree of interference with daily functioning of 78 patient-reportable symptomatic toxicities ( Basch et al. 2014; Dueck et al. 2015). The PRO-CTCAE consists of 124 questions rated either dichotomously (to determine presence versus absence) or on a 5-point scale (to determine frequency of occurrence, severity, and interference with daily functioning). including. Treatment toxicity can occur with observable signs (eg vomiting) or unobservable symptoms (eg nausea).

The standard PRO-CTCAE recall period is the preceding 7 days.

A subset of 11 symptoms considered most applicable to current treatment was selected for this study. Symptoms were consistent with previous studies with atezolizumab plus tiragolumab (Rodriguez-Abreu et al. 2020), symptomatic treatment toxicities associated with immunotherapy reported by patients and clinicians (Hansen et al. 2020, and in head and neck cancer). Selected based on recommendations for symptoms to be measured (Cella et al. 2011; Chera et al. 2014).

Blood Samples for Whole Genome Sequencing or Whole Exome Sequencing At participating sites, blood samples will be taken for DNA extraction to allow WGS or WES to predict response to study drug and more severe disease states. It allows us to identify tumor-specifically occurring variants associated with progression to . Somatic variants can be identified by comparing DNA extracted from blood to DNA extracted from tissue to distinguish germline variants from somatic variants. Samples can be sent to one or more laboratories for analysis.

Collection and submission of blood samples for WGS or WES is subject to review and approval of the investigative study by each institution's IRB/EC and, where applicable, appropriate regulatory bodies. If a site is not WGS or WES approved, this section of the protocol will not apply to that site.

Genomics is increasingly facilitating investigator's understanding of disease pathobiology. WGS and WES provide comprehensive genomic and exome characterization, respectively, along with the clinical data collected in this trial, to monitor efficacy and safety, or to determine which patients will respond to drug or adverse events. It may increase opportunities to develop new therapeutic approaches or new methods to predict whether an event is more likely to develop. Data will be analyzed in relation to this study, but can also be examined together with data from other studies. The availability of larger datasets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

Please refer to the laboratory manual for sampling procedures, storage conditions and transport instructions.

Blood samples collected for WGS or WES must be stored until no longer needed or until exhausted. However, the retention period is subject to the IRB/EC approved informed consent form and applicable legislation (eg, requirements of health authorities).

Specimens for Research Biosample Repository The Research Biosample Repository (RBR) is a centralized management system used for long-term storage of human biological samples, including body fluids, solid tissues and their derivatives (e.g. DNA, RNA, proteins, peptides). It is a facility group of type. The collection, storage, and analysis of RBR samples may facilitate the rational design of new pharmaceuticals and development of diagnostic tests, enabling personalized drug therapy for future patients.

RBR samples are collected from patients who specifically consent to participate in this optional study. RBR samples are analyzed to achieve one or more of the following objectives:
• To test the association of biomarkers with efficacy or disease progression • To identify safety biomarkers that are associated with susceptibility to adverse event development or that may lead to improved monitoring or surveillance of adverse events • To enhance knowledge and understanding of disease biology and drug safety To test drug effects and drug responses, including processes of drug absorption and disposition To develop biomarker or diagnostic assays and characterize the performance of these assays to establish

Sample Collection The following samples will be stored in RBR and used for research purposes, including but not limited to studies on atezolizumab, tiragolumab, head and neck cancer, or biomarkers related to drug safety.
- Residual blood, plasma, including residual tissue samples from medically designated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the discretion of the Investigator during the course of the study , PBMCs, and tumor tissue samples (excluding remaining archival tissue blocks returned to the scene) and any derivatives thereof (e.g., DNA, RNA, proteins, peptides)
- Optional blood samples for DNA extraction collected at any time during the study - Collected pre-dose on Cycle 1, Day 1 and Cycle 2, Day 15 and pre-dose on Cycle 3, Day 1 , any stool sample. These samples may be collected at home.

The above samples are sent to one or more laboratories for analysis of the microbial population by whole metagenomic sequencing, microbial culture, germline or somatic mutation via WGS, WES, or other genomic analysis method. can be Genomics is increasingly facilitating investigator's understanding of disease pathobiology. WGS and WES provide comprehensive genomic and exome characterization, respectively, along with the clinical data collected in this trial, to monitor efficacy and safety, or to determine which patients will respond to drug or adverse events. It may increase opportunities to develop new therapeutic approaches or new methods to predict whether an event is more likely to develop.

Data generated from the RBR samples are analyzed in conjunction with this study, but can also be examined together with data from other studies. The availability of larger datasets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

RBR samples should be stored until no longer needed or exhausted. However, the RBR retention period is subject to IRB/EC approved informed consent forms and applicable legislation (eg, requirements of health authorities).

G. Treatment and Patient Discontinuation Treatment Discontinuation Patients must permanently discontinue study treatment if they experience any of the following:
- unacceptable treatment-related toxicity, including the occurrence of immune-mediated adverse events that the investigator judged to be unacceptable given the individual patient's potential response to treatment and the severity of the event; Any medical condition that may compromise patient safety if treatment is continued.
- Investigator's or sponsor's judgment that discontinuation of treatment would be most beneficial to the patient - Use of another non-protocol anticancer therapy - Pregnancy - Radiation disease progression by RECIST v 1.1

Exception: Patients are allowed to continue study treatment after RECIST v1.1 criteria for progressive disease are met, provided they meet all of the criteria outlined for treatment beyond radiographic progression.
For patients treated beyond radiological progression by RECIST v1.1: clinical as determined by the investigator after integrated assessment of radiological data, biopsy results (if available) and clinical status loss of profit

The primary reason for discontinuing study treatment should be documented in the appropriate eCRF. Patients who discontinue study treatment early are not replaced.

Patients return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study treatment. A visit where a response rating indicates progressive disease can be used as a discontinuation visit, in which case all ratings associated with the discontinuation visit should be made at that time.

If the patient discontinued study treatment for an adverse event considered related to study treatment (including adverse events of special interest) and the event is ongoing 30 days after the last dose of study treatment, The event must be followed until resolution or determination by the investigator that the event has become stable or irreversible.

Follow-up assessment Tumor assessment RECIST v. Patients who discontinue study treatment (for any reason, including but not limited to clinical decline or toxicity) in the absence of radiographic disease progression according to 1.1 will allow the patient to start a new anti-cancer therapy. Continue to receive tumor response assessment as outlined in the activity schedule until radiological disease progression, withdrawal of consent, death or sponsor termination, whichever occurs first, regardless of whether There must be. At the investigator's discretion, scans should be performed whenever progressive disease is suspected.

Survival and Subsequent Treatment After treatment discontinuation, information regarding survival follow-up and new anticancer therapy will be available approximately until death (unless the patient withdraws consent for survival follow-up or the sponsor terminates the study). Collected by phone, patient medical records and/or clinic visits every 3 months.

Information regarding subsequent anticancer therapy includes systemic therapy (e.g., chemotherapy, targeted therapy, immunotherapy), surgery (e.g., removal of local and/or metastatic disease), and radiation treatment (e.g., for tumor lesions). radiation therapy).

Patient Withdrawal Patients have the right to voluntarily withdraw from the study at any time for any reason. Additionally, the investigator has the right to withdraw a patient from the study at any time.

Reasons for patient withdrawal from the study may include, but are not limited to:
● patient withdrawal of consent ● study termination or site closure ● loss of follow-up ● patient non-compliance, defined as non-compliance with protocol requirements as determined by the investigator or sponsor

Every effort should be made to obtain the patient's reason for discontinuation from the trial. The primary reason for study discontinuation should be documented in the appropriate eCRF. If a patient requests withdrawal from the study (ie, a request to withdraw from all living follow-up), this request must be documented in the source document and signed by the investigator. Patients who leave the study (ie, survival follow-up) will not be replaced.

If a patient discontinues from the study (ie, survival follow-up), study staff can obtain information on survival status using publicly available sources (eg, county records).

H. Analysis Efficacy Analysis Primary Efficacy Endpoint The primary efficacy endpoint is confirmed ORR. A confirmed objective response is defined as either CR or PR on two consecutive occasions >4 weeks apart, as determined by the investigator using RECIST v1.1. Patients who do not meet these criteria, including those who do not have a post-baseline tumor assessment, are considered non-responders. Confirmed ORR is defined as the proportion of patients with a confirmed objective response.

The primary efficacy analysis will be performed after all patients have been enrolled and a minimum follow-up of approximately 5 months has been achieved among patients with ongoing follow-up for ORR assessment.

The primary efficacy analysis population consisted of all randomized patients grouped according to assigned treatment. Estimates of the ORR and its 95% CI are calculated using the Clopper-Pearson method for each treatment group.

Secondary Efficacy Endpoints Duration of Response DOR will be assessed in patients who achieve a confirmed objective response as determined by the Investigator according to RECIST v1.1. DOR is measured from the date of first confirmed objective response to the first date of progressive disease or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1. Defined as a time interval. Patients who have not progressed and who have not died at the time of analysis will be censored at the date of the last tumor assessment. Estimate the median DOR for each treatment arm using the Kaplan-Meier method and generate a Kaplan-Meier curve Use the Brookmeyer-Crowley methodology to construct the 95% Cl for the median DOR for each treatment arm .

Progression-free survival, including progression-free survival at 6 months PFS is defined as the date of randomization and the date of first documented disease progression or death as assessed by the investigator according to RECIST v1.1. defined as the time between (whichever occurs first). Patients who have never experienced disease progression or who do not die by the data cutoff date will be censored at the last tumor assessment. Patients with no post-baseline tumor assessment will be censored at the date of randomization.

Estimate the median PFS for each treatment arm using the Kaplan-Meier method and generate a Kaplan-Meier curve Use the Brookmeyer-Crowley methodology to construct the 95% Cl for the median PFS for each treatment arm . PFS rates 6 months after randomization are estimated using the Kaplan-Meier method for each treatment group, with 95% CIs calculated using standard errors derived from the Greenwood equation.
Overall survival including overall survival at 6 months and 12 months

OS is defined as the time between the date of randomization and death from any cause. Data for patients not reported to have died by the data cutoff date will be censored on the date they were last known to be alive. Data for patients with no post-baseline information will be censored at the date of randomization. OS and OS rates at 6 months and 12 months are analyzed using the same methods as described for PFS.

Patient Reported Outcomes PROMIS® Item Bank v 2.0 - Physical Function - TTCD for Physical Function Using Short Form 10b was first confirmed clinically relevant from date of randomization defined as the time to a certain degradation of A confirmed clinically meaningful decline in physical function must be maintained for at least two consecutive assessments or the first clinically meaningful decrease from baseline over baseline. defined as a meaningful increase in A T-score change of greater than 4 points is considered clinically significant for the physical function subscale scores.

TTCD is assessed in the ITT population. Patients who have not experienced clinically meaningful deterioration confirmed at the clinical cut-off date will be censored at the end of completing the assessment. If no baseline or post-baseline assessments are made, patients will be censored on the randomization day. TTCD using the PROMIS® scale is analyzed using the same method as PFS.

An exploratory analysis of the PROMIS® Scale (Pain, Fatigue and Physical Function) reported by use of the PROMIS® Pain, PROMIS® Fatigue and PROMIS® Physical Function Questionnaire, ITT population summary statistics and mean change from baseline calculated according to the PROMIS® Scoring Manual are included.

Summary statistics including counts and rates are presented for PGI-CI, PGI-S and most important symptoms and they are exploratory.

Analyzes of PRO-CTCAEs are exploratory in nature and primarily descriptive, with a focus on characterizing the toxicity patterns of the disease and symptomatic treatments under study. The results of these exploratory analyzes are presented separately from other safety analyses. PRO-CTCAE data will be analyzed at the item level in line with current NCI recommendations for data processing. For each treatment group, the number (percentage) of patients reporting symptoms by "frequency," "severity," "interference," and "presence" categories are reported at each rating.

In addition, symptom frequency is cross-tabulated with symptom severity to examine the impact of symptoms when they occur. A summary table of the proportion of patients reporting symptom severity as "severe" or "very severe" during the study by treatment group is also provided.

Safety Analysis The safety analysis population consists of all randomized patients who received atezolizumab or tiragolumab/placebo at least one dose.

Safety analyzes are performed by treatment group and are based on the actual treatment received. Specifically, patients are included in the atezolizumab plus tiragolumab group in the safety analysis if they received any dose of tiragolumab, regardless of their initial treatment assignment at randomization.

Drug exposure is summarized including duration, dosage and dose intensity.

Verbal descriptions of adverse events will be mapped to MedDRA synonyms and graded according to the NCI CTCAE v5.0, and the severity of CRS will also be graded by investigators according to the ASTCT consensus grading scale. All adverse events will be summarized by treatment group and NCI CTCAE grade. CRS is also summarized by treatment group and ASTCT consensus grade. In addition, serious adverse events, immune-mediated adverse events, and adverse events leading to discontinuation or discontinuation of study treatment will be summarized as appropriate. Multiple occurrences of the same event are counted once at maximum severity.

All deaths and causes of death are summarized by treatment group.

Experimental data with values outside the normal range are identified. In addition, selected experimental data including ADA results are summarized.

Pharmacokinetic Analysis In this study, PK samples of tiragolumab and atezolizumab are collected. Tiragolumab and atezolizumab serum concentration data (minimum and maximum serum concentrations) will be collected and summarized.

Descriptive statistics include mean, median, range and standard deviation as appropriate.

Further PK analysis will be performed as needed based on data availability.

Immunogenicity Analysis The immunogenicity analysis includes patients with any ADA assessment and groups the patients according to the treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients are summarized by treatment group.

Relationships between ADA status and safety, efficacy and PK endpoints can be analyzed and reported using descriptive statistics.

Biomarker Analysis Biomarker analysis is exploratory. Descriptive statistics are used to summarize biomarker subgroups and their relationship to efficacy endpoints. Data can be analyzed in the context of this study and in conjunction with data from other studies.

Interim Analysis An interim analysis of efficacy is planned to enroll approximately 60 patients and be reviewed by the IMC when given the opportunity to be followed up for approximately at least 5 months.

Example 16. A Phase Ib/II, Open-label, Multicenter, Randomized, Comprehensive Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients with Muscle-Invasive Bladder Cancer (MIBC) Muscle-invasive Bladder The time from cancer (MIBC) diagnosis to cystectomy is typically 4-8 weeks, providing a window of opportunity to provide patients with neoadjuvant therapy to improve recurrence rates and OS. . Benefits of neoadjuvant chemotherapy are moderate, with a 5% increase in overall survival (OS) in patients treated with neoadjuvant chemotherapy compared to cystectomy alone (Vale et al., Eur Urol, 48:202-205, 2005). Patients who achieved a pathological complete response (pCR) benefited most from receiving neoadjuvant cisplatin-based chemotherapy, with 80-90% surviving at 5-year follow-up, although patients up to 50% of patients may have residual high-risk disease (pT 2 or greater) at the time of surgery, with a 5-year survival rate of less than 50% (Rosenblatt et al., Eur Urol, 61:1229-1238, 2011 Bhindi et al., Eur Urol, 72:660-664, 2017). Therefore, pCR may serve as a surrogate marker for efficacy and increased survival in neoadjuvant therapy for MIBC.

WO39613 is a Phase Ib/II open-label, multicenter, randomized comprehensive study evaluating the efficacy and safety of multiple immunotherapy-based treatments and combinations in patients with cisplatin-ineligible MIBC. This trial will open new treatment arms as new treatments become available, close existing treatment arms showing minimal clinical activity or unacceptable toxicity, or alter the patient population (e.g., prior anticancer designed with flexibility for treatment or biomarker status). Patients are randomly assigned to a control group (atezolizumab (Atezo)) or an experimental group consisting of atezolizumab (Atezo+Tira) in combination with tiragolumab (Figure 24 and Table 69).

The targets and proposed mechanistic classifications for atezolizumab and tiragolumab are summarized in Table 70.

The specific objectives and corresponding endpoints of this study are outlined in Table 71.

Overall response at one time point will be assessed by the investigator using RECIST v 1.1. Overall response by iRECIST will be calculated programmatically by the sponsor based on investigator-assessed individual lesion data.

Approximately 150-350 patients are enrolled and divided into MIBC Cohort 1 (PD-L1+) and MIBC Cohort 2 (PD-L1-). Enrollment within the experimental group is conducted in two phases, a preliminary phase followed by an expansion phase. All treatment arms are the same for MIBC cohort 1 (PD-L1+) and MIBC cohort 2 (PD-L1-) during the preliminary phase. After central PD-L1 examination of transurethral resection of bladder tumor (TURBT) specimens using the VENTANA PD-L1 (SP142) assay, patients were assigned to MIBC Cohort 1 (PD-L1+) or MIBC Cohort 2 (PD-L1-). Assign to either. 2 or 3, corresponding to the presence of any intensity of discernible PD-L1 staining in tumor cells, tumor-infiltrating immune cells covering 5% or more of the tumor area occupied by associated intratumoral and adjacent peritumoral stroma. Patients with a PD-L1 immune cell (IC) score of (IC2/3) are assigned to MIBC cohort 1 (PD-L1+). 0 or 0, corresponding to the presence of any intensity of discernible PD-L1 staining in tumor-infiltrating immune cells covering up to 5% of the tumor area occupied by tumor cells, associated intratumoral, and adjacent peritumoral stroma Patients with an IC score of 1 (IC0/1) are assigned to MIBC cohort 2 (PD-L1-).

During the preliminary phase, up to 30 patients will be enrolled in the Atezo+Tira arm and approximately 15 patients in all other arms for each of the MIBC PD-L1 cohorts. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients will be enrolled in that group during the expansion phase.

Sponsors may decide to delay or suspend enrollment within a given treatment arm. Experimental groups with inadequate clinical activity or unacceptable toxicity will not be expanded. Additional patients can be enrolled to ensure balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers, to allow for further subgroup analysis.

Randomization will depend on the number of experimental groups available (e.g., if groups are added or group enrollment is suspended pending analysis of results from the preliminary phase) and the control group There is a provision that the probability of being assigned to is 35% or less. Randomization takes into account group-specific exclusion criteria. Patients are ineligible for a particular group if they meet any of the exclusion criteria outlined for that group (see below).

Patients in the atezolizumab control and experimental groups will be integrated with radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening symptoms such as pain secondary to disease). Treatment is until unacceptable toxicity or loss of clinical benefit as determined by the Investigator after evaluation. Patients will undergo treatment for up to 1 year postoperatively, followed by 3-month follow-up assessments for 2 years.

A. Rating and monitoring

All patients were closely monitored for adverse events throughout the study, and adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). )). Patients undergo tumor assessments every 9 weeks for the first 54 weeks (starting on Day 1 of Cycle 1) and every 12 weeks thereafter. The response is
Eisenhauer et al., assessed by investigators using RECIST v 1.1. , Eur J Cancer, 45:228-247, 2009)). If clinical activity is demonstrated in the experimental group, the donor may request a tumor assessment scan for it.

It may be required that the group's tumor assessment scans be submitted for evaluation by an independent reading center.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, archiving of tumor tissue may be submitted. Patients discontinuing Stage 1 due to unacceptable toxicity or loss of clinical benefit, as determined by the Investigator (if considered clinically feasible by the Investigator). Collected from These samples, as well as blood samples taken during the study, are utilized in biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points before and during study treatment administration.

B. End of test and test period

End of study is defined as the date the last patient in both stages completed the last visit (including survival follow-up visits conducted by telephone or on-site visit).

The total length of the trial, from initial patient screening to study termination, is approximately 3-5 years.

C. RATIONALE OF THE STUDY DESIGN RATIONALE AND BENEFITS OF THE STUDY - RISK ASSESSMENT

This study is designed to accelerate the development of cancer immunotherapy (CIT) combinations by identifying early signals and establishing proof-of-concept clinical data in cisplatin-ineligible MIBC patients.

Platinum-based neoadjuvant chemotherapy is associated with improved OS, but is suitable for only a minority of patients. Given the relatively limited treatment options for patients with cisplatin-ineligible MIBC, and the poor prognosis and potential toxicity associated with treatment of locally advanced or metastatic UC, these populations are in need of treatment options. and therefore considered suitable for testing new therapeutic candidates. Current prevalent CIT approaches target T cell inhibitors such as programmed death ligand 1 (PD-L1)/programmed death 1 (PD-1) to circumvent immune evasion mechanisms and enhance anti-tumor responses. is to reactivate

CIT has demonstrated clear clinical efficacy, with significant survival benefits observed across multiple advanced malignancies, and PD-1/PD-L1 checkpoint blockade demonstrated pCR and durable responses in UC patients. (Powles et al., Nat Med, 25:1706-1714, 2019; Necchi et al., Int J Clin Oncol, 36:3353-3360, 2018). Although these targets have provided remarkable clinical success for a variety of cancer indications, ongoing research indicates that a series of stepwise events are required to generate an effective anti-tumor immune response. (Chen and Mellman, Immunity, 39:1-10, 2013). Each event is critical for an effective response and each is susceptible to several tumor immune evasion mechanisms. Therefore, the need to identify and evade various factors that account for the lack or evasion of effective anti-cancer immune responses is critical to propagating cancer immunity and advancing the field of CIT. Combining atezolizumab with agents that target different immune evasion mechanisms or novel second-generation CPIs may increase response rates and further reduce disease relapse rates in this population.

A potential risk for MIBC patients is associated with adverse events related to study treatment. In most countries, patients wait an average of 4-8 weeks between establishing a diagnosis of urothelial carcinoma and surgery. Participation in this trial, including preoperative treatment, is not expected to result in associated delays in surgery for participants. Furthermore, atezolizumab did not affect surgical indications or increase surgery-related risks in the ABACUS trial (Powles et al., Nat Med, 25:1706-1714, 2019).

Rationale for Perioperative Treatment in Muscle-Invasive Bladder Cancer The therapeutic contribution of neoadjuvant therapy and postoperative maintenance therapy is unclear. The WO39613 trial is designed to assess treatment efficacy and perform extensive biomarker analysis on serial patient tissues.

IMVigor010 is a phase III randomized trial that randomly assigned patients with MIBC to receive atezolizumab versus observation as adjuvant therapy after surgical excision and lymphadenectomy. Although this trial did not meet its primary endpoint of demonstrating a disease-free survival benefit with atezolizumab adjuvant therapy in the intention-to-treat population, subgroup analyzes of T3 and T4 patients and nonclinical data (Liu et al. Pai et al., Immunity, 50:477-492, 2019; Hussain et al., J Clin Oncol, 38 (15 Suppl.): 5000, 2020). It is suggested that therapy may require that patients with residual or active disease be effective for checkpoint immunotherapy.

D. Evidence for immunotherapy in patients with muscle-invasive bladder cancer who are not eligible for cisplatin-based chemotherapy

Approximately 50% of patients with MIBC are ineligible to receive cisplatin-based neoadjuvant chemotherapy, and there is currently no perioperative systemic treatment recommended for these patients, bilateral pelvic lymphadenectomy Cystectomy with surgery is the standard treatment. Moreover, less than half of patients with MIBC who are eligible for neoadjuvant chemotherapy will receive it due to personal preference or other comorbidities. Therefore, new therapeutic modalities are needed to improve the outcome of MIBC patients.

PD-1/PD-L1 checkpoint immunotherapy for all patients who progressed on chemotherapy to mUC and patients with 1 L mUC to platinum-based chemotherapy if the tumor is PD-L1+ Approved for patients who are ineligible or ineligible for cisplatin-based chemotherapy. The largest studies investigating the safety and efficacy of PD-1/PD-L1 checkpoint neoadjuvant immunotherapy in MIBC patients were the ABACUS and PURE-01 studies (Powles et al., Nat Med, 25: 1706-1714, 2019; Necchi et al., Int J Clin Oncol, 36:3353-3360, 2018).

E. Rationale for complete pathologic response as the primary endpoint

Complete pathologic response (pCR) as well as reduction in pathologic extent (exploratory endpoints) have been validated as surrogate markers of activity in this setting due to their association with durable remission-free survival ( Rosenblatt et al., Eur Urol, 61:1229-1238, 2011; Bhindi et al., Eur Urol, 72:660-664, 2017).

An increase in baseline CD8 T-cell infiltration and PD-L1+ disease has been shown to increase the probability of pCR with immunotherapy in a neoadjuvant setting (Powles et al., Nat Med, 25:1706-1714, 2019). ).

F. Rationale for using atezolizumab as a comparator

There is no standard treatment for providing systemic therapy before or after surgical excision in MIBC patients who refuse or are ineligible for cisplatin-based neoadjuvant chemotherapy.

Atezolizumab demonstrated that ABACUS and PURE-01 studies demonstrated that PD-1/PD-L1 checkpoint immunotherapy was efficacious and safe in MIBC patients, with response rates comparable to those historically observed with cisplatin-based chemotherapy. It was selected as a comparison treatment because it showed efficacy. Based on ABACUS and PURE-01 data, compared to mUC, MIBC are typically more inflamed and thus PD-L1 expression was treated for mUC in IMVigor211 and KN-045 studies, respectively. Observed in only 25% and 28.5% of patients, it is likely to benefit from PD-1/PD-L1 checkpoint immunotherapy.

Randomized trials evaluating combinations of immunotherapies may allow the identification of safe and effective treatments for patients with MIBC who are ineligible for cisplatin-based chemotherapy, while improving our understanding of cancer biology. and improve the ability to iterate in designing new tests and treatments for all patients with MIBC. This study may also include potential future groups and cohorts using immunotherapeutic combinations that have demonstrated sufficient clinical safety.

G. Rationale for separate PD-L1+ and PD-L1− cohorts

PD-1/PD-L1 blockade has been approved by the FDA for 2L mUC and for patients with PD-L1+mUC who are ineligible to receive cisplatin-based chemotherapy, but not for patients with MIBC. do not have. The benefit of pCR in the ABACUS trial was greater in atezolizumab-treated patients with PD-L1+ (37.1%; n=13/35) than PD-L1- (24.5%; n=12/49) disease. However, some patients with PD-L1- disease may still benefit from a combination of atezolizumab or immunotherapy. The study design allowed the sponsor to separately assess the efficacy of atezolizumab and other immunotherapy combinations in these patient subsets, and to evaluate each patient for which there was no evidence of benefit without affecting investigations in other cohorts. Enrollment in groups in the cohort can be terminated.

H. Rationale for Investigating the Impact of Perioperative Treatment on ctDNA for a Muscle-Invasive Bladder Cancer Cohort

Changes in circulating tumor DNA (ctDNA) levels over time can be used to detect disease recurrence (Moding et al., Nat Cancer, 1:176-183, 2020). CtDNA released into peripheral blood from cancer cells can be collected non-invasively and tested for the presence of tumor-specific mutations. Several features of UC make it a strong candidate for prognosis of disease recurrence using ctDNA testing.

• UC has a high somatic mutation rate; therefore, a very small number of genes or targeted regions can be highly informative for predicting disease traits (Todenhoefer et al., Bladder Cancer, 4:1929, 2018).
• Metastatic recurrences in UC have been observed to have a clonal origin and are not significantly different from the original tumor in mutational analysis (Thomsen et al., Sci Rep, 7:11702, 2017).
Analysis of paired tumors in UC identified few subclones, supporting the prognostic potential of long-term ctDNA testing after definitive therapy (Lamy et al., Cancer Res, 76:5894, 2016; Nodentoft et al., Cell Rep, 7:1649-1663, 2014).
• Longitudinal samples from 68 MIBC patients who received neoadjuvant chemotherapy and underwent cystectomy were analyzed using the Natera Signatera ctDNA assay. This analysis showed that patients whose specimens were ctDNA positive at any time after cystectomy versus those who remained ctDNA negative after cystectomy (median follow-up of 21 months) were 76% It was found to have an overall recurrence rate of 0% (Christiensen et al. J Clin Oncol. 37(18):1547-1557, 2019).

These data present a biomarker-selected subpopulation of MIBC patients with a high unmet need for acute treatment options. However, currently there are 1) effects of neoadjuvant immunotherapy on ctDNA before and after cystectomy in patients with urothelial cancer; 2) maintenance immunotherapy after cystectomy in patients treated with neoadjuvant immunotherapy; whether maintenance immunotherapy helps prevent recurrence of urothelial carcinoma;

There are no data regarding whether patients treated with neoadjuvant immunotherapy have a reduced risk of disease recurrence if they have measurable ctDNA after cystectomy.

As part of this study, ctDNA will be measured retrospectively in all patients with PD-L1 + MIBC treated with atezolizumab and atezolizumab plus tiracolumab at four time points: 1) Day 1 prior to Cycle 1; 3) 4-6 weeks after cystectomy; 4) 6 months after cystectomy. The association between ctDNA results at these time points and symptom-free survival (EFS) and OS is examined. These results demonstrate the effects of neoadjuvants, as well as

To inform the design of future trials of maintenance therapy value in patients receiving checkpoint immunotherapy. Pending the results of these studies and the clinical activity observed in other groups, ctDNA was investigated at these time points in other groups of the study.

This design and use of ctDNA has been shown to: 1) impact of neoadjuvant therapy on ctDNA and pathological responses; 2) impact of surgery on residual ctDNA after neoadjuvant immunotherapy; Allows assessment of ctDNA in patients and whether it reduces the risk of disease recurrence.

Example 17. Materials and methods for testing of WO39613A. Inclusion Criteria Patients must meet all of the following criteria:
● Age ≥ 18 years old.
- Ability to comply with the protocol, as determined by the investigator - East Coast Cancer Trials Group (ECOG) performance status of 0 or 1 - Patients who refuse neoadjuvant cisplatin-based chemotherapy, or patients who are not suitable for neoadjuvant cisplatin-based therapy. Cisplatin ineligible for this study is defined by creatinine clearance <60 mL/min and/or grade ≧2 hearing loss and/or grade ≧2 neuropathy.
• Conforms and is scheduled for cystectomy.
• Histologically documented MIBC (pT2-4, N0, M0), also called TCC or urothelial cell carcinoma of the bladder.
o Residual disease after TURBT (surgical findings, cystoscopy/endoscopy or radiological presence).
o Patients with mixed histology should have a predominant transitional cell pattern.
• Availability of TURBT specimens suitable for determination of PD-L1 and further biomarker status by central laboratories.
o TURBT specimens must be submitted with relevant pathology reports. Tumor tissue is processed by two different methods (ie, paraffin-fixed and fresh tissue are required for separate biomarker analyses). Bladder or upper urinary tract tumor tissue should be of good quality based on total and viable tumor content, muscle-invasive component of tumor verified by local pathology review (i.e., T2 or greater) must contain
o Patients with additional tissue samples from procedures performed at different times during the course of MIBC (e.g., samples from previous TURBT) are required to submit these samples to central review as well ( but not required).
• NO or M0 disease by CT or MRI (within 4 weeks of enrollment).
- Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10 ⁹ /L (1500/μL) without G-CSF support
- white blood cell (WBC) count ≥ 2.5 x 10 ⁹ /L (2500/μL)
- Lymphocyte count ≧0.5×10 ⁹ /L (500/μL).
- Platelet count ≧100×10 ⁹ /L (100,000/μL) without transfusion
- hemoglobin ≥ 90 g/L (9.0 g/dL)

Patients may be transfused, but transfusions are not permitted within 2 weeks of clinical screening for eligibility.

Patients with single kidney disease or chronic kidney disease with low erythropoietin production may use erythropoietin stimulants.
- AST, ALT and alkaline phosphatase (ALP) < 2.5 x upper limit of normal (ULN)
- Bilirubin ≤ 1.5 x ULN, except:
Patients with known Gilbert's disease: bilirubin level < 3 x ULN.
- Albumin > 25 g/L (2.5 g/dL).
- Creatinine clearance ≧30 mL/min (calculated using the Cockcroft-Gault formula)
- In patients not receiving therapeutic anticoagulation:
Partial thromboplastin time (PTT) or aPTT ≤ 1.5 x ULN
Prothrombin Time (PT) or International Normalized Ratio (INR) < 1.5 x ULN
• Negative HIV test at screening.
o Patients without prior positive HIV test results will be tested for HIV at screening unless permitted by local regulations.
• Negative total hepatitis B core antibody (HBcAb) test at screening or positive total HBcAb test at screening followed by quantitative hepatitis B virus (HBV) DNA <500 IU/mL at screening.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening.
• For women of childbearing potential: consent to abstinence (abstinence from heterosexual intercourse) or use of contraceptive means, and consent to refrain from donating eggs.
• For men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and to refrain from donating sperm.

B. Exclusion Criteria Patients meeting any of the following criteria will be excluded: Event grading in exclusion criteria is based on NCI CTCAE v4.0.
- Prior treatment with systemic immunostimulants (including but not limited to agents targeting CTLA-4, interferon and interleukin-2) prior to initiation of study treatment - Eligibility for control arm only - Prior allogeneic stem cells or solid organ transplantation Systemic immunosuppressants (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-tumor necrosis factor) within 2 weeks prior to initiation of study treatment, with the following exceptions- treatment with alpha agents) or prediction of need for systemic immunosuppressants during study treatment:

Patients who received an acute low-dose systemic immunosuppressant or a single pulse dose of systemic immunosuppressant (eg, 48-hour corticosteroids for contrast allergy) are eligible for the study.

Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. be.
• Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study treatment or during atezolizumab treatment or within 5 months after the last dose of atezolizumab • Uncontrolled tumor-related pain. Patients requiring analgesics must be on a stable regimen at study entry.
Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis Active or history of autoimmune disease or immunodeficiency activity, including but not limited to, excluding:

Patients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormone are eligible for the study.

Patients with controlled type 1 diabetes on a stable insulin regimen are eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following conditions are met: is.
- The rash must cover <10% of body surface area.
- Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UVA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors within the past 12 months , or no acute exacerbation of underlying symptoms requiring high-potency or oral corticosteroids.
A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia, or idiopathic interstitial pneumonia, or a screening chest computed tomography (CT) scan Evidence of active interstitial pneumonia.
Appropriately treated cervical carcinoma in situ, nonmelanoma cutaneous carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer with negligible risk of metastasis or death (e.g., 5-year OS rate >90%) History of non-UC malignancy within 2 years prior to screening, excluding malignancies. Patients with localized prostate cancer (defined as stage ≤ pT2c, Gleason score ≤ 7 and prostate specific antigen (PSA) ≤ 20 ng/mL at diagnosis of prostate cancer) treated with curative intent and without PSA recurrence are eligible is. Patients with pre-existing low-risk prostate cancer (stage cT 1/T 2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naïve and undergoing active surveillance are eligible .
- Active tuberculosis (TB) (ie, having signs and symptoms of TB).
- Severe infection (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia) within 4 weeks prior to initiation of study treatment, or opinion of investigator Any active infection that may affect patient safety.
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment be;
• Significant cardiovascular disease such as New York Heart Association heart disease (class III or higher), myocardial infarction or cerebrovascular disease, unstable arrhythmia or unstable angina pectoris within 3 months prior to randomization.
- Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >95 mmHg). Antihypertensive therapy to achieve these parameters is acceptable.
- Grade 3 or greater bleeding or bleeding event within 28 days prior to initiation of study treatment.
• Expected need for major non-diagnostic surgery within 4 weeks prior to initiation of study procedure or major surgical procedure other than cystectomy or nephroureterectomy during study. Placement of a central venous access catheter (eg, port, etc.) is not considered a major surgical procedure and is therefore acceptable.
Any other disease, metabolic dysfunction, physical examination findings, or laboratory findings that contraindicate the use of the study drug may affect the interpretation of results or impair the patient's ability to participate in the study. , or may put the patient at increased risk for procedural complications.
• History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.
• Known intolerance or hypersensitivity to any of the excipient study drugs (including histidine, trehalose dihydrate, and polysorbate 20).
• Known intolerance to any drug required for premedication (acetaminophen, ranitidine, diphenhydramine, methylprednisolone).
• Pregnancy or lactation, or intention to become pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

Additional Exclusion Criteria for Atezolizumab + Tiragolumab Arm Patients meeting any of the following criteria will be excluded from the atezolizumab + tiragolumab arm:
Active Epstein-Barr virus (EBV) infection at screening and known or suspected chronic active EBV infection

Patients with a positive EBV viral capsid antigen (VCA) IgM test at screening are excluded from this group. To screen for suspected active or chronically active infection, an EBV polymerase chain reaction (PCR) test must be performed as clinically indicated. Patients with a positive EBV PCR test are excluded from this group.

C. Allowed Treatments Patients will be allowed to use the following treatments during the study.
● Oral contraceptives ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (warfarin or low molecular weight heparin, etc.)
● Prophylactic antibiotics or antiviral treatment administered according to institutional standards ● Inactivated influenza vaccination ● Megestrol acetate given as an appetite stimulant ● Mineralcorticoids (eg, fludrocortisone)
o Corticosteroids given for chronic obstructive pulmonary disease or asthma o Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency o Gonadotropin-releasing hormone agonists or antagonists for prostate cancer Hormonal therapy used Palliative radiation therapy (e.g. treatment of known bone metastases or symptomatic relief of pain) outlined below:
After 2 cycles of treatment. Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with atezolizumab may be continued during palliative radiotherapy.
- Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:
Patients experiencing a mixed response requiring local therapy for control of 3 or fewer lesions may still be eligible to continue study treatment after obtaining medical monitor approval. Patients receiving local therapy directed at target lesions are no longer evaluable for radiological response, but remain evaluable for progression.

Premedication with antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent atezolizumab infusions, at the discretion of the Investigator.

Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine) or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and _β2- adrenergic should be administered by a sexual agonist).

D. Atezolizumab Group Materials and Methods Atezolizumab was administered at the approved dose (TECENTRIQ® US Prescribing; 1200 mg per day) (Table 72). Anti-tumor activity was observed over doses ranging from 1-20 mg/kg Q3W. In the PCD4989g study, the maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicity was observed at any dose. Based on both nonclinical studies (Deng et al., MAbs, 8:593-603, 2016) and available clinical pharmacokinetic, efficacy and safety data, a fixed dose of 1200 mg Q3W (mean weight-based dose 15 mg/kg Q3W) was selected.

Patients in the atezolizumab control group were evaluated after integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as pain secondary to disease). Treatment is received until unacceptable toxicity or loss of clinical benefit as determined by the Investigator. Treatment must be initiated within 7 days after treatment assignment. Patients should undergo surgery after Cycle 3 and treatment for Cycle 4 should be resumed 4-6 weeks after surgery.

Administration of atezolizumab occurs in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Atezolizumab infusions will be administered according to the instructions outlined in Table 73.

D. Materials and Methods for Atezolizumab + Tiragolumab Group Atezolizumab will be administered as described above (see Table 73).

Tiragolumab is administered at a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of each 21-day cycle). A fixed dose of 600 mg IV Q3W was selected based on available clinical PK, efficacy, and safety data from single-agent tiragolumab in combination with atezolizumab or the Phase Ia/Phase Ib GO30103 study in combination with tiragolumab bottom. In the Phase Ia portion of the study with tiragolumab as a single agent, the MTD was not reached and no DLTs were observed with dose escalation. Clinical cutoff date

, anti-drug antibodies (ADA) to tiragolumab were rare in Phase Ia or Phase Ib portions across all dose levels. Long-term stable disease was observed in patients in the Phase Ia portion of the study at tiragolumab doses starting at 400 mg. The MTD was not reached in the phase Ib portion of the trial with tiragolumab plus atezolizumab. Anti-tumor activity, as measured by radiation partial response, was observed across doses for tiragolumab ranging from 30 mg to 600 mg in combination with 1200 mg atezolizumab.

Patients in the atezolizumab plus tiragolumab group will receive integrated assessments of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening symptoms such as pain secondary to disease). Receive treatment as outlined in Table 74 until unacceptable toxicity or loss of clinical benefit later determined by the Investigator. Patients will undergo surgery after Cycle 3 and treatment will resume for the 4th cycle 4-6 weeks after surgery.

Tiragolumab was administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle with a post-infusion observation period, as described in Table 75. Administration of tiragolumab will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Example 18. SAFETY ASSESSMENT OF THE WO39613 TRIAL A.1. Safety parameters and definitions

Safety assessment includes monitoring and recording of adverse events (including serious adverse events and adverse events of particular interest), conducting protocol-specified safety laboratory evaluations, and protocol-specified vital signs. and other protocol-specified studies considered important to the safety evaluation of the study.

B. Adverse Events According to the International Council for Harmonization (ICH) Guidelines for Good Clinical Practice, an adverse event is any adverse event in a clinical trial subject receiving a drug, regardless of the causal attribute. Medical event. Adverse events are

Adverse events can therefore be any of the following:

• Any unfavorable and unintended signs (including abnormal laboratory findings), symptoms or diseases temporally associated with the use of the medicinal product, whether or not considered medicinal-related.
• New disease or exacerbation of existing disease (worsening of known symptom features, frequency, or severity).
- Recurrence of intermittent medical symptoms (eg, headache) not present at baseline.
• Decrease in laboratory values or other laboratory tests (eg, ECG, X-ray) related to symptoms or leading to change in study treatment or concomitant therapy, or discontinuation from study treatment.
• Protocol-specified intervention-related adverse events, eg, those that occur prior to study treatment assignment (eg, screening for invasive procedures such as biopsies).

Serious Adverse Event A serious adverse event is any adverse event that meets any of the following criteria:
• Fatal (ie, the adverse event actually caused or resulted in death).
• Life-threatening (ie, the adverse event puts the patient at immediate risk of death from the investigator's perspective). This does not include adverse events that may have caused death if they occurred or continued in more severe forms.
• Require or prolong hospitalization of inpatients.
• Result in persistent or significant disability/incapacity (ie, the adverse event results in substantial disruption of the patient's ability to perform normal life functions).
• Congenital anomalies/birth defects in neonates/infants born to mothers exposed to the study treatment.
Is a significant medical event in the investigator's judgment (e.g., may endanger the patient or require medical/surgical intervention to prevent one of the consequences listed above) there's a possibility that).

The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe, or according to the NCI CTCAE) and the event itself may be relatively medically insignificant (further findings severe headache without pain, etc.).

Adverse Events of Special Note Adverse events of particular note for the atezolizumab plus tiragolumab arm were:
• Cases of potential drug-induced liver injury, including elevated ALT or AST combined with either elevated bilirubin or clinical jaundice, as defined by Hy's law.
Suspected transmission of infectious agents by study procedures defined below:
Any pathogenic or non-pathogenic organism, virus or infectious particle (eg, the prion protein that transmits infectious spongiform encephalopathy) is considered an infectious agent. Transmission of infectious agents can be suspected from clinical symptoms or laboratory findings indicative of infection in patients exposed to the drug. This term applies only when contamination of the study procedure is suspected.
● Interstitial pneumonia.
●Colitis.
• Endocrine insufficiency: diabetes mellitus, pancreatitis, adrenal insufficiency, and hypophysitis.
• Hepatitis (including AST or ALT) >10 x upper limit of normal.
● Systemic lupus erythematosus.
• Neuropathy: Guillain-Barré syndrome, myasthenia syndrome or myasthenia gravis, and meningoencephalitis.
• Events suggestive of hypersensitivity, IRR, cytokine release syndrome, influenza-like illness, HLH and MAS.
- Nephritis.
o ocular toxicity (eg uveitis, retinitis, optic neuritis);
●Myositis.
• Myopathy, including rhabdomyolysis.
• Cardiac disorders of grade ≧2 (eg, atrial fibrillation, myocarditis, pericarditis).
• Vasculitis.
●Autoimmune hemolytic anemia.
• Severe skin reactions (eg Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrolysis).

Example 19. Statistical Considerations and Analysis Plan for the WO39613 Study The WO39613 study analysis is based on patient data collected by study discontinuation. Unless otherwise stated, efficacy analyzes were based on the efficacy evaluable population defined as all patients who received at least one dose of each drug on their assigned treatment regimen; Based on a safety evaluable population defined as all patients who received any amount of study treatment.

Analysis results are summarized by the treatment actually received by the patient. Data are described and summarized as warranted by sample size. Continuous variables are summarized by using mean, standard deviation, median, and minimum and maximum values. Categorical variables are summarized by the use of counts and percentages. If the sample size is small, use lists instead of tables.

A. Determination of Sample Size The WO39613 test was not designed to take into account explicit power and Type I errors for hypothesis testing.

Instead, this study is designed to obtain preliminary efficacy, safety, and PK data for immunotherapy-based treatment combinations when administered to patients with cisplatin-ineligible MIBC. Approximately 150-350 patients are randomly assigned to control and experimental groups during the study.

B. Efficacy Analysis Primary Efficacy Endpoint The primary efficacy endpoint was pathologic complete response (pCR), defined as the proportion of patients without residual invasive cancer in completely resected specimens . pCR rates are calculated for each group with 90% confidence intervals. Differences in pCR between experimental and control groups are also calculated with 90% confidence intervals. Confidence intervals are estimated by the exact method or the Wald method, depending on the sample size. Patients with missing or no response ratings are classified as non-responders.

Secondary Efficacy Endpoints Secondary efficacy endpoints are landmark recurrence-free survival (RFS), landmark disease-free survival (EFS), and landmark overall survival (OS) at specific time points, respectively. Yes (eg, 12, 18, 24 months). These evaluation items are described below. Landmark RFS, landmark EFS, and landmark OS rates are estimated for each study group using the Kaplan-Meier method and 90% CIs are calculated using the Greenwood formula.

Exploratory Efficacy Endpoints Exploratory efficacy endpoints are RFS, EFS, OS, and percent reduction in pathologic progression.

Recurrence-free survival (RFS) is defined as the time from day 1 in the first cycle after surgery to the first documented recurrence of disease or death from any cause. For patients with no documented disease recurrence or death, RFS will be censored on the day of the last postoperative tumor assessment.

Disease-free survival (EFS) is defined as disease progression precluding surgery as assessed by the investigator from randomization; local or distant disease recurrence; or death from any cause, whichever event occurs first. defined as the time to Patients who have not experienced such an event will be censored at the last post-tumor tumor assessment.

Overall survival (OS) is defined as the time from randomization to death from any cause. Data for non-deceased patients are censored at the last date known to be alive.

Rate of reduction in pathologic extent is defined as the proportion of patients reaching ≤ pT1 pN0 at the time of cystectomy.

The Kaplan-Meier method is used to estimate the median RFS, EFS and OS for each study group. The Brookmeyer and Crowley method is used to construct the 90% CI for the median RFS, EFS and OS for each study arm.

C. Safety Analysis Verbal adverse event terms are mapped to the Medical Dictionary for Regulatory Activities thesaurus terms and adverse event severity is graded according to the NCI CTCAE v 4.0.

Safety will be assessed through a summary of adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to study drug. Exposure to combination treatment and length of safety follow-up are summarized by treatment group within each phase.

Treatment-emergent adverse events occurring after treatment initiation will be summarized. For each patient, the maximum reported severity of each adverse event will be used in the summary by severity grade. List all n treatment emergent adverse events, serious adverse events, adverse events leading to discontinuation of study treatment, grade ≥3 adverse events, deaths, and causes of death, mapped terms, appropriate synonym level , and by NCI CTCAE severity grade.

Relevant laboratory, vital signs (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data are displayed by time with grades identified as appropriate. In addition, a shift table of selected laboratory test results will be used to summarize baseline and post-baseline maximum severity grades. Summarize changes in vital signs.

D. Pharmacokinetic analysis

Sparse samples are collected for PK analysis of atezolizumab (patients who received at least 1 dose of atezolizumab) and drugs administered in combination with atezolizumab (patients who received at least 1 dose of drug). Serum or plasma concentrations of various study drugs were reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range) by treatment group and, where appropriate and data permitted, by cycle and day. , the geometric mean, and the geometric mean coefficient of variation). Individual and median serum or plasma concentrations of the various study drugs are plotted by treatment group and cycle and day. PK data for formulations can be compared to available historical data from internal and previous published studies. Concentration data can be pooled 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.

Relationships between PK parameters and safety, efficacy, PK, and biomarker endpoints can be analyzed and reported by descriptive statistics.

E. Immunogenicity analysis

Immunogenicity is assessed for atezolizumab and other study treatments as appropriate. Immunogenicity analysis included all patients who had at least one anti-drug antibody (ADA) assessment. Patients are grouped according to the treatment received or assigned treatment if they had not received treatment prior to study discontinuation.

For atezolizumab, the numbers and percentages of ADA-positive and ADA-negative patients at baseline (baseline prevalence) and after drug administration (post-baseline incidence) are summarized by treatment group. When determining post-baseline incidence, if a patient is ADA-negative or has missing data at baseline but develops an ADA response after study drug exposure (treatment-induced ADA response), or ADA positive if the patient is ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response) is considered to be If the patient is ADA-negative or has missing data at baseline and all post-baseline samples are negative, or if the patient is ADA-positive at baseline but the titer of the baseline sample is higher than Patients are considered ADA-negative if they have no post-baseline sample with a titer at least 0.60 titer units greater (treatment is unaffected).

For other test procedures that test for ADA, positivity is determined according to standard methods established in previous testing of that drug.

Relationships between ADA status and safety, efficacy, PK, and biomarker endpoints can be analyzed and reported via descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analyzes should be conducted to understand the association between these biomarkers and response to study drug, considering efficacy, safety, PK, immunogenicity, and other biomarker endpoints. will be

G. Interim Analyzes Interim analyzes will be performed during the study, with the earliest interim analysis performed when at least one study arm has completed pre-enrollment and patients have completed postoperative pCR assessments. Further interim analyzes may be performed as deemed appropriate by the sponsor. Posterior probabilities can be used to guide further enrollment based on interim analyzes of clinical activity in the experimental group compared to the control group. For each MIBC cohort, an additional 25 patients can be enrolled in the experimental group (expansion phase) if the interim analysis suggests that the activity in the experimental group is higher than that in the control group. The final decision to expand and terminate the Phase 1b trial will take into consideration the overall benefit-risk balance and overall data, including time-to-event endpoints and safety data, as well as new external information.

Example 20. WO39613 is a phase Ib/II, open-label, multicenter, randomized, comprehensive study evaluating the efficacy and safety of tiragolumab in combination with atezolizumab in patients with metastatic urothelial carcinoma (mUC) in platinum-containing regimens or A Phase Ib/II, open-label, multicenter, randomized, global study evaluating the efficacy and safety of tiragolumab in combination with atezolizumab in patients with later-advanced locally advanced or metastatic UC. This trial will open new treatment arms as new treatments become available, close existing treatment arms showing minimal clinical activity or unacceptable toxicity, or alter the patient population (e.g., prior anticancer designed with flexibility for therapeutic or biomarker status). Eligible patients are initially assigned to one of several treatment groups (see Figure 25). Patients who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen for Stage 2 (see Figure 25).

A. stage 1
During Stage 1, patients are randomly assigned to a control group (atezolizumab [Atezo]) or an experimental group consisting of atezolizumab in combination with tiragolumab (Atezo+Tira) (see Figure 25 and Table 76).

Enrollment within the experimental group is conducted in two phases, a preliminary phase followed by an expansion phase. Approximately 15 patients will be enrolled during the preliminary phase. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients may be enrolled in that group during the expansion phase.

Sponsors may decide to delay or suspend enrollment within a given treatment arm. Experimental groups with inadequate clinical activity or unacceptable toxicity will not be expanded. Additional patients can be enrolled to ensure balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers, to allow for further subgroup analysis. New experimental groups can be added during a trial by amending the protocol.

Patients are randomly assigned to treatment groups, with the exception of the Stage 2 treatment group. Randomization is also dependent on the number of experimental groups available (e.g., if groups are added or group enrollment is suspended pending analysis of results from the preliminary phase) and control There is a provision that the probability of being assigned to a group is 35% or less. Randomization takes into account group-specific exclusion criteria. Patients are ineligible for a particular group if they meet any of the exclusion criteria outlined for that group (see below).

Patients in the atezolizumab control and experimental groups will be integrated with radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening symptoms such as pain secondary to disease). Treatment is until unacceptable toxicity or loss of clinical benefit as determined by the Investigator after evaluation. In the context of cancer immunotherapy (CIT)-induced T-cell responses (called pseudoprogression), due to the possibility of an initial increase in tumor burden caused by immune cell infiltration, Response Evaluation Criteria in Solid Tumors, Radiographic progression by version 1.1 (RECIST v1.1) may not indicate true disease progression. In the absence of unacceptable toxicity, patients who meet the criteria for disease progression by RECIST v1.1 while receiving treatment with a CIT drug are allowed to continue study treatment if they meet all of the following criteria: :
• Evidence of clinical benefit as determined by the investigator after review of all available data.
• Absence of symptoms and signs (including laboratory values, eg, new or worsening hypercalcemia) of definite disease progression.
No decline in ECOG PS that could be attributed to disease progression No tumor progression in critical anatomic sites (e.g., leptomeningeal disease) that cannot be controlled by protocol-allowed medical interventions lack

B. stage 2
Patients who have experienced loss of clinical benefit or unacceptable toxicity as determined by the investigator during Stage 1 are eligible to receive different treatment combinations during Stage 2 if they meet the eligibility criteria. It is possible (see Figure 25). Stage 2 patients who are eligible for more than one treatment arm will be assigned by the Investigator to a Treatment Arm Investigator.

Stage 2 treatment must be initiated within 3 months after the patient experiences loss of clinical benefit or unacceptable toxicity and continue until loss of clinical benefit or unacceptable toxicity as determined by the investigator. do. Patients are encouraged to begin Stage 2 treatment as soon as possible.

Sponsor withholds or discontinues enrollment in Stage 2 treatment arms, as appropriate, based on review of safety data, preliminary efficacy data and supporting information (e.g., biomarker study data) can decide.

C. Rationale for Study Design Patient population and atezolizumab control arm rationale

This trial will enroll patients with locally advanced or metastatic UC who have progressed during or following a platinum-containing regimen.

Atezolizumab (Tecentriq®) is approved for the treatment of UC in patients who have progressed during or after platinum-containing regimens, non-small cell lung cancer, small cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma and melanoma. Approval for second-line treatment of UC patients who progressed on previous platinum-containing regimens was based on data from Cohort 2 of the ongoing Phase II trial GO 29293 (IMvigor 210), followed by IMvigor 210 and Phase III GO29294 trials. (IMvigor211), full approval followed for the same indication in Europe. IMvigor 210 Cohort 2, as of July 12, 2017, enrolled 310 patients with an ORR of 16% (95% CI: 13, 21) and a complete response (CR) rate of 7%, and A median duration of response (DOR) of 24.8 months was observed (95% CI: 13.8, 30.4). Treatment-related grade 3 or 4 adverse events by safety assessment, with 8% of patients having adverse events leading to treatment discontinuation and 16% of patients with fatigue, diarrhea and pruritus being the most common events had an event. Overall, immune-mediated events occurred in 12% of patients, and 7% of patients had grade 3 or 4 immune-mediated events (grade 3 or 4 rash [1%], ALT increased [2%] , increased blood bilirubin [2%], and rhabdomyolysis [1%]). For IMvigor211, median OS of 8.6 months, ORR of 13.4% (10.5, 16.9) and DOR of 21.7 months in the intent to treat (ITT) population as of March 13, 2017 A median value was observed.

Despite the promise of single-agent checkpoint inhibition, only a relatively small number of patients experience benefit, underscoring the need for concomitant immunotherapy. Multiple combination partners in this trial are expected to stimulate the immune system through various mechanisms with the aim of extending the benefit of atezolizumab to the larger population of inoperable locally advanced and metastatic UC.

Rationale for Stage 2 The advent of immunotherapy has revealed real progress in mUC for the first time in 30 years. Despite this progress, substantially more work needs to be done to extend benefits to a larger proportion of patients. A key to the ability to advance immunotherapy will be a better understanding of the underlying tumor immune environment and how sequencing of treatments influences responses.

The Stage 2 portion of this trial will allow some patients to undergo subsequent CIT after disease progression to advance the scientific understanding of immune evasion mechanisms in patients who do not respond to or are unable to proceed with CIT regimens. It is possible to proceed with the combined use. Critical to the ability of patients to enroll in Stage 2 is their ability to undergo a biopsy to allow assessment of the immune environment and any changes that may occur during Stage 1 treatment. Participation in Stage 2 allows patients and providers access to treatment options with the potential for durable responses and improved toxicity profiles not available with conventional chemotherapy. Patients may have a survival benefit by enrolling in Stage 2 during the Stage 2 consent process, as Stage 2 treatment precludes treatment with other potentially more standard options. It is informed that it is a treatment to

Rationale for Atezo+EV and Atezo+SG Groups in Stage 2 Patients may be given the opportunity to receive Stage 2 treatment with Atezo+EV or Atezo+SG after they have lost clinical benefit.

The Atezo+EV combination was selected for Stage 2 because of the documented robust treatment response in patients receiving single-agent enfortumab vedotin who had previously received CPI treatment. Specifically, in a phase I trial of enfortumab vedotin, 8 of 17 people with metastatic bladder treated with the recommended phase II enfortumab vedotin dose (47%; 95% CI :23, 72.2) patients obtained a PR (Petrylak et al., J Clin Oncol, 35(15 Suppl):106, 2017). These findings suggest that enfortumab vedotin may provide benefits in the post-CPI space. Addition of atezolizumab to enfortumab vedotin has the potential to improve response durability. Furthermore, microtubule-disrupting therapy has the potential to induce immunogenic cell death and initiate anti-tumor immune responses.

The Atezo+SG combination was selected for Stage 2 because of the strong treatment responses observed in patients with mUC receiving single-agent sacituzumab govitecan who had progressed on platinum-based and checkpoint inhibitor therapy. rice field. Specifically, in the Phase II TROPHY-U-01 trial, sacituzumab govitecan demonstrated an ORR of 29% in 35 patients, including an ORR of 25.0% in patients with liver metastases. ORR (Tagawa et al., J Clin Oncol, 37(7 Suppl):3199-3212, 2019). These findings suggest that suctuzumab govitecan may provide benefits in the post-CPI space. Combination of atezolizumab and sacituzumab govitecan in patients who have progressed after chemotherapy and immunotherapy Atezolizumab enhances anti-tumor immune responses derived from inflammation mediated by the anti-tumor activity of sacituzumab govitecan synergy may be provided by enabling

Rationale for Immunotherapy-Based Treatment Beyond Early Radiological Progression In immunotherapeutic studies, CR, partial response (PR), and stable disease have each been associated with radiological evidence of a clear increase in tumor burden. shown to occur later. This initial increase in tumor burden caused by immune cell infiltration in the context of a T cell response is called pseudoprogression (Hales et al., Ann Oncol, 21:1944-1951, 2010).

In the PCD4989g study, evidence of tumor growth and subsequent response was observed in several tumor types. Moreover, in some responding patients with radiological evidence of progression, biopsies of new lesions or areas of new growth in existing lesions reveal immune cells and viable cancer cells. it wasn't. Because of the potential for responses after pseudoprogression, this study evaluated whether patients randomly assigned to immunotherapy-based treatment groups continued on combination treatment after overt radiological progression by RECIST v 1.1. possible, but only if the benefit-risk ratio is deemed favorable by the investigator. In the event of unacceptable toxicity or loss of clinical benefit as determined by the investigator after integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical status, patients will be should be discontinued.

The specific objectives of the study and corresponding endpoints are outlined in Tables 78 and 79.

D. Rating and monitoring

All patients were closely monitored for adverse events throughout the study, and adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). )). Patients undergo tumor assessments every 9 weeks for the first 54 weeks (starting on Day 1 of Cycle 1) and every 12 weeks thereafter. Responses will be assessed by the investigator using RECIST v 1.1 (Eisenhauer et al., Eur J Cancer, 45:228-247, 2009)). If clinical activity is demonstrated in an experimental group, the sponsor may request that tumor assessment scans of that group be submitted for evaluation by an independent reading center.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, archiving of tumor tissue may be submitted. Patients discontinuing Stage 1 due to unacceptable toxicity or loss of clinical benefit, as determined by the Investigator (if considered clinically feasible by the Investigator). Collected from These samples, as well as blood samples taken during the study, are utilized in biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points before and during study treatment administration.

E. End of Study and Study Duration End of study is defined as the date the last patient in both stages completed the last visit (including survival follow-up visits conducted by telephone or on-site visit).

The total length of the trial, from initial patient screening to study termination, is approximately 3-5 years.

Example 21. Materials and methods for mUC testing of WO39613A. Inclusion Criteria for Stage 1 Patients must meet all of the criteria outlined below to be eligible for Stage 1:
● Age at the time of signature is ≧18 years old.
• Investigator-determined life expectancy ≧3 months.
- Histologically documented locally advanced (T4b, any N; or any T, N2-N3) or metastatic UC (M1, stage IV) (TCC or urothelial cell carcinoma of the urinary tract) also called; includes renal pelvis, ureter, bladder, and urethra). Patients with mixed histology should have a predominant transitional cell pattern. Locally advanced bladder cancer must be inoperable based on pelvic sidewall or adjacent visceral involvement (clinical stage T4b) or must be large lymph node metastasis (N2-N3) Central examination Availability of representative tumor specimens suitable for determination of PD-L1 and/or additional biomarker status by. A baseline tumor tissue sample is preferably collected from all patients by biopsy performed at study enrollment.

At least 16 slides containing formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or unstained freshly cut serial sections must be submitted along with the relevant pathology report. Patients may still be eligible for the study if only 10-15 slides are available. Tumor tissue must be of good quality based on total tumor content and viable tumor content.

Fine needle aspirations, brushings, cell pellets from pleural effusions, bone metastases, and lavage fluid samples are not permitted. For core needle biopsy specimens, at least three cores should be submitted for evaluation. Patients with less than 3 cores available may still be eligible. TURBT specimens must contain a muscle-invasive component of bladder tumor (ie, T2 or greater) verified by review of local pathology. If the TURBT specimen does not contain a muscle-infiltrating component, specimens obtained at the time of cystectomy/nephroureterectomy or metastatic spread (ie, specimens from metastatic lesions) are required prior to randomization.
• Disease progression during or after treatment with no more than one platinum-containing regimen (eg, GC, MVAC, CarboGem) for inoperable, locally advanced or metastatic UC or disease recurrence. A regimen is defined by the patient receiving at least two cycles of a platinum-containing regimen. Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with platinum-containing adjuvant/neoadjuvant therapy are considered second-line patients. Patients may have received no more than two prior treatment regimens (including required platinum-based regimens) for advanced or metastatic UC. Patients must have documented disease progression during or after all previous regimen(s). Patients with disease progression after chemoradiation must demonstrate progression outside the previous radiotherapy port.

B. Inclusion Criteria for Stage 1 and Stage 2 Patients must meet all of the criteria outlined below to be eligible for Stage 1 or 2:
• Ability to comply with the study protocol, as determined by the investigator • ECOG PS 0 or 1.
- Measurable disease (at least one target lesion) according to RECIST v 1.1 Previously irradiated lesions are only measurable if progressive disease is clearly documented at the site after irradiation can be considered a disease.
- Adequate hematologic and end-organ function as defined by the following laboratory results obtained within 14 days prior to initiation of study treatment:
- ANC ≧1.5×10 ⁹ /L (1500/μL) without granulocyte colony stimulating factor support.
- WBC count ≧2.5×10 ⁹ /L (2500/μL).
- Lymphocyte count ≧0.5×10 ⁹ /L (500/μL).
- Platelet count ≧100×10 ⁹ /L (100,000/μL) without transfusion.
- Hemoglobin > 90 g/L (9.0 g/dL).

Patients may be transfused, but transfusions are not permitted within 2 weeks of clinical screening for eligibility.

Patients with single kidney disease or chronic kidney disease with low erythropoietin production may use erythropoietin stimulants.
- AST, ALT and alkaline phosphatase (ALP) < 2.5X upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases: AST and/or ALT ≤ 5XULN
Patients with documented liver or bone metastases: ALP ≤ 5XULN
- Bilirubin ≤ 1.5 XULN, except:
Patients with known Gilbert's disease: bilirubin level < 3XULN.
- Albumin > 25 g/L (2.5 g/dL).
- Creatinine clearance ≧30 mL/min (calculated using the Cockcroft-Gault formula).
- In patients not receiving therapeutic anticoagulation:
PTT or PTT≤1.5XULN
PT or INR≤1.5XULN.
• For patients on therapeutic anticoagulation: a stable anticoagulation regimen for 14 days prior to initiation of study treatment.
• Negative HIV test at screening. Patients without prior positive HIV test results will undergo HIV testing at screening unless permitted by local regulations.
• Negative total hepatitis B core antibody (HBcAb) test at screening or positive total HBcAb test at screening followed by quantitative hepatitis B virus (HBV) DNA <500 IU/mL at screening. HBV DNA testing is performed only on patients with a positive overall HBcAb test.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening. HCV RNA testing is performed only for patients who test positive for HCV antibodies.
• For women of childbearing potential: consent to abstinence (abstinence from heterosexual intercourse) or use of contraceptive means, and consent to refrain from donating eggs.
• For men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptives and to refrain from donating sperm.

C. Inclusion Criteria for Stage 2 Patients must meet all of the following criteria to be eligible for Stage 2:
• Patients in the atezolizumab control arm: Ability to initiate Stage 2 treatment within 3 months after loss of clinical benefit as determined by the investigator while receiving control treatment.
Patients in the experimental arm during Stage 1: Within 3 months after experiencing unacceptable toxicity or loss of clinical benefit unrelated to atezolizumab as determined by the Investigator while receiving Stage 1 treatment Ability to initiate stage 2 treatment at
• Availability of tumor specimens from biopsies performed at Stage 1 withdrawal.

D. Exclusion criteria

Patients meeting any of the following criteria are excluded from enrollment during Stage 1 and Stage 2: Event grades in exclusion criteria are based on NCI CTCAE v 4.0.

Stage 1 Exclusion Criteria Patients meeting any of the following criteria are excluded from Stage 1:
- Prior treatment with T cell costimulatory therapy or CPIs including anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies.
Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, Nectin-4 targeting agents, Signal regulatory protein α-targeting agents, TIGIT targeting agents, Trop-2 targeting agents, FAP targets Prior treatment with any protocol-specified study treatment, including chemotherapy, 4-1 BB (CD 137) targeted therapy, or treatment with a topoisomerase 1 inhibitor.
- Treatment with study therapy within 28 days prior to initiation of study treatment.
- Any approved anticancer therapy, including chemotherapy or hormone therapy, within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
- Palliative radiotherapy for bone metastases or soft tissue lesions should be completed >14 days before baseline imaging.
- Hormone replacement therapy or oral contraceptives Eligibility for control group only

Exclusion Criteria for Stage 1 and Stage 2 Patients meeting any of the following criteria are excluded from Stage 1 and Stage 2:
- Prior allogeneic stem cell or solid organ transplantation - Systemic immune stimulants (including but not limited to interferon and interleukin-2) within 4 weeks or 5 half-lives (whichever is longer) of drug prior to initiation of study treatment ) treatment.
- Systemic immunosuppressants (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, with the following exceptions ) or prediction of need for systemic immunosuppressants during study treatment:

Patients who received an acute low-dose systemic immunosuppressant or a single pulse dose of systemic immunosuppressant (eg, 48-hour corticosteroids for contrast allergy) are eligible for the study.

Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. be.
- Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study treatment or during atezolizumab treatment or within 5 months after the last dose of atezolizumab - Requires uncontrolled pleural effusion, pericardial effusion, or recurrent drainage treatment Ascites (monthly or more frequently) use of an indwelling catheter (eg, PLEURX®) is permitted.
• Uncontrolled tumor-related pain. Patients requiring analgesics must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy (eg bone metastases or metastases causing nerve impingement) must be treated prior to enrollment. Patients must recover from the effects of radiation. There is no minimum recovery period required. Asymptomatic metastatic lesions that may cause functional impairment with further growth (e.g., epidural metastases not currently associated with spinal cord compression) or intractable pain should be treated with locoregional therapy, if appropriate, prior to enrollment. should be considered.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL or corrected serum calcium > ULN).
• Symptomatic, untreated or actively progressing CNS metastases. Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:
- Measurable disease by RECIST v1.1 must be present outside the CNS - Patient has no history of intracranial or spinal cord hemorrhage.
- Patient has had stereotactic radiotherapy within 7 days prior to the start of study treatment, whole brain radiotherapy within 14 days prior to the start of study treatment, or neurosurgical resection within 28 days prior to the start of study treatment do not have.
- Patient has no ongoing need for corticosteroids as treatment for CNS disease. Anticonvulsant therapy at stable doses is acceptable.
A history of leptomeningeal disease.
Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis Active or history of autoimmune disease or immunodeficiency activity, including but not limited to, excluding:

Patients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormone are eligible for the study. Patients with controlled type 1 diabetes on a stable insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following conditions are met: is.
- The rash must cover <10% of body surface area.
- Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UVA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors within the past 12 months , or no acute exacerbation of underlying symptoms requiring high-potency or oral corticosteroids.
A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia, or idiopathic interstitial pneumonia, or a screening chest computed tomography (CT) scan Evidence of active interstitial pneumonia. A history of radiation pneumonitis (fibrosis) in the radiology area is acceptable.
Appropriately treated cervical carcinoma in situ, nonmelanoma cutaneous carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer with negligible risk of metastasis or death (e.g., , 5-year overall survival [OS] >90%) History of malignancy other than UC within 2 years prior to screening, excluding malignancy. Patients with localized prostate cancer (defined as stage ≤ pT2c, Gleason score ≤ 7 and prostate specific antigen (PSA) ≤ 20 ng/mL at diagnosis of prostate cancer) treated with curative intent and without PSA recurrence are eligible is. Patients with preexisting low-risk prostate cancer (stage cT 1/T2a, Gleason score < 6, and PSA < 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
- Active tuberculosis (TB) (ie, having signs and symptoms of TB).
- Severe infection (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia) within 4 weeks prior to initiation of study treatment, or opinion of investigator Any active infection that may affect patient safety.
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving prophylactic antibiotics (e.g., to prevent exacerbations of urinary tract infections or chronic obstructive pulmonary disease) are eligible for the study;
• Significant cardiovascular disease such as New York Heart Association heart disease (class III or higher), myocardial infarction or cerebrovascular disease, unstable arrhythmia or unstable angina pectoris within 3 months prior to randomization.
- Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >95 mmHg). Antihypertensive therapy to achieve these parameters is acceptable.
• Grade ≥3 bleeding or bleeding event within 28 days prior to initiation of study treatment.
- Major surgical procedure (non-diagnostic) within 4 weeks prior to initiation of study procedure, or anticipation of need for major surgical procedure during study Placement of central venous access catheter (e.g., port, etc.) is not considered and is therefore permissible.
• Adverse events from previous anti-cancer therapy that have not improved to grade ≤ 1, except for any grade of alopecia and grade ≤ 2 peripheral neuropathy.
Any other disease, metabolic dysfunction, physical examination findings, or laboratory findings that contraindicate the use of the study drug may affect the interpretation of results or impair the patient's ability to participate in the study. , or may put the patient at increased risk for procedural complications.
• History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.
• Known intolerance or hypersensitivity to any of the excipient study drugs (including histidine, trehalose dihydrate, and polysorbate 20).
• Known intolerance to any drug required for premedication (acetaminophen, ranitidine, diphenhydramine, methylprednisolone).
• Patients entering Stage 2: During Stage 1, atezolizumab is not tolerated.
• Pregnancy or lactation, or intention to become pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
Patients entering Stage 2: Immunotherapy-related adverse events ≥ Grade 1 at consent or not resolving to baseline, with the following exceptions: Patients with ongoing endocrine events that are adequately controlled with replacement therapy are eligible.

Additional Exclusion Criteria for the Atezo+Tira Group During Stage 1 Patients meeting any of the following criteria will be excluded from the Atezo+Tira group during Stage 1.
• Active EBV infection at screening and known or suspected chronic active EBV infection Patients with a positive EBV viral capsid antigen IgM test at screening are excluded from this group. An EBV polymerase chain reaction (PCR) test is performed as clinically indicated to screen for suspected active or chronically active infection. Patients with a positive EBV PCR test are excluded from this group.

E. Allowed treatment

Patients will be allowed to use the following therapies during the study.
● Oral contraceptives ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (warfarin or low molecular weight heparin, etc.)
● Prophylactic antibiotics or antiviral treatment administered according to institutional standards ● Inactivated influenza vaccination ● Megestrol acetate given as an appetite stimulant ● Mineralcorticoids (eg, fludrocortisone)
o Corticosteroids given for chronic obstructive pulmonary disease or asthma o Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency o Gonadotropin-releasing hormone agonists or antagonists for prostate cancer Hormonal therapy used Palliative radiation therapy (e.g. treatment of known bone metastases or symptomatic relief of pain) outlined below:
After 2 cycles of treatment. Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with atezolizumab may be continued during palliative radiotherapy.
- Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:
Patients experiencing a mixed response requiring local therapy for control of 3 or fewer lesions may still be eligible to continue study treatment after obtaining medical monitor approval. Patients receiving local therapy directed at target lesions are no longer evaluable for radiological response, but remain evaluable for progression.

Premedication with antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent atezolizumab infusions, at the discretion of the Investigator.

Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and _β2- adrenergic must be administered by a sexual agonist).

D. Atezolizumab Group Materials and Methods Atezolizumab was administered at the approved dose (TECENTRIQ® US Prescribing; 1200 mg per day) (Table 80). Anti-tumor activity was observed over doses ranging from 1-20 mg/kg Q3W. In the PCD4989g study, the maximum tolerated dose of atezolizumab was not reached and no dose-limiting toxicity was observed at any dose. Based on both nonclinical studies (Deng et al., MAbs, 8:593-603, 2016) and available clinical pharmacokinetic, efficacy and safety data, a fixed dose of 1200 mg Q3W (mean weight-based dose 15 mg/kg Q3W) was selected.

Patients in the atezolizumab control group were evaluated after integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening symptoms such as pain secondary to disease). Treatment is received until unacceptable toxicity or loss of clinical benefit as determined by the Investigator. Treatment must be initiated within 7 days after treatment assignment. Patients should undergo surgery after Cycle 3 and treatment for Cycle 4 should be resumed 4-6 weeks after surgery.

Administration of atezolizumab occurs in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Atezolizumab infusions will be administered according to the instructions outlined in Table 81.

F. Materials and Methods for Atezolizumab + Tiragolumab Group Atezolizumab will be administered as described above (see Table 81).

Tiragolumab is administered at a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of each 21-day cycle). A fixed dose of 600 mg IV Q3W was selected based on available clinical PK, efficacy, and safety data from single-agent tiragolumab in combination with atezolizumab or the Phase Ia/Phase Ib GO30103 study in combination with tiragolumab bottom. In the Phase Ia portion of the study with tiragolumab as a single agent, the MTD was not reached and no DLTs were observed with dose escalation. Anti-drug antibodies (ADA) to tiragolumab were rare in Phase Ia or Phase Ib portions across all dose levels for clinical cut-off dates. Long-term stable disease was defined as:

Observed at tiragolumab doses starting at 400 mg. The MTD was not reached in the phase Ib portion of the trial with tiragolumab plus atezolizumab. Anti-tumor activity, as measured by radiation partial response, was observed across doses for tiragolumab ranging from 30 mg to 600 mg in combination with 1200 mg atezolizumab.

Patients in the atezolizumab plus tiragolumab arm will receive integrated assessments of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening symptoms such as pain secondary to disease). Receive treatment as outlined in Table 82 until unacceptable toxicity or loss of clinical benefit later determined by the Investigator. Patients will undergo surgery after Cycle 3 and treatment will resume for the 4th cycle 4-6 weeks after surgery.

Tiragolumab was administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle with a post-infusion observation period, as described in Table 83. Administration of tiragolumab will occur in a monitored setting with ready access to trained personnel and appropriate equipment and medications to manage potentially serious reactions.

Safety assessment of the WO39613 mUC test is performed as described in Example 18.

Example 22. Statistical Considerations and Analysis Plan for the WO39613 mUC Study The WO39613 study analysis is based on patient data collected by study discontinuation. Unless otherwise stated, efficacy analyzes were based on the efficacy evaluable population defined as all patients who received at least one dose of each drug on their assigned treatment regimen; Based on a safety evaluable population defined as all patients who received any amount of study treatment.

Analysis results are summarized by the treatment the patient is actually undergoing and by stage (Stage 1 or Stage 2) if applicable. Data are described and summarized as warranted by sample size. Continuous variables are summarized by using mean, standard deviation, median, and minimum and maximum values. Categorical variables are summarized by the use of counts and percentages. If the sample size is small, use lists instead of tables.

A. Determination of Sample Size The WO39613 test was not designed to take into account explicit power and Type I errors for hypothesis testing.

Instead, the study will provide preliminary efficacy, safety and PK data for immunotherapy-based treatment combinations when administered to patients with locally advanced or metastatic UC who have progressed on or after platinum-containing regimens. designed to Approximately 160-385 patients are randomly assigned to control and experimental groups during the study.

B. Effectiveness analysis

The primary efficacy endpoint is the objective response rate (ORR) at 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 ratings are classified as non-responders.

ORR is defined as the proportion of patients with CR or PR and is calculated for each group with a 90% CI (Clopper-Pearson exact method). The difference in ORR between experimental and control groups is also calculated with a 90% CI. CI is estimated by the exact method or the Wald method, depending on the sample size.

Secondary Efficacy Endpoints Secondary efficacy endpoints are progression-free survival (PFS), OS, OS at a specified time point (e.g., 12 months), DOR, and Stage 1 as defined above. disease control (see Table 78). PFS, DOR and disease control will be determined by the investigator according to RECIST v1.1.

DOR is derived for efficacy evaluable patients with CR or PR.

For patients with no documented disease progression or death during the study phase, PFS and DOR will be censored on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day known to be alive.

Median PFS, OS, and DOR are estimated using the Kaplan-Meier method, and 90% CIs are constructed using the Brookmeyer and Crowley method. The OS rate at specific time points is also estimated using the Kaplan-Meier method and the 90% CI is calculated based on the Greenwood estimate of variance.

Disease control rate is defined as the proportion of patients with stable disease, PR or CR for ≧18 weeks and is calculated for each treatment arm, with 90% CIs estimated by use of the Clopper-Pearson exact method.

Exploratory Efficacy Endpoints The exploratory efficacy endpoints are ORR, PFS, DOR and disease control at Investigator-Determined Stage 1 per iRECIST and Investigator-Determined Stage per RECIST v 1.1 and iRECIST. 2 objective response, PFS, DOR and disease control. ORR, PFS, DOR and disease control

DOR analyzed by use of the same method as described above is derived for evaluable patients with CR or PR.

C. Interim Analyzes Interim analyzes will be conducted during the study, with the earliest interim analysis occurring when at least one study arm has completed enrollment in Stage 1 preliminary and patients have been followed for a minimum of 9 weeks. Further interim analysis may be performed as needed. Posterior probabilities can be used to guide further enrollment based on interim analyzes of clinical activity in the experimental group compared to the control group. If the interim analysis suggests that the activity of the experimental group is higher than that of the control group, an additional 25 patients can be enrolled in the experimental group (expansion phase). final decision

The expansion and completion of this Phase 1b study will take into account the overall benefit-risk balance and overall data including time-to-event endpoints and safety data, as well as new external information.

Approximately 15 patients will be enrolled in the Stage 2 treatment arm and followed for a minimum of 9 weeks, after which an interim analysis will also be performed. If clinical activity is not observed in a Stage 2 treatment group, further enrollment in that group will be halted.

D. Other Analyzes Safety, pharmacokinetic, immunogenicity, and biomarker analyzes are performed as described in Example 19.

Example 23. A Phase Ib/II, Open-label, Multicenter, Randomized, Comprehensive Study Evaluating the Efficacy and Safety of Combination Immunotherapy-Based Treatments in Patients With Locally Advanced or Metastatic Esophageal Cancer. Study Design Overview YO39609 is a Phase Ib/II, open-label, multicenter, randomized, comprehensive study evaluating the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in patients with esophageal cancer. This study is designed to obtain preliminary efficacy, safety, and PK data for immunotherapy-based treatment combinations when administered to patients with esophageal cancer. The trial may also open new treatment arms as new treatments become available, close existing treatment arms showing minimal clinical activity or unacceptable toxicity, or alter the patient population (e.g. designed with flexibility for cancer therapy or biomarker status).

Esophageal cancer patients who have had no prior systemic treatment for their disease are enrolled in this study. Eligible patients are randomized to one of three treatment groups. Patients in the control group who experience disease progression or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different Stage 2 treatment regimen.

Stage 1 Treatment During Stage 1, patients with esophageal cancer were treated in either a chemotherapy control group (cisplatin + 5-FU) or two experimental groups: tiragolumab and atezolizumab in combination with chemotherapy (Atezo + tiragolumab + cisplatin + 5-FU) or Randomly assigned to one of atezolizumab (Atezo+cisplatin+5-FU) in combination with chemotherapy. Stage 1 treatment regimen details are shown in Table 84.

The specific objectives and corresponding endpoints for Stage 1 of this study are outlined in Table 85.

Enrollment of the two experimental groups occurs in two phases: a preliminary phase followed by an expansion phase.

Approximately 100-165 patients are enrolled during Stage 1. To ensure a sufficient number of patients with high TIGIT and PD-L1 expression to facilitate assessment of benefits and risks within this subpopulation, up to approximately 40 patients were enrolled in two experimental arms during the preliminary phase. be registered. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients may be enrolled in that group during the expansion phase. Sponsors may decide to delay or suspend enrollment within a given treatment arm.

Experimental groups with minimal clinical activity or unacceptable toxicity will not receive expansion. New experimental groups can be added during a trial by amending the protocol.

Patients in Stage 1 were randomly assigned to treatment groups, and the randomization rate was determined by the number of experimental groups available (e.g., groups were added pending analysis of results from the preliminary phase, or were added to groups). There is a stipulation that the chance of being assigned to the control group is 35% or less depending on when enrollment is suspended). Randomization ratios can be modified to increase enrollment in experimental arms that demonstrate promising clinical activity. Randomization takes into account group-specific exclusion criteria. Patients are ineligible for a particular group if they meet any of the exclusion criteria outlined for that group.

Patients in the control group are treated until unacceptable toxicity or disease progression according to RECIST v1.1. Patients in the experimental group will be enrolled in the study after integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as pain secondary to disease). Treat until unacceptable toxicity or loss of clinical benefit as determined by the attending physician. In the context of cancer immunotherapy (CIT)-induced T-cell responses (called pseudoprogression), radiology according to RECIST v1.1 is recommended due to the possibility of an initial increase in tumor burden caused by immune cell infiltration. progressive progression may not represent true disease progression. In the absence of unacceptable toxicity, patients who meet the criteria for disease progression by RECIST v1.1 while receiving treatment with a CIT drug are allowed to continue study treatment if they meet all of the following criteria: :
- Evidence of clinical benefit as determined by the investigator after review of all available data.
- Absence of symptoms and signs (including laboratory values, e.g., new or worsening hypercalcemia) indicative of definite disease progression - Absence of decline in ECOG performance status attributable to disease progression - Conducting the study Absence of tumor progression in critical anatomic sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical intervention - other treatments to continue study treatment at initial disease progression Written consent of the patient authorizing deferment of choice.

Stage 2 Treatment Patients in the control arm who experienced disease progression by RECIST v1.1 will receive different treatment combinations during Stage 2 if they meet eligibility criteria and the Stage 2 arm is open for enrollment given a choice. The stage 2 treatment regimen is atezolizumab plus tiragolumab.

Patients in the control group who experience unacceptable toxicity may be eligible for Stage 2 treatment after obtaining medical monitor approval. Stage 2 treatment must be initiated within 3 months after the patient experiences disease progression due to Stage 1 RECIST v1.1 or unacceptable toxicity, and no unacceptable toxicity or clinical Continue until loss of profit.

The specific objectives and corresponding endpoints for Stage 2 of this study are outlined in Table 86.

Stage 2 treatment must be initiated within 3 months after the patient experiences disease progression due to Stage 1 RECIST v1.1 or unacceptable toxicity, and no unacceptable toxicity or clinical Continue until loss of profit. However, it is recommended that patients begin Stage 2 treatment as soon as possible.

Sponsors may also discontinue enrollment in Stage 2 treatment arms based on review of safety data, preliminary efficacy data and supporting information (e.g., biomarker study data), as appropriate. can be determined.

A. End of Study and Study Duration End of study is defined as the date the last patient completed the last visit (including survival follow-up visits conducted by telephone or on-site visit).

The total length of the trial, from initial patient screening to study termination, is approximately 3-6 years.

B. Study Design Rationale and Patient Population This study is designed to accelerate the development of cancer immunotherapy (CIT) combinations by identifying early signals and establishing proof-of-concept clinical data in patients with esophageal cancer. ing.

CIT has demonstrated extraordinary success, with significant survival benefits observed across multiple advanced malignancies. Currently popular CIT approaches circumvent immune evasion mechanisms by identifying and targeting T-cell co-inhibitory surface receptors, such as CTLA-4 and PD-L1/PD-1, to circumvent immune evasion mechanisms and enhance anti-tumor responses. is to reactivate Although these targets have provided remarkable clinical success for a variety of cancer indications, ongoing research indicates a series of stepwise events required to generate a continuous anti-tumor immune response (Chen and Mellman, Immunity, 39:1-10, 2013). Each event is critical for an effective response and each is susceptible to several tumor immune evasion mechanisms. Therefore, the need to identify and evade various factors involved in tumor immune evasion is important for propagating anti-tumor immune responses and possibly advancing the field of CIT through combination regimens.

Esophageal cancer is a disease of high unmet medical need, with a 5-year survival rate of 5% in the setting of metastatic disease and 24% in the setting of locally advanced disease. Patients with advanced or metastatic esophageal cancer have limited treatment options, poor prognosis, and minimal overall survival benefit. Therefore, there is a continuing need for more effective and better tolerated treatments for this patient population.

Example 24. Materials and Methods for the YO Study 39609 Study Approximately 100-165 patients with esophageal cancer who have not received prior systemic therapy in this setting are randomized into control and experimental groups during the YO 39609 study.

A. Inclusion Criteria for Stage 1 Patients must meet all of the following criteria outlined below to be eligible for Stage 1:
● Age at the time of signature is 18 years or older ● ECOG performance status is 0 or 1
- Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or adenocarcinoma of the esophagus in locally advanced or metastatic disease.
- A definitive diagnosis of metastatic esophageal cancer is made by evaluating histopathological data in conjunction with clinical and radiological data.
- No prior systemic treatment for esophageal cancer, except for:
- Patients treated with chemotherapy in a locally advanced setting: occurrence of metastases 6 months after the last dose of chemotherapy.
• For patients with adenocarcinoma: no documented ISH-negative HER2 expression in tumor tissue previously collected and assessed at initial diagnosis of disease.
- HER2-negative status defined as ISH unamplified (HER2 to CEP17 ratio <2.0 or single-probe average HER2 gene copy number <4 signals/cell) IHC 0 or IHC 1+ (multiple test results available; If all results do not meet the inclusion criteria definitions, all results should be discussed with the medical monitor to establish patient eligibility).
Investigator-determined life expectancy ≥3 months Creatinine clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula)
• Availability of representative tumor specimens suitable for determination of PD-L1 and TIGIT levels by IHC and/or further biomarker status by retrospective central examination.
- A baseline tumor tissue sample is collected from all patients, preferably by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, archival tumor tissue may be submitted after medical monitor approval, provided that the tissue was obtained from a biopsy performed within 6 months prior to enrollment. provided that the patient had not received any anticancer therapy from the time of biopsy.
- 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. Patients may still be eligible for the study after medical monitor approval if only 10-15 slides are available.

B. Inclusion Criteria for Stages 1 and 2 Patients must meet all of the following criteria outlined below to be eligible for Stages 1 and 2:
- Signed informed consent form - Ability to comply with the study protocol, as determined by the investigator - Measurable disease by RECIST v1.1 - Previously irradiated lesions progressing at the site after irradiation A sexually transmitted disease can only be considered a measurable disease if it is clearly documented.
- Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:
- ANC ≧1.5×10 ⁹ /L (1500/μL) without granulocyte colony stimulating factor support
- Lymphocyte count ≧0.5×10 ⁹ /L (500/μL).
- Platelet count ≧100×10 ⁹ /L (100,000/μL) without transfusion
- Hemoglobin ≥ 90 g/L (9 g/dL) Patients can be transfused to meet this criterion.
- AST, ALT and alkaline phosphatase (ALP) < 2.5 x upper limit of normal (ULN), with the following exceptions:
Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
Patients with documented liver or bone metastases: ALP ≤ 5 x ULN.
- Bilirubin ≤ 1.5 x ULN, except:
Patients with known Gilbert's disease: bilirubin level < 3 x ULN.
- Albumin > 25 g/L (2.5 g/dL).
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN.
- Patients on therapeutic anticoagulants: Stable anticoagulant regimen Negative HIV test at screening, with the following exceptions: Patients with a positive HIV test at screening are stable on antiretroviral therapy Eligible if they have a CD4 count of ≥200/μL and have an undetectable viral load.
Negative hepatitis B surface antigen (HBsAg) test at screening Negative total hepatitis B core antibody (HBcAb) test at screening or positive total HBcAb test at screening followed by quantitative hepatitis B virus at screening (HBV) DNA <500 IU/mL. HBV DNA testing is performed only on patients with a positive overall HBcAb test.
●Negative hepatitis C virus (HCV) antibody test at screening, or negative HCV RNA test after positive HCV antibody test at screening. HCV RNA testing is performed only for patients who test positive for HCV antibodies.
For women of childbearing potential: consent to abstinence (abstinence from heterosexual intercourse) or use contraceptives, and consent to refrain from donating eggs consent to refrain from sexual intercourse) or to use contraceptives and to refrain from donating sperm

C. Inclusion Criteria for Stage 2 Patients must meet all of the following criteria outlined below to be eligible for Stage 2:
• ECOG performance status of 0, 1, or 2;
• Patients randomly assigned to the control arm during Stage 1: Unacceptable toxicity, if medical monitor approval for entry into Stage 2, or RECIST v while receiving control treatment. 1. Ability to initiate Stage 2 treatment within 3 months after experiencing disease progression with 1.
• Creatinine ≤ 1.5 x ULN or CrCl ≥ 30 mL/min (calculated using the Cockcroft-Gault formula).
• Availability of tumor specimens from biopsies performed at Stage 1 discontinuation due to unacceptable toxicity or disease progression according to RECIST v1.1 (if deemed clinically feasible).

D. Exclusion Criteria Patients meeting any of the following criteria are excluded from enrollment between Stage 1 and Stage 2:

Stage 1 Exclusion Criteria Patients meeting any of the following criteria are excluded from Stage 1:
• Prior treatment with any protocol-specified study treatment.
●Patients with known hearing impairment.
• Grade ≥2 peripheral neuropathy as defined by the NCI CTCAE v4.0 criteria.
• Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism that predisposes the patient to 5-FU toxicity.

Exclusion Criteria for Stage 1 and Stage 2 Patients meeting any of the following criteria are excluded from Stage 1 and Stage 2:
• High risk of developing an esophageal fistula by prior medical history or concomitant symptoms of an esophageal fistula, or by clinical assessment or imaging such as T4 classification by endoscopic ultrasound.
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:
- Measurable disease by RECIST v1.1 must be present outside the CNS - Patient has no history of intracranial or spinal cord hemorrhage.
- Patient has had stereotactic radiotherapy within 7 days prior to the start of study treatment, whole brain radiotherapy within 14 days prior to the start of study treatment, or neurosurgical resection within 28 days prior to the start of study treatment do not have.
- Patient has no ongoing need for corticosteroids as treatment for CNS disease. Anticonvulsant therapy at stable doses is acceptable.
- Metastases are restricted to the cerebellar or supratentorial regions (ie, no metastases to the midbrain, pons, medulla oblongata, or spinal cord).
- No evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment.
- Asymptomatic patients with newly detected CNS metastases at screening are eligible for the study after undergoing radiotherapy or surgery and do not require repeat screening brain scans.
Active EBV infection at screening and known or suspected chronic active EBV infection Patients who are positive for EBV IgG and/or Epstein-Barr virus nuclear antigen Eligible only in some cases.
A history of leptomeningeal disease.
• Uncontrolled tumor-related pain. Patients requiring analgesics must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy (eg bone metastases or metastases causing nerve impingement) must be treated prior to enrollment. Patients must recover from the effects of radiation. There is no minimum recovery period required. Asymptomatic metastatic lesions likely to cause functional impairment or intractable pain with further growth (e.g., epidural metastases not currently associated with spinal cord compression) should be treated with locoregional, if appropriate, prior to enrollment. Treatment should be considered.
• Patients with uncontrolled pleural effusions, pericardial effusions, or ascites requiring recurrent drainage procedures (monthly or more frequently) with indwelling catheters (eg, PLEURX®) are permitted.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL, or corrected calcium > ULN).
Myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis Active or history of autoimmune disease or immunodeficiency activity, including but not limited to, excluding:

Patients with a history of autoimmune-related hypothyroidism taking thyroid replacement hormone are eligible for the study.

Patients with controlled type 1 diabetes on an insulin regimen are eligible for the study.

Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with skin manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study if all of the following conditions are met: is.
- The rash must cover less than 10% of body surface area.
- Disease is well controlled at baseline, requiring only low-potency topical corticosteroids - Psoralen + UVA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors within the past 12 months , or no acute exacerbation of underlying symptoms requiring high-potency or oral corticosteroids Idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced interstitial pneumonia, or history of idiopathic interstitial pneumonia or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scan. A history of radiation pneumonitis (fibrosis) in the radiology area is acceptable.
● Active tuberculosis.
- Significant cardiovascular disease (New York Heart Association Class II or greater heart disease, myocardial infarction, cerebrovascular accident, etc.), unstable arrhythmia or unstable angina pectoris within 3 months prior to initiation of study treatment.
o Major surgical intervention (other than diagnosis) within 4 weeks prior to initiation of study procedure or anticipation of need for major surgical procedure during study o Appropriately treated cervical carcinoma in situ, non-melanoma skin pre-screening2, except for malignancies with negligible risk of metastasis or death (e.g., 5-year OS >90%) such as cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer History of malignancy other than esophageal cancer within 1 year.
- Severe infection within 4 weeks prior to initiation of study treatment (including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia)
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment - Patients receiving prophylactic antibiotics (e.g., to prevent exacerbation of urinary tract infection or chronic obstructive pulmonary disease) are eligible for the study is;
- Prior allogeneic stem cell or solid organ transplantation - Any other disease, metabolic dysfunction, physical examination findings, or laboratory findings that contraindicate study drug use may affect interpretation of results or may put the patient at increased risk of procedural complications.
• Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study treatment or during atezolizumab treatment or within 5 months after the last dose of atezolizumab • Current treatment with antiviral therapy for HBV.
• Known allergy or hypersensitivity to the study drug or any of its excipients.
- Treatment with study therapy within 28 days prior to initiation of study treatment.
- Pretreatment with CD137 agonist or immune checkpoint blockade therapy including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies.
• Treatment with systemic immune stimulants (including but not limited to interferon and interleukin-2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
- Treatment with systemic immunosuppressants (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, except: or prediction of need for systemic immunosuppressants during study treatment:
- Patients who received acute low-dose systemic immunosuppressants or single pulse-dose systemic immunosuppressants (e.g., 48-hour corticosteroids for contrast allergy) after obtaining medical monitor approval , are eligible for the test.
- patients who have received mineralocorticoids (e.g. fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency Eligible for testing.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese Hamster Ovary Cell Products or any component of Atezolizumab and Tiragolumab formulations.
- Pregnancy or lactation, or intention to become pregnant during study treatment or within 5 months after the last dose of atezolizumab and within 5 months after the last dose of tiragolumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

E. Allowed Treatments Patients will be allowed to use the following treatments during the study.
● Oral contraceptives ● Hormone replacement therapy ● Prophylactic or therapeutic anticoagulant therapy (such as stable-dose warfarin or low-molecular-weight heparin)
Inactivated influenza vaccination Megestrol acetate given as an appetite stimulant Mineralcorticoids (eg fludrocortisone)
o Corticosteroids given for chronic obstructive pulmonary disease or asthma o Low-dose corticosteroids given for orthostatic hypotension or adrenal insufficiency o Palliative radiation therapy as outlined below (e.g., Treatment of known bone metastases or symptomatic relief of pain):

Palliative radiotherapy is permissible as long as it does not interfere with the assessment of tumor target lesions (eg, the irradiated lesion should not be the only site of measurable disease). Treatment with atezolizumab may be continued during palliative radiotherapy.
- Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:
Patients experiencing a mixed response requiring local therapy for control of 3 or fewer lesions may still be eligible to continue study treatment after obtaining medical monitor approval. Patients receiving local therapy directed at target lesions are no longer evaluable for radiological response but remain evaluable for progression.

Premedication with antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent atezolizumab infusions, at the discretion of the Investigator.

Patients experiencing infusion-related symptoms should be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice. can be done. Severe infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, oxygen desaturation, or rapid breathing should be treated with clinically indicated supportive care (e.g., supplemental oxygen and _β2- adrenergic must be administered by a sexual agonist).

F. Dosing and Administration Patients in the following treatment groups will be provided with radiological and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as pain secondary to disease). Receive the treatment outlined until unacceptable toxicity or loss of clinical benefit as determined by the Investigator after the pooled assessment.

Atezolizumab + Tiragolumab + Cisplatin + 5-Fluorouracil Group Patients in the atezolizumab + tiragolumab + cisplatin + 5-FU group receive the treatments outlined in Table 87.

Atezolizumab + Cisplatin + 5-Fluorouracil Group Patients in the atezolizumab + cisplatin + 5-FU group receive the treatments outlined in Table 88.

Control group (cisplatin + 5-FU)
Cisplatin is administered by IV infusion over 120 minutes at a dose of 80 mg/m ² on day 1 of the first six 21-day cycles. 5-FU is administered by continuous IV infusion starting on Day 1 of each 21-day cycle at a dose of 800 mg/m ² /24 hours over Days 1-5 (120 hours). Cisplatin therapy is continued for a total of 6 cycles unless unacceptable toxicity occurs or the patient is withdrawn from study treatment for any reason. Patients in the cisplatin+5-FU control group receive treatment until unacceptable toxicity or disease progression according to RECIST v1.1.

Stage 2 Treatment of Control Arm (Atezolizumab + Tiragolumab) Patients in the atezolizumab + tiragolumab arm receive the treatments outlined in Table 89.

Patients who experience disease progression according to RECIST v1.1 will be given the option to receive different treatment combinations during Stage 2 if they meet the eligibility criteria and the Stage 2 arms of the trial are open for enrollment.

Patients who experience unacceptable toxicity may be eligible to receive treatment during Stage 2 only after meeting eligibility criteria and obtaining medical monitor approval. Stage 2 treatment must be initiated within 3 months after the patient experiences disease progression or unacceptable toxicity. Tumor assessments performed prior to or at the time of disease progression or unacceptable toxicity during Stage 1, provided primary assessment is performed within 28 days prior to initiation of Stage 2 treatment (i.e., Day 1 of Cycle 1) , can serve as a baseline assessment for Stage 2. Stage 2 treatment continues until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Atezolizumab infusions will be administered according to the instructions outlined in Table 90.

Tiragolumab infusions will be administered according to the instructions outlined in Table 91.

G. Safety Evaluation Phase To account for potential overlapping toxicities in the atezolizumab + tiragolumab + cisplatin + 5-FU arm, enrollment will be discontinued after approximately 6 patients have been enrolled to allow for safety assessment. Safety assessment will consist of a minimum of 6 subjects who received at least 1 dose of treatment (i.e., 1 dose of each drug for a given combination) and who completed safety follow-up during at least 1 full treatment cycle. based on safety data from patients with If the combination is determined to be sufficiently safe, enrollment will resume in that group.

H. Assessment and Monitoring All patients were closely monitored for adverse events throughout the study, and adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE). v4.0)). Patients undergo tumor assessments every 6 weeks (starting on Day 1 of Cycle 1) for the first 12 months and then every 6 or 12 weeks thereafter. Responses will be assessed by the investigator using RECIST v1.1 (Eisenhauer et al., Eur J Cancer, 45:228-247, 2009). Responses per modified RECIST v1.1 to immune-based therapeutics (iRECIST) are programmatically determined based on investigator-assessed individual lesion data (Seymour et al., Lancet Oncol, 18:e143- 152, 2017). If clinical activity is demonstrated in an experimental group, the sponsor may request that tumor assessment scans of that group be submitted for evaluation by an independent reading center.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy performed at study enrollment. If a biopsy is not considered feasible by the Investigator, archiving of tumor tissue may be submitted. Unacceptable toxicity, disease progression by RECIST v 1.1 (control arm), or loss of clinical benefit (experimental arm) as determined by the investigator, if deemed clinically feasible Tumor tissue is collected from patients who discontinue Stage 1 because of For patients enrolled in the experimental arm during the expansion phase, unless an in-treatment tissue sample was already collected and determined to be evaluable from a minimum of 15 patients treated with the same CIT combination, In-treatment tumor tissue samples will be collected 4 weeks after initiation of Stage 1 treatment (if clinically feasible). These samples, as well as blood samples taken during the study, are utilized in biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points before and during study treatment administration.
Tumor and response assessment

Patients were evaluated until radiographic disease progression by RECIST v 1.1 at baseline and every 6 weeks for the first 12 months after starting treatment (± 1 week), then every 12 weeks (± 2 weeks) regardless of dose delay, and such patients will undergo tumor assessments every 8 weeks (± 1 week) to undergo tumor assessment.

Therefore, for patients who discontinue treatment for reasons other than disease progression or loss of clinical benefit, tumor assessment should be performed on schedule, even if the patient starts a new non-protocol-specified anticancer therapy. should be continued in accordance with At the investigator's discretion, tumor assessments can be repeated whenever progressive disease is suspected.

A Stage 2 baseline tumor assessment must be performed within 28 days prior to initiation of Stage 2 treatment (ie, Day 1 of Cycle 1). For patients eligible for Stage 2, a tumor assessment performed prior to or at the time of unacceptable toxicity or disease progression due to RECIST v1.1 (control group) or loss of clinical benefit (experimental group) during Stage 1; May serve as a Stage 2 baseline assessment if performed within 28 days prior to initiation of Stage 2 treatment.

All measurable and evaluable lesions should be assessed and documented at screening (both Stage 1 and Stage 2). Brain metastases treated with radiotherapy or surgery are documented as sites of metastatic disease, although they are not considered measurable or evaluable. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment need not be repeated at Screening.

Screening evaluations must include CT scans (with oral and/or IV contrast) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis. A spiral CT scan of the chest can be obtained, but this is not a requirement. If contrast-enhanced CT scans are contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be performed and an MRI scan of the abdomen and pelvis (if available). with IV contrast) should be performed. A bone scan and a CT scan of the neck should also be performed if clinically indicated. Other methods of measurable disease assessment according to RECIST v1.1 may be used at the investigator's discretion.

If CT scans for tumor assessment are performed on a positron emission tomography/CT scanner, the CT acquisition must conform to the standard for full contrast-enhanced diagnostic CT scans.

All measurable and/or evaluable lesions identified at baseline should be re-evaluated at subsequent tumor assessments. Baseline-identified brain metastases that have been treated with radiotherapy or surgery are not measurable or assessable unless disease progression in the brain is suspected (i.e., the patient becomes symptomatic). not considered. Therefore, no subsequent head CT scan is necessary unless clinically indicated. The same X-radiation procedure used to assess disease sites at screening should be used for subsequent tumor assessment (eg, same contrast protocol for CT scan). To facilitate assessment of response by iRECIST, tumor assessment should be continued after disease progression by RECIST v1.1 for patients treated beyond progression. This includes continuous measurement of target lesions, assessment of non-target lesions (including monitoring for further deterioration of any non-target lesion that has demonstrated definite progression), and any new Evaluation of identified lesions (including measurements if lesions are measurable) is included. Overall response at one time point will be assessed by the investigator using RECIST v1.1.

Biomarker assessment Exploratory biomarker studies include, but are not limited to, tumor molecular subtypes and tumor immunobiology, PD-L1, lymphocyte subpopulations, T cell receptor repertoire, T cell activation of IC and subsets thereof or analysis of genes or gene signatures associated with cytokines related to density, localization and activation state, including DNA or RNA extraction, analysis of somatic mutations, and next generation sequencing (NGS) (whole experiment). The use of some-body sequencing (WES)) may be included.

Blood samples for biomarker assessment are collected at baseline and during the study. Changes in biomarkers in blood can provide evidence of biological activity of a particular treatment 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 are It may allow the development of blood-based biomarkers that help define future treatments that may predict whether they are more likely to benefit from a particular combination of treatments.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy performed at study enrollment. Tumor tissue samples collected at baseline are used for determination of PD-L1 and TIGIT expression and for exploratory studies for biomarkers. If deemed clinically viable by the Investigator, the tumor tissue is Stage 1 for unacceptable toxicity, disease progression by RECIST v1.1, or loss of clinical benefit as determined by the Investigator. Allowing analysis of tumor tissue biomarkers collected from patients who discontinued during the course of study and associated with study treatment resistance, disease progression, and clinical benefit.

If deemed clinically feasible by the Investigator, patients enrolled in the experimental arm during the expansion phase must have already collected on-treatment tissue samples from a minimum of 15 patients treated with the same CIT combination. Undergo an in-treatment biopsy 4 weeks (±7 days) after initiation of Stage 1 therapy, unless determined to be evaluable. In-treatment tissue samples are used to try to better understand potential biological changes that occur during treatment with CIT combinations (including immune evasion), to provide evidence of pharmacodynamic effects, or to be hypothesized. Collected in an attempt to ascertain the mechanism of action.

Tumor samples are evaluated for biomarkers such as tumor infiltration IC, PD-L1, TIGIT and CD8. Evaluation of the tumor microenvironment in response to treatment within each group, including changes in the number of tumor-infiltrating ICs and functional status, will allow validation of postulated mechanisms of action, as well as appropriate doses and doses for specific treatment combinations. It can provide confirmation that exposure has been achieved.

Tumor tissue and blood samples are analyzed by use of NGS, including WES, to predict response to study drug, associated with progression to more severe disease states, associated with acquired resistance to study drug, of adverse events. Somatic mutations can be identified that are associated with developmental susceptibility or that can enhance knowledge and understanding of disease biology.

Example 25. Statistical Considerations and Analysis Plan for the YO39609 Study Final study analysis is based on patient data collected through study discontinuation. Unless otherwise stated, efficacy analyzes were based on the efficacy evaluable population defined as all patients who received at least one dose of each drug on their assigned treatment regimen; Based on a safety evaluable population defined as all patients who received any amount of study treatment.

Analysis results are summarized by the treatment actually received by the patient. Results are summarized by stage (stage 1 or 2) whenever stage 2 treatment is available. Data are described and summarized as warranted by sample size. Continuous variables are summarized using mean, standard deviation, median, range, and interquartile range. Categorical variables are summarized by the use of counts and percentages. If the sample size is small, use lists instead of tables.

New baseline values will be established for Stage 2 efficacy and safety analyses. A new baseline tumor assessment is established for assessment of tumor response. For other endpoints (eg, change from baseline in vital signs or laboratory test results), the patient's last non-missing value before the first dose during Stage 2 serves as the new baseline.

Determination of Sample Size This test was not designed to take explicit power and Type I errors into account for hypothesis testing. Instead, this study is designed to obtain preliminary efficacy, safety, and PK data for immunotherapy-based treatment combinations when administered to patients with esophageal cancer.

The trial enrolls patients with esophageal cancer who have never received prior systemic therapy in this setting. Approximately 100-165 patients are randomly assigned to control and experimental groups during the study.

A. Efficacy Analysis The efficacy evaluable population is defined as all patients who received at least one dose of each drug for their assigned treatment regimen. Efficacy endpoints will be summarized by actual treatment group.

Primary Efficacy Endpoint The primary efficacy endpoint is the Objective Response Rate (ORR) during Stage 1 according to RECIST v1.1, defined as the proportion of patients who achieve an objective response. An objective response is defined as two consecutive chance complete or partial responses at least 4 weeks apart, as determined by the investigator using RECIST v 1.1. Patients who do not meet this criteria, including those who do not have a post-baseline tumor assessment, are considered non-responders. Summarize the ORR and its 95% CI (Clopper-Pearson method). The ORR analysis population is the efficacy evaluable population.

Secondary Efficacy Endpoints As defined in Table 77, the secondary efficacy endpoints were PFS, OS, OS at specified time points (e.g., 6 months and 12 months), duration of response (DOR) , disease control during stage 1, objective response in patients with TIGIT-positive tumors, and objective response in patients with PD-L1-positive tumors. PFS, DOR and disease control will be determined by the investigator according to RECIST v1.1.

DOR is derived for efficacy evaluable patients with confirmed complete or partial response. For patients with no documented disease progression or death during the study phase, PFS and DOR will be censored on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day known to be alive.

The Kaplan-Meier method is used to estimate median PFS, OS, and DOR, and 90% confidence intervals (CI) are constructed by using the Brookmeyer and Crowley method. The OS rate at a particular time point was also estimated using the Kaplan-Meier method and the 90% CI is calculated based on Greenwood's estimate of variance.

Disease control rate, defined as the proportion of patients with stable disease, partial response, or complete response over 16 weeks, was calculated for each treatment group, and 90% CIs were estimated by using the Clopper-Pearson exact method. be.

Exploratory Efficacy Endpoints Exploratory efficacy endpoints were objective response, PFS, DOR and disease control at Stage 1 as determined by the investigator according to iRECIST, and investigator-determined according to RECIST v1.1 and iRECIST. Stage 2 objective response, PFS, DOR and disease control.

B. Safety Analysis The safety analysis includes all patients who received at least one dose of any component of the study treatment. Exposure to study treatments is summarized overall and by actual treatment group within each phase.

Verbal adverse event terms are mapped to the Medical Dictionary for Regulatory Activities thesaurus terms and adverse event severity is graded according to NCI CTCAE v 4.0.

Safety will be assessed through a summary of adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to study drug. Exposure to combination treatment and length of safety follow-up are summarized by treatment group within each phase.

Treatment-emergent adverse events occurring after treatment initiation will be summarized. For each patient, the maximum reported severity of each adverse event will be used in the summary by severity grade. List all n treatment emergent adverse events, serious adverse events, adverse events leading to discontinuation of study treatment, grade ≥3 adverse events, deaths, and causes of death, mapped terms, appropriate synonym level , and by NCI CTCAE severity grade.

Relevant laboratory, vital signs (pulse rate, respiratory rate, pulse oximetry, blood pressure, and temperature), and ECG data are displayed by time with grades identified as appropriate. In addition, baseline and post-baseline maximum severity grades will be summarized using a shift table of selected laboratory tests. Summarize changes in vital signs and ECG.

C. Pharmacokinetic Analysis Collect sparse samples for PK analysis of atezolizumab (patients who received atezolizumab at least 1 dose) and the indicated drugs administered in combination with atezolizumab (patients who received at least 1 dose of drug) . Serum or plasma concentrations of various study drugs were reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range) by treatment group and, where appropriate and data permitted, by cycle and day. , the geometric mean, and the geometric mean coefficient of variation). Individual and median serum or plasma concentrations of various study drugs are plotted by treatment group, cycle and day. PK data for formulations can be compared to available historical data from internal and previous published studies. Atezolizumab concentration data can be pooled 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.

D. Immunogenicity Analysis Immunogenicity is assessed for atezolizumab and other study treatments as appropriate. The atezolizumab immunogenicity analysis includes all patients with at least one anti-drug antibody (ADA) assessment. Patients are grouped according to the treatment received or assigned treatment if they had not received treatment prior to study discontinuation. For atezolizumab, baseline (baseline prevalence) and post-baseline (post-baseline incidence) numbers and percentages of ADA-positive and ADA-negative patients are summarized by treatment group. For other test treatments that test for ADA, ADA positivity is determined according to standard methods established for previous testing of these drugs. Relationships between ADA status and safety, efficacy, PK, and biomarker endpoints can be analyzed and reported using descriptive statistics.

E. Biomarker Analyzes Exploratory biomarker analyzes are performed to understand the association between these biomarkers and response to study drug in view of efficacy and safety endpoints.

F. Interim Analyzes Interim analyzes will occur over the course of the study, with the earliest (Phase 1) interim analyzes occurring when at least one study arm has completed pre-phase enrollment and patients have been followed for a minimum of 6 weeks. Posterior probabilities can be used to guide further enrollment into treatment groups based on interim analysis of clinical activity in experimental groups compared to controls. If the interim analysis suggests that the activity of the experimental group is higher than that of the control group, an additional 25 patients can be enrolled in the experimental group. Approximately 15 patients will be enrolled in the Stage 2 treatment arm and followed for a minimum of 6 weeks, after which an interim analysis will also be performed. If clinical activity is not observed in a Stage 2 treatment group, further enrollment in that group will be halted.

Example 26. PD-L1 as a predictive biomarker for tiragolumab plus atezolizumab treatment
In a phase Ib trial (GO30103; NCT02794571), tiragolumab was well tolerated as monotherapy and in combination with atezolizumab in multiple solid tumor types. The randomized phase II CITYSCAPE trial (NCT03563716) in 1L NSCLC showed clinically meaningful improvements in ORR and PFS with tiragolumab + atezolizumab versus placebo + atezolizumab in the intention-to-treat (ITT) population. Greater improvement was seen in the subgroup with PD-L1 Tumor Proportion Score (TPS) ≥50% (as assessed using the PharmDx 22C3 IHC assay; data cut-off December 2019; median follow-up 10.9 months). ).

The values of PD-L1 as a predictive biomarker for tiragolumab plus atezolizumab treatment were found to be consistent across different PD-L1 assays. PD-10 for all available patient samples using the pharmDx 22C3 assay (ITT population) and the Conformite Europeenne in vitro diagnostics (CE-IVD 0 VENTANA SP 263 IHC assay (biomarker evaluable population)). IHC was performed to assess L1 protein expression and the level of PD-L1 expression was scored using an established algorithm for each assay.The baseline characteristics of the BEP and ITT populations were similar. (Table 92).

The prevalence of the PD-L1 subgroup was similar between the two IHC assays (Figure 26). For the PD-L1 22C3 assay, high TP was classified as TPS≧50% and low TPS as TPS 1-49%. For the SP263 IHC assay, high TC was classified as TC≧50% and low TC as TC1-49%. PD-L1-positive (TC ≥ 1%) subgroup defined by SP263 (PFS HR 0.56, 95% CI: 0.34-0.92) and PD-L1-positive (TPS ≥ 1%) defined by 22C3 %) subgroups (Figures 27A, 27B, 28A, 28B) with comparable ORR and PFS improvements with tiragolumab plus atezolizumab versus atezolizumab monotherapy. PD-L1 high (TC ≥ 50%) subgroup defined by SP263 (PFS HR 0.23, 95% CI: 0.10-0.53) and PD-L1 high (TPS ≥ 50%) defined by 22C3 %) subgroups (Figures 29A, 29B, 30A, 30B) also showed comparable ORR and PFS improvements with tiragolumab plus atezolizumab versus atezolizumab monotherapy.

High PD-L1 expression as assessed by either 22C3 or SP263 IHC may be an important predictive biomarker for tiragolumab plus atezolizumab combination therapy.

VII. Other embodiment

Some embodiments of the technology described herein can be defined according to any of the following numbered embodiments of embodiment sets A, B, and C.

Embodiment set A:
1. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, PD-1 axis at a dose of about 900 mg to about 1500 mg every three weeks. administering to said subject a dosing regimen comprising one or more dosing cycles comprising a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

2. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis at a dose of about 1400 mg to 2000 mg every 4 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

3. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis at a dose of about 600 mg to about 1200 mg every two weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

4. 4. The method of embodiment 2 or 3, wherein said method further comprises administering one or more chemotherapeutic agents to said subject.

5. The method of any of embodiments 1-4, wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3);
(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);
(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO:5); and (f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO:6).
6. The method of any one of embodiments 1-5, comprising

7. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and (d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and the following heavy chain variable region FRs:
(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where 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).
7. The method of any one of embodiments 1-6, further comprising

8. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or (c) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18. , SEQ ID NO:19.

9. The method of any one of embodiments 1-8, wherein said anti-TIGIT antagonist antibody is tiragolumab.

10. The method of any one of embodiments 1-9, wherein said 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 1-10, wherein said 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 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 13. The method of embodiment 12.

14. The method of any one of embodiments 1-13, wherein said PD-1 axis binding antagonist is a monoclonal antibody.

15. The method of any one of embodiments 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21.

17. The method of any one of embodiments 2-16, wherein said method comprises administering to said subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. 18. The method of embodiment 1 or 17, wherein said non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. 19. The method of embodiment 18, wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331, especially etoposide.

20. 20. The method of embodiment 18 or 19, wherein said topoisomerase II inhibitor is administered at a dose of 100 mg/m2.

21. 21. The method of any one of embodiments 17-20, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin, particularly carboplatin.

22. The method of any one of embodiments 17-21, wherein said platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration.

23. The method of any one of embodiments 1-22, wherein said method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. wherein the induction phase comprises four initial dosing cycles, 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; 24. The method of embodiment 23, wherein

25. 25. The method of embodiment 23 or 24, wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent and/or non-platinum-based chemotherapeutic agent.

26. 26. The method of any one of embodiments 1-25, wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody.

27. The method of any one of embodiments 1-26, wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody.

28. 28. The method of any one of embodiments 1-27, wherein said cancer is lung cancer.

29. 29. The method of embodiment 28, wherein said lung cancer is small cell lung cancer (SCLC), particularly extensive-stage SCLC (ES-SCLC).

30. 29. The method of embodiment 28, wherein said lung cancer is non-small cell lung cancer (NSCLC), particularly locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. 29. The method of embodiment 28, wherein said lung cancer is locally advanced, unresectable or metastatic non-squamous NSCLC.

32. 29. The method of embodiment 28, wherein said lung cancer is resectable lung cancer.

33. 28. The method of any one of embodiments 1-27, wherein said cancer is cervical cancer.

34. 28. The method of any one of embodiments 1-27, wherein said cancer is early triple negative breast cancer (eTNBC).

35. 28. The method of any one of embodiments 1-27, wherein the cancer is head and neck cancer.

36. 28. The method of any one of embodiments 1-27, wherein said cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. 28. The method of any one of embodiments 1-27, wherein said cancer is bladder cancer.

38. 38. The method of embodiment 37, wherein said cancer is urothelial carcinoma (UC), in particular metastatic urothelial carcinoma (mUC).

39. 28. The method of any one of embodiments 1-27, wherein said cancer is pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC).

40. 28. The method of any one of embodiments 1-27, wherein said 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 with cancer according to the method of any one of embodiments 1-40.

42. 42. The kit of embodiment 41, wherein said 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 with cancer, wherein the method is as described in any one of embodiments 1-40. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

44. 41. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject with cancer in combination with a PD-1 axis binding antagonist, said treatment being a method according to any one of embodiments 1-40. is due to use.

45. 45. Use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

46. 45. Use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single formulation.

47. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis at a dose of about 80 mg to 2000 mg every 4 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

48. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis at a dose of about 20 mg to 1600 mg every 4 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

49. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks and a PD-1 axis at a dose of about 20 mg to about 1600 mg every two weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

50. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every 2 weeks and a PD-1 axis at a dose of about 80 mg to 2000 mg every 4 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

51. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis at a dose of about 100 mg to 1000 mg every 6 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist.

52. The method of any one of embodiments 47-51, wherein said method further comprises administering to said subject one or more chemotherapeutic agents.

53. 53. The method of embodiment 52, wherein said method comprises administering to said subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

54. A method of treating a subject with cancer, said method comprising an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis at a dose of about 80 mg to about 1600 mg every 3 weeks. administering to said subject a dosing regimen comprising one or more dosing cycles comprising a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

55. 55. The method of embodiment 53 or 54, wherein said method comprises an induction phase and a maintenance phase.

56. 56. The method of embodiment 55, wherein said induction phase and maintenance phase each comprise one or more dosing cycles.

57. 57. The method of embodiment 55 or 56, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent.

58. 58. The method of any one of embodiments 55-57, wherein said maintenance phase does not comprise administration of said non-platinum chemotherapeutic agent.

59. The maintenance phase comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at doses of about 200 mg to about 2000 mg every 4 weeks and the PD-1 axis binding antagonist at doses of about 80 mg to about 2000 mg every 4 weeks. , embodiment 58.

60. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every three weeks and an anti-PD- administering to said subject a dosing regimen comprising one or more dosing cycles of an antagonist antibody, wherein said anti-PD-1 antagonist antibody is pembrolizumab.

61. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein said pembrolizumab is administered about every 6 weeks A method wherein a dose of between 100 mg and about 1000 mg is administered.

62. A method for treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks, between about 80 mg and about 1600 mg every three weeks A PD-1 axis binding antagonist at a dose and an antimetabolite at a dose between about 10 mg/m2 and about 10000 mg/m2 orally twice daily every 3 weeks for 2 weeks on/1 week off. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of an agent.

63. A method of treating a subject with cancer, said method comprising an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis at a dose of about 80 mg to about 1600 mg every 3 weeks. A method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist, gemcitabine and nab-paclitaxel.

64. 53. The method of embodiment 52, wherein said one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel.

65. A method for treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks, between about 80 mg and about 1600 mg every three weeks administering to said subject a dosing regimen comprising a dose of a PD-1 axis binding antagonist and one or more dosing cycles of a VEGF antagonist at a dose between about 1 mg/kg and about 35 mg/kg every three weeks. ,Method.

66. 1. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase,
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding antagonist every 3 weeks and a non-platinum chemotherapeutic agent every 3 weeks; The method, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent.

67. 1. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase,
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more times of said anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and said PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks; wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent or said non-platinum-based chemotherapeutic agent.

68. The method of any one of embodiments 56-59, 66 and 67, wherein said induction phase comprises 4-6 dosing cycles.

69. The method of any one of embodiments 53-59 and 66-68, wherein
(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel, or (c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is etoposide,
The method of any one of embodiments 53-59 and 66-68.

70. 70. The method of any one of embodiments 47-69, wherein said cancer is a solid tumor.

71. 71. The method of any one of embodiments 47-70, wherein said cancer is locally advanced or metastatic.

72. the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, renal cancer, 72. The method of any one of embodiments 47-71, which is melanoma, or ovarian cancer.

73. 73. The method of embodiment 72, wherein the cancer is lung cancer.

74. 74. The method of embodiment 73, wherein said lung cancer is NSCLC, particularly locally advanced unresectable NSCLC.

75. 75. The method of embodiment 74, wherein the NSCLC is stage IIIB NSCLC.

76. 76. The method of any one of embodiments 73-75, wherein said lung cancer is recurrent or metastatic NSCLC.

77. 77. The method of embodiment 76, wherein the NSCLC is Stage IV NSCLC.

78. 78. The method of embodiment 77, wherein said subject has not been previously treated for Stage IV NSCLC.

79. 74. The method of embodiment 73, wherein said lung cancer is small cell lung cancer (SCLC).

80. A method of treating a subject or population of subjects having lung cancer, said method comprising administering an effective amount of 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. administering to said subject or population of subjects a dosing regimen comprising cycles, wherein said treatment comprises said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor, without said anti-TIGIT antagonist antibody. A method of prolonging progression-free survival (PFS) of said subject compared to treatment with an agent.

81. A method of treating a subject population with lung cancer, said method 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. administering to said subject population a dosing regimen comprising said subject population, wherein said treatment results in a median PFS of said subject population of from about 8.2 months to about 9.2 months.

82. said treatment compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody, overall survival of said subject or subject population ( 82. The method of embodiment 80 or 81, wherein OS) is extended.

83. said treatment reduces the PFS of said subject or subject population by at least about 2 compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without an anti-TIGIT antagonist antibody; 83. The method of any one of embodiments 80-82, wherein the method is extended for 4 months.

84. said treatment reduces said PFS of said subject or subject population at least as compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody 84. The method of embodiment 83, extended from about 3 months to about 4 months.

85. A method of treating a subject or population of subjects having lung cancer, said method comprising administering an effective amount of 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. administering to said subject or population of subjects a dosing regimen comprising cycles, wherein said treatment comprises said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor, without said anti-TIGIT antagonist antibody. A method of prolonging OS in said subject compared to treatment with an agent.

86. A method of treating a subject population having lung cancer, said method 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. administering to said subject population a dosing regimen comprising said subject population, wherein said treatment results in a median OS of said subject population of from about 15.3 months to about 17.6 months.

87. said treatment reduces the OS of said subject or subject population by at least about 3, compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without an anti-TIGIT antagonist antibody; 87. The method of any one of embodiments 82-86, wherein the method is extended for 3 months.

88. said treatment reduced the OS of said subject or subject population by at least about 3, compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without an anti-TIGIT antagonist antibody; 87. The method of any one of embodiments 82-86, extending from months to about 5.3 months.

89. 89. 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. the method of.

90. 89. Any one of embodiments 80-89, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are further administered in one or more additional cycles following said fourth initial dosing cycle. the method of.

91. 91. The method of embodiment 90, wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of said one or more additional dosing cycles.

92. The method of any one of embodiments 80-91, wherein said platinum-based chemotherapeutic agent is carboplatin and said topoisomerase II inhibitor is etoposide.

93. The method of any one of embodiments 80-92, wherein said lung cancer is small cell lung cancer (SCLC).

94. 94. The method of embodiment 93, wherein said SCLC is extensive SCLC (ES-SCLC).

95. 95. The method of embodiment 94, wherein said one or more subjects are treatment-naive for ES-SCLC.

96. 96. The method of any one of embodiments 80-95, wherein said one or more subjects do not have the presence or history of brain metastases.

97. 97. The method of any one of embodiments 80-96, wherein said lung cancer is not selected for PD-L1 expression.

98. The method of any one of embodiments 80-96, wherein said lung cancer is selected for PD-L1 expression.

99. 99. The method of embodiment 98, wherein said lung cancer is selected for PD-L1 expression by a detectable level of PD-L1 expression.

100. 99. The method of any one of embodiments 80-99, wherein said lung cancer is metastatic.

101. 101. The method of embodiment 100, wherein said lung cancer has metastasized to the brain, liver, lymph nodes and/or adrenal glands.

102. 102. The method of embodiment 100 or 101, wherein said lung cancer has not metastasized to the brain.

103. 103. The method of any one of embodiments 100-102, wherein said treatment results in a complete response (CR) or partial response (PR).

104. 104. The method of any one of embodiments 80-103, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 2, 3 or 4 weeks.

105. 105. The method of any one of embodiments 80-104, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2, 3 or 4 weeks.

106. 106. The method of any one of embodiments 80-105, wherein said PD-1 axis binding antagonist, anti-TIGIT antagonist antibody, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered sequentially.

107. 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. 107. The method of embodiment 106, wherein

108. 108. The method of any one of embodiments 80-107, wherein said anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered intravenously.

109. 109. Any one of embodiments 80-108, wherein one or more of said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are administered subcutaneously. Method.

110. A method for treating a subject with SCLC, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on day 1 of each dosing cycle, about 80 mg to about 80 mg on day 1 of each dosing cycle. Atezolizumab at a dose of approximately 1600 mg, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and Days 1, 2, and 3 of each dosing cycle wherein said treatment is compared to treatment with atezolizumab, carboplatin and etoposide without said anti-TIGIT antagonist antibody. to extend the subject's PFS and/or OS.

111. A method for treating a subject with SCLC, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg on day 1 of each dosing cycle, about 900 mg to about 900 mg on day 1 of each dosing cycle. Atezolizumab at a dose of approximately 1500 mg, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and Days 1, 2, and 3 of each dosing cycle wherein said treatment is compared to treatment with atezolizumab, carboplatin and etoposide without said anti-TIGIT antagonist antibody. to extend the subject's PFS and/or OS.

112. One or more additions of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each additional dosing cycle 112, wherein carboplatin and etoposide are omitted from each of the one or more additional dosing cycles.

113. A method for treating a subject or subject population with ES-SCLC, said method administering to said subject or subject population four initial dosing cycles followed by one or more additional dosing cycles. including
(a) the four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, and 1 of each initial dosing cycle; Carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 and etoposide at a dose of 100 mg/m on each of Days 1, 2 and 3 of each initial dosing cycle including
(b) said one or more additional dosing cycles administering a dose of about 600 mg tiragolumab on day 1 of each additional dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each additional dosing cycle; including
each of the four initial dosing cycles and the one or more additional dosing cycles is a 21-day dosing cycle, and the treatment is compared to a treatment comprising atezolizumab, carboplatin and etoposide without the tiragolumab; A method of prolonging PFS and/or OS of a subject or subject population.

114. 1. A method of treating a subject or population of subjects having lung cancer, said method comprising: an anti-TIGIT antagonist antibody; a PD-1 axis binding antagonist; a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent; administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of a second chemotherapeutic agent that is a therapeutic agent.

115. 115. The method of embodiment 114, wherein said lung cancer has not been evaluated for PD-L1 expression.

116. 116. The method of embodiment 114 or 115, wherein said one or more subjects have not been determined to have a PD-L1 positive tumor cell fraction of 50% or greater.

117. 117. The method of embodiment 116, wherein said one or more subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. 118. The method of embodiment 116 or 117, wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, said anti-PD-L1 antibody is SP263 or 22C3.

119. 119. The method of any one of embodiments 114-118, wherein the one or more subjects do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

120. 120. The method of any one of embodiments 114-119, wherein said one or more subjects have not received prior systemic therapy for said lung cancer.

121. 121. The method of any one of embodiments 114-120, wherein said lung cancer is locally advanced lung cancer.

122. 122. The method of any one of embodiments 114-121, wherein said lung cancer is NSCLC, particularly locally advanced unresectable or metastatic non-squamous NSCLC.

123. 123. The method of embodiment 122, wherein said non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The dosing regimen comprises an induction phase comprising four dosing cycles, 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 in the induction phase 124. The method of any one of embodiments 114-123, administered on Day 1 of each dosing cycle of .

125. wherein said dosing regimen comprises a maintenance phase following said induction phase, said maintenance phase comprising one or more dosing cycles, said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist and said non-platinum chemotherapeutic agent is administered on Day 1 of each dosing cycle of said maintenance phase.

126. 126. The method of embodiment 125, wherein said one or more dosing cycles of said maintenance phase do not include administration of said platinum-based chemotherapeutic agent.

127. 127. The method of any one of embodiments 114-126, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin and said non-platinum-based chemotherapeutic agent is pemetrexed.

128. A method of treating a subject or subject population with advanced non-squamous NSCLC, said method comprising administering to said subject or subject population four 21-day dosing cycles of tiragolumab, atezolizumab, carboplatin or cisplatin and pemetrexed. administering a dosing regimen wherein, on day 1 of each of said four 21-day dosing cycles, said tiragolumab is administered at a dose of about 600 mg every 3 weeks and said atezolizumab is administered at a dose of about 1200 mg every 3 weeks; wherein said carboplatin is administered at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, or said cisplatin is administered at a dose of 75 mg/m2 every 3 weeks, said The method wherein pemetrexed is administered at a dose of about 500 mg/m2 every three weeks.

129. 1. A method of treating a subject or subject population having advanced non-squamous NSCLC, said method comprising:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin. including
The method, wherein said subject or subject population has not received prior systemic therapy for said advanced non-squamous NSCLC.

130. A method of treating a subject with advanced non-squamous NSCLC, said method comprising:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin;
administering with
The method, wherein said subject has no prior systemic therapy for said advanced non-squamous NSCLC.

131. A method of treating a subject with advanced non-squamous NSCLC, said method administering to said subject a dosing regimen comprising four 21-day dosing cycles of tiragolumab, atezolizumab, carboplatin or cisplatin and pemetrexed. wherein on day 1 of each of said four 21-day dosing cycles, said tiragolumab is administered at a dose of about 600 mg every 3 weeks and said atezolizumab is administered at a dose of about 1200 mg every 3 weeks; The method wherein cisplatin is administered at a dose of 75 mg/m2 and said pemetrexed is administered at a dose of about 500 mg/m2.

132. 132. The method of any one of embodiments 114-131, wherein said treatment prolongs PFS of said subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The method of any one of embodiments 114-132, wherein said treatment results in a median PFS for said subject population of about 12.5 months to about 14.7 months.

134. 134. The method of any one of embodiments 114-133, wherein said treatment prolongs OS of said subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. 135. The method of any one of embodiments 114-134, wherein said treatment results in a median OS for said subject population of from about 27.5 months to about 32.0 months.

136. A method for treating a subject with resectable lung cancer, said method comprising anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every 3 weeks and about 80 mg and about 1600 mg every 3 weeks. administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose between .

137. A method for treating a subject with resectable lung cancer, said method comprising anti-TIGIT antagonist antibody at a dose between about 300 mg and about 800 mg every 3 weeks and about 900 mg and about 1500 mg every 3 weeks. administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose between .

138. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, at least one of said anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every 3 weeks and said PD-1 axis binding antagonist between about 80 mg and about 1600 mg every 3 weeks as a neoadjuvant treatment. administering to said subject at a dose of

139. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, at least one of said anti-TIGIT antagonist antibody at a dose between about 300 mg and about 800 mg every 3 weeks and said PD-1 axis binding antagonist between about 900 mg and about 1500 mg every 3 weeks as a neoadjuvant treatment. administering to said subject at a dose of

140. At least one of said dosing cycles comprises, as an adjuvant treatment, said anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks and said PD-1 axis binding antagonist at a dose between about 80 mg and about every three weeks. 140. The method of embodiment 138 or 139, comprising administering to said subject at a dose of between 1600.

141. At least one of said dosing cycles comprises, as an adjuvant treatment, said anti-TIGIT antagonist antibody at a dose between about 500 mg and about 700 mg every 3 weeks and said PD-1 axis binding antagonist at a dose between about 900 mg and about 900 mg every 3 weeks. 141. The method of embodiment 140, comprising administering to said subject at a dose of between 1500.

142. 142. The method of any one of embodiments 138-141, wherein said lung cancer is resectable lung cancer.

143. 143. The method of any one of embodiments 136-142, wherein said lung cancer is early stage lung cancer.

144. 144. The method of any one of embodiments 136-143, wherein said lung cancer is stage II, IIIA or IIIB lung cancer.

145. 145. The method of any one of embodiments 136-144, wherein said lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

146. 146. The method of any one of embodiments 136-145, wherein said subject is eligible for R0 enucleation with curative intent.

147. 147. The method of any one of embodiments 136-146, wherein said subject has no prior treatment for lung cancer.

148. 148. The method of embodiment 147, wherein said prior treatment is immunotherapy, chemotherapy, or radiation therapy.

149. The method of any one of embodiments 136-148, wherein said subject is eligible to undergo a platinum-based chemotherapy regimen.

150. 149. The method of any one of embodiments 136-149, wherein said first dosing cycle is initiated prior to surgery.

151. 151. The method of embodiment 150, wherein at least 1, 2, 3 or 4 dosing cycles are completed prior to said surgery.

152. The method of embodiment 150 or 151, wherein 4 dosing cycles are completed prior to said surgery.

153. 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 said surgery.

155. 155. The method of any one of embodiments 150-154, wherein said surgery is segmentectomy, lobectomy, bilobectomy, or pneumonectomy.

156. 156. The method of any one of embodiments 136-155, wherein said method further comprises radiation therapy.

157. 157. The method of embodiment 156, wherein said radiation therapy is postoperative radiation therapy.

158. 158. The method of any one of embodiments 136-157, wherein said method further comprises administering one or more chemotherapeutic agents.

159. 159. The method of embodiment 158, wherein said one or more chemotherapeutic agents are administered post-operatively.

160. 160. The method of embodiment 159, wherein said one or more chemotherapeutic agents are administered in four dosing cycles after said surgery.

161. 161. The method of any one of embodiments 158-160, wherein said one or more chemotherapeutic agents are platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents.

162. (a) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine;
(c) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel;
(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or (e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. is
162. The method of embodiment 161.

163. 163. The method of any one of embodiments 136-162, wherein said treatment results in an increase in MPR rate compared to the baseline significant pathological response (MPR) rate.

164. The reference MPR rate is
MPR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 164. The method of embodiment 163, wherein

165. 165. The method of any one of embodiments 136-164, wherein said treatment results in pathological complete response (pCR) and/or increased pCR rate compared to baseline pCR rate.

166. The reference pCR rate is
pCR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 166. The method of embodiment 165, wherein

167. 167. The method of any one of embodiments 136-166, wherein said treatment results in increased EFS time compared to baseline symptom-free survival (EFS).

168. the reference EFS time,
EFS time in a subject population that has received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 168. The method of embodiment 167, wherein

169. A method for treating a subject with resectable lung cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 600 mg every three weeks and between about 80 mg and about 1600 mg every three weeks. administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose between .

170. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, at least one of said anti-TIGIT antagonist antibody at a dose between about 30 mg and about 600 mg every 3 weeks and said PD-1 axis binding antagonist between about 80 mg and about 1600 mg every 3 weeks as a neoadjuvant treatment. administering to said subject at a dose of

171. A method for treating a subject with resectable lung cancer, said method comprising: an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every 3 weeks; administering to said subject one or more dosing cycles of between doses of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent.

172. A method for treating a subject with lung cancer, said method comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent. wherein at least one of said dosing cycles comprises administering to said subject a dose of said anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg every 3 weeks, about 80 mg every 3 weeks and about 80 mg every 3 weeks as a neoadjuvant treatment. administering to said subject a dose of between about 1600 mg of said PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent.

173. A method for treating a subject with resectable lung cancer, said method comprising: an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every 3 weeks; and (a)(i) a dose of a platinum-based chemical aimed at achieving an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks. or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every three weeks and (b)(i) about 500 mg/m2 every three weeks on days 1 and 8 of each dosing cycle. or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks. A method comprising administering the above dosing cycle to a subject.

174. A method for treating a subject with lung cancer, said method comprising administering 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. administering to said subject, wherein at least one said dosing cycle comprises: (a) said anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 600 mg every 3 weeks; and (b) for 3 weeks. (c) said platinum-based chemotherapeutic agent, wherein (i) an AUC of 5 mg/mL/min or 6 mg every 3 weeks; (ii) a dose of about 75 mg/m every 3 weeks of the platinum-based chemotherapeutic agent; and (d) the non-platinum-based chemotherapeutic agent. (i) an antimetabolite at a dose of 500 mg/m2 every 3 weeks, or 1000 mg/m2 or 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) 100 mg every 3 weeks a non-platinum chemotherapeutic agent that is a taxane at a dose of /m2, 175 mg/m2 or 200 mg/m2, wherein said treatment is neoadjuvant treatment.

175. A method for treating a subject with resectable lung cancer, said method comprising administering to said subject tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks;
(a)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and,
(b)
(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks, or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) every 3 weeks. and one or more dosing cycles of paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2.

176. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. wherein at least one of said dosing cycles administered to said subject (a) tiragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks; A therapeutic agent which is (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) about 75 mg every 3 weeks (d) the non-platinum-based chemotherapeutic agent, which is (i) 500 mg/m2 every 3 weeks or on day 1 of each dosing cycle; and a non-platinum chemotherapeutic agent that is pemetrexed at a dose of 1000 mg/m2 or 1250 mg/m2 on day 8, or (ii) paclitaxel at a dose of 100 mg/m2, 175 mg/m2 or 200 mg/m2 every three weeks; and wherein said treatment is neoadjuvant treatment.

177. A method for treating a subject with non-squamous NSCLC, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab, (a) at least one of said dosing cycles (b) at least one of the premedication cycles comprises administering to said subject a dose of about 600 mg of tiragolumab every 3 weeks and atezolizumab at a dose of 1200 mg every 3 weeks as neoadjuvant treatment; administering to said subject a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of said atezolizumab every 3 weeks.

178. A method for treating a subject with non-squamous NSCLC, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) at least One is a neoadjuvant treatment, wherein the subject is given (a) tiragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; (ii) 6 mg/mL/min every 3 weeks; carboplatin at a dose targeted to achieve a minute AUC and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and administering pemetrexed at a dose of about 500 mg/m2 every 3 weeks; and administering a dose of an anti-TIGIT antagonist antibody between about 80 mg and about 1600 mg every three weeks of a PD-1 axis binding antagonist.

179. 1. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) at least one of the dosing cycles comprises: (a) tiragolumab at a dose of about 600 mg every 3 weeks, (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment, (c) (i) 3 carboplatin at a dose targeted to achieve a weekly AUC of 5 mg/mL/min and gemcitabine at a dose of approximately 1000 mg/m2 on days 1 and 8 of each dosing cycle, (ii) every 3 weeks Carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min of and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) about 75 mg/m2 every 3 weeks m and a dose of gemcitabine of about 1250 mg/m on days 1 and 8 of each dosing cycle, and (II) at least one of said dosing cycles comprises, as an adjuvant treatment, administering to said subject a dose of tiragolumab between about 30 mg and about 1200 mg every three weeks and atezolizumab at a dose of between about 80 mg and about 1600 mg every three weeks.

180. 1. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab,
(I) at least one of said dosing cycles is a neoadjuvant treatment, wherein said subject comprises:
(a) tiragolumab at a dose of about 1200 mg every 3 weeks;
(b) atezolizumab at a dose of about 1200 mg every 3 weeks as a neoadjuvant treatment;
(c)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;
(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii)3 administering a weekly dose of cisplatin of about 75 mg/m2 and a dose of gemcitabine of about 1250 mg/m2 on days 1 and 8 of each dosing cycle;
(II) at least one of said dosing cycles comprises, as an adjuvant treatment, giving said subject tiragolumab at a dose of between about 300 mg and about 800 mg every three weeks and a dose of between about 900 mg and about 1500 mg every three weeks; A method comprising administering atezolizumab.

181. 1. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) at least one of the dosing cycles comprises: (a) tiragolumab at a dose of about 600 mg every 3 weeks, (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment, (c) (i) 3 carboplatin at a dose targeted to achieve a weekly AUC of 5 mg/mL/min and gemcitabine at a dose of approximately 1000 mg/m2 on days 1 and 8 of each dosing cycle, (ii) every 3 weeks Carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min of and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) about 75 mg/m2 every 3 weeks m and a dose of gemcitabine of about 1250 mg/m on days 1 and 8 of each dosing cycle, and (II) at least one of said dosing cycles comprises, as an adjuvant treatment, administering to said subject a dose of approximately 600 mg of tiragolumab every 3 weeks, and a dose of atezolizumab of approximately 1200 mg every 3 weeks.

182. 1. A method for treating a subject with resectable squamous NSCLC, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab; at least one is a neoadjuvant treatment, wherein the subject is administered (a) tiragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as a neoadjuvant treatment; ) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle, ( ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) 3 weeks (II) at least one of said dosing cycles comprising , administering to said subject, as an adjuvant treatment, tiragolumab at a dose of approximately 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

183. The method of any one of embodiments 136-182, wherein detectable PD-L1 protein expression levels are determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263.

184. 184. The method of embodiment 183, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or greater.

185. The method of any one of embodiments 73, 114-121, and 136-184, wherein said lung cancer is NSCLC.

186. 186. The method of embodiment 185, wherein the NSCLC is squamous NSCLC.

187. 186. The method of embodiment 185, wherein the NSCLC is non-squamous NSCLC.

188. 73. The method of embodiment 72, wherein the cancer is cervical cancer.

189. A method for treating a subject or subject population having cervical cancer with detectable levels of PD-L1 expression, said method comprising anti-TIGIT at a dose between about 30 mg and about 1200 mg every 3 weeks. administering to said subject or population of subjects one or more dosing cycles of an antagonist antibody and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks.

190. A method for treating a subject or subject population having cervical cancer with detectable levels of PD-L1 expression, said method comprising anti-TIGIT at a dose of between about 300 mg and about 800 mg every three weeks. administering to said subject or population of subjects one or more dosing cycles of an antagonist antibody and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every three weeks.

191. A method of selecting treatment for a subject with cervical cancer, comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - for said subject with an L1 expression level, an anti-TIGIT antagonist antibody administered every three weeks at a dose of between about 30 mg and about 1200 mg based on detected PD-L1 expression on tumor cells and about 80 mg and selecting a treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist administered every three weeks at a dose of between about 1600 mg.

192. 192. The method of any one of embodiments 189-191, wherein said cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma.

193. 192. The method of any one of embodiments 189-191, wherein said cervical cancer is stage IVB, metastatic, recurrent or persistent.

194. 194. The method of any one of embodiments 189-193, wherein said cervical cancer is metastatic and/or recurrent PD-L1 positive cervical carcinoma.

195. 195. The method of any one of embodiments 189-194, wherein said one or more subjects have received at least one prior treatment.

196. 196. The method of any one of embodiments 189-195, wherein said one or more subjects have received two prior treatments.

197. 197. The method of any one of embodiments 189-196, wherein said one or more subjects have not received 3 or more prior treatments.

198. 195. The method of any one of embodiments 189-194, wherein said one or more subjects have no prior treatment.

199. 199. The method of any one of embodiments 195-198, wherein said prior treatment is chemotherapy, surgery and/or radiotherapy.

200. The method of any one of embodiments 189 and 192-199, wherein said treatment results in a clinical response.

201. 201. The method of embodiment 200, wherein said clinical response is an increase in ORR in said subject population compared to a baseline objective response rate (ORR).

202. 202. The method of embodiment 201, wherein said baseline ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

203. 201. The method of embodiment 200, wherein the baseline ORR is at least about 14.6% to about 26%.

204. 201. The method of embodiment 200, wherein said clinical response is CR or PR.

205. wherein said clinical response is increased in said subject's PFS time compared to baseline progression-free survival (PFS), increased in said subject's DOR time compared to baseline duration of response (DOR), or baseline overall survival (OS) 205. The method of any one of embodiments 200-204, wherein the increase in OS time of the compared subjects.

206. 206. The method of embodiment 205, wherein:
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
Method.

207. [Embodiment 177] A method for treating a subject having cervical cancer with detectable levels of PD-L1 expression, said method comprising administering to said subject anti-TIGIT at a dose of 600 mg every three weeks. A method comprising administering an antagonist antibody and one or more dosing cycles of atezolizumab at a dose of 1200 mg every 3 weeks.

208. A method of identifying a subject with cervical cancer who is likely to benefit from treatment comprising an anti-TIGIT antagonist antibody and one or more dosing cycles of atezolizumab, said method comprising:
(a) providing a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (c) PD-L1 expression on the detected tumor cells. based on the likely benefit from treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. A method comprising identifying a subject.

209. A method of selecting treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject with L1 expression level selecting a treatment comprising one or more dosing cycles of atezolizumab administered.

210. A method for treating a subject having cervical cancer with detectable levels of PD-L1 expression, said method comprising administering to said subject tiragolumab at a dose of about 600 mg every 3 weeks and administering one or more dosing cycles of atezolizumab at a dose of about 1200 mg.

211. A method of treating a subject with cervical cancer, said method comprising:
(a) providing a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) based on detected PD-L1 expression on tumor cells, one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. and (d) administering said treatment to said identified subject.

212. A method of selecting treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks for said subjects with L1 expression levels based on detected PD-L1 expression on tumor cells selecting a treatment comprising one or more dosing cycles of

213. A method of treating a subject with metastatic and/or recurrent cervical cancer, said method comprising:
(a) providing a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) based on detected PD-L1 expression on tumor cells, one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. and (d) administering said treatment to said identified subject.

214. A method of selecting a treatment for a subject with metastatic and/or recurrent cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks for said subjects with L1 expression levels based on detected PD-L1 expression on tumor cells selecting a treatment comprising one or more dosing cycles of

215. The method of any one of embodiments 189-214, wherein said subject is identified as likely to benefit from said treatment based on detected PD-L1 expression on tumor cells.

216. The method of any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263.

217. 217. The method of any one of embodiments 189-216, wherein said detectable PD-L1 expression level is 5% or more tumor-associated immune cells (TIC) in a sample from said subject.

218. The method of any one of embodiments 189-215, wherein PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.

219. 217. The method of any one of embodiments 189-216, wherein said detectable PD-L1 expression level is a composite positive score (CPS) of 1 or more in a sample from said subject.

220. 73. The method of embodiment 72, wherein said cancer is breast cancer.

221. A method of treating a subject or subject population having breast cancer, comprising tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and about 3 weeks on/1 week off. administering to said subject or subject population a dosing regimen comprising one or more dosing cycles of nab-paclitaxel at a dose of 100 mg/m2.

222. 222. The method of embodiment 220 or 221, wherein said breast cancer is triple negative breast cancer (TNBC).

223. 223. The method of embodiment 222, wherein said TNBC is unresectable locally advanced or metastatic TNBC.

224. 224. The method of any one of embodiments 220-223, wherein said subject has had no prior systemic therapy for metastatic breast cancer.

225. The method of any one of embodiments 220-224, wherein said treatment results in an ORR of the subject population of at least about 53% to about 67.5%.

226. The method of any one of embodiments 222-225, wherein said treatment results in a median OS for said subject population of about 25.0 months.

227. A method of treating a subject with early triple negative breast cancer (eTNBC), said method comprising an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks and a dose of about 20 mg to 1600 mg every two weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist of.

228. 228. The method of embodiment 227, wherein said method further comprises administering one or more chemotherapeutic agents to said subject.

229. 229. The method of embodiment 228, wherein said one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a taxane, or a taxane and a platinum-based chemotherapeutic agent, and (b) the anti-TIGIT One dose of an antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) 228. The method of embodiment 227, further comprising administering the above dosing cycle.

231. 231. The method of embodiment 229 or 230, wherein said alkylating agent is cyclophosphamide.

232. 232. The method of embodiment 231, wherein said cyclophosphamide is administered at a dose of about 600 mg/m2.

233. The method of any one of embodiments 227-229, 231, and 232, wherein said method further comprises administering G-CSF or GM-CSF to said subject.

234. 234. The method of embodiment 230 or 233, wherein said G-CSF is pegfilgrastim or filgrastim.

235. 235. The method of embodiment 234, wherein said G-CSF is pegfilgrastim.

236. 236. The method of embodiment 235, wherein said pegfilgrastim is administered at a dose of about 6 mg.

237. Embodiments 228, 229, and 231-236, wherein said method further comprises administering said one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF to said subject The method according to any one of .

238. Embodiments 228, 229, and 231, wherein said one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once weekly, once every two weeks, or once every three weeks, respectively 237. The method of any one of clauses 1-237.

239. The platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF Or the method of any one of embodiments 229-238, wherein GM-CSF is administered every two weeks.

240. 239. The method of any one of embodiments 229-239, wherein said taxane, or said taxane and said platinum-based chemotherapeutic agent are administered for the first 12 weeks of said dosing regimen.

241. 240. Any one of embodiments 229-240, wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered during weeks 13 through 19 of the dosing regimen. the method of.

242. The method of any one of embodiments 227-241, wherein the total length of said dosing regimen is 19 weeks.

243. The method of any one of embodiments 227-242, wherein said method is a neoadjuvant treatment.

244. 244. The method of any one of embodiments 227-243, wherein said dosing regimen is followed by surgery.

245. 245. The method of embodiment 244, wherein said surgery is performed between 2 and 6 weeks after the last administration of said dosing regimen.

246. 246. The method of embodiment 244 or 245, wherein said surgery comprises a mastectomy.

247. 247. The method of any one of embodiments 244-246, wherein said surgery comprises axillary lymph node surgery.

248. The method of any one of embodiments 229-247, wherein said topoisomerase II inhibitor is doxorubicin.

249. 248. 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 of embodiment 248 or 249, wherein doxorubicin is administered at a dose of about 60 mg/m2.

251. A method of treating a subject with eTNBC, said method comprising anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and PD-1 axis binding at a dose of about 600 mg to about 1200 mg every two weeks. an antagonist, and
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

252. A method of treating a subject with eTNBC, said method comprising an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-L1 binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks. and,
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

253. A method of treating a subject with eTNBC, said method comprising an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and an anti-PD-1 antagonist at a dose of about 600 mg to about 1200 mg every two weeks. an antibody;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

254. A method of treating a subject with eTNBC, said method comprising tiragolumab at a dose of about 300 mg to about 600 mg every two weeks and an anti-PD-1 antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

255. A method of treating a subject with eTNBC, said method comprising an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

256. A method of treating a subject with eTNBC, said method comprising tiragolumab at a dose of about 300 mg to about 600 mg every two weeks and atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

257. A method of treating a subject with eTNBC, said method comprising tiragolumab at a dose of about 420 mg every two weeks and atezolizumab at a dose of about 840 mg every two weeks;
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and administering to said subject a dosing regimen comprising: and said method further comprising surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen.

258. 258. The method of any one of embodiments 220-257, wherein the detectable PD-Ll protein expression level in a tumor sample from said subject is determined by an IHC assay comprising staining with the anti-PD-Ll antibody SP142. .

259. 259. The method of embodiment 258, wherein the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs) in said tumor sample is 1% or more.

260. 260. The method of any one of embodiments 227-259, wherein said eTNBC is T2-4d TNBC when presented.

261. 261. The method of any one of embodiments 227-260, wherein said eTNBCs are cT2-cT4, cN0-cN3, and cM0 TNBCs when presented.

262. 262. The method of any one of embodiments 227-261, wherein said subject has no previous treatment for eTNBC.

263. 263. The method of any one of embodiments 227-262, wherein said treatment results in a pathological complete response (pCR).

264. 264. The method of any one of embodiments 227-263, wherein said treatment results in increased overall survival (OS) or symptom-free survival (EFS).

265. 73. The method of embodiment 72, wherein said cancer is head and neck cancer.

266. 266. The method of embodiment 265, wherein said head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN).

267. A method for treating a subject or subject population having nSCCHN with detectable PD-L1 expression levels, said method comprising administering an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks; and administering to said subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks.

268. 1. A method for treating a subject or subject population having SCCHN with detectable PD-L1 expression levels, said method comprising administering an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every three weeks; and administering to said subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every three weeks.

269. A method of selecting a treatment for a subject or subject population with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg every 3 weeks, based on detected PD-L1 expression, for said subject or subject population having a level of selecting a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 1200 mg.

270. A method for treating a subject or population of subjects having SCCHN with detectable levels of PD-L1 expression, said method comprising administering to said subject or population of subjects tiragolumab at a dose of about 600 mg every three weeks, and administering one or more dosing cycles of atezolizumab at a dose of about 1200 mg every three weeks.

271. 271. The method of any one of embodiments 267-270, wherein the tumor sample obtained from said one or more subjects has been determined to have a detectable level of PD-Ll expression.

272. 272. The method of any one of embodiments 266-271, wherein said SSCHN is human papillomavirus (HPV) positive.

273. 273. The method of any one of embodiments 266-272, wherein said SSCHN is HPV negative.

274. 274. The method of embodiment 272 or 273, wherein HPV status is determined by p16 IHC, in situ hybridization or PCR.

275. 275. The method of any one of embodiments 266-274, wherein said SCCHN is recurrent and/or metastatic SCCHN.

276. 276. The method of any one of embodiments 265-275, wherein said one or more subjects have no prior treatment.

277. 277. The method of embodiment 276, wherein said prior treatment is prior systemic therapy for recurrent and/or metastatic disease.

278. The method of any one of embodiments 265-268 and 270-277, wherein said treatment results in CR or PR.

279. The method of any one of embodiments 265-268 and 270-277, wherein said treatment results in an increase in ORR in said subject population compared to a baseline objective response rate (ORR).

280. 280. The method of embodiment 279, wherein said baseline ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

281. 281. The method of embodiment 279 or 280, wherein said baseline ORR is from about 19% to about 36%.

282. wherein said treatment increases PFS time of said subject or subject population compared to baseline progression-free survival (PFS), increases DOR time of said subject or subject population compared to baseline duration of response (DOR), or baseline overall survival The method of any one of embodiments 265-268 and 270-281, which results in an increase in OS time for said subject or subject population compared to duration (OS).

283. 283. The method of embodiment 282, wherein:
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
Method.

284. 283. The method of embodiment 282, wherein the baseline DOR time is from at least about 6.7 months to about 23.4 months.

285. 283. The method of embodiment 282, wherein the baseline OS time is at least about 11.6 months to about 14.9 months.

286. A method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising administering a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks; and administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks.

287. A method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising administering a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and about administering to said subject one or more dosing cycles of a 600 mg dose of an anti-TIGIT antagonist antibody.

288. A method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising administering a PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks; administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg weekly.

289. A method for treating a subject having SCCHN with detectable levels of PD-L1 expression, said method comprising administering atezolizumab at a dose between about 80 mg and about 1600 mg every 3 weeks and about administering to said subject one or more dosing cycles of tiragolumab at a dose of between 30 mg and about 1200 mg.

290. A method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. administering to said subject one or more dosing cycles of

291. A method of treating a subject with SCCHN, said method comprising:
(a) providing a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable PD-L1 expression level.

292. A method of treating a subject with SCCHN, said method comprising:
(a) providing a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) may benefit from treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable PD-L1 expression level.

293. A method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) potential to benefit from treatment comprising one or more dosing cycles of atezolizumab at doses between about 80 mg and about 1600 mg every 3 weeks and tiragolumab at doses between about 30 mg and about 1200 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable level of PD-L1 expression.

294. A method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) identifying subjects likely to benefit from treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks; (d) administering said treatment to said identified subject having a detectable PD-L1 expression level.

295. A method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg and about 1200 mg every 3 weeks, based on detected PD-L1 expression, for said subjects with levels of selecting a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at between doses.

296. A method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. 1 of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks, based on detected PD-L1 expression, for said subjects with levels of selecting a treatment comprising one or more dosing cycles.

297. A method of selecting treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. atezolizumab at a dose between about 80 mg and about 1600 mg every 3 weeks, and tiragolumab at a dose between about 30 mg and about 1200 mg every 3 weeks for said subjects with levels of selecting a treatment comprising one or more dosing cycles of

298. A method of selecting treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on detected PD-L1 expression for said subject with a level selecting a.

299. Embodiment 267- wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level determined by an immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP263 298;

300. the detectable PD-L1 protein expression level in the tumor sample is
(a) 5% or more,
299. The method of embodiment 299, wherein (b) 5% or more and less than 20%, or (c) 20% or more tumor-associated immune cells (TIC).

301. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. A method of identifying a subject as likely to benefit from a treatment comprising a dosing cycle, said method comprising detecting PD in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining. - a method comprising determining the L1 protein expression level, wherein a TIC PD-L1 protein expression level of 5% or more identifies said subject as likely to benefit from said treatment.

302. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. A method of identifying a subject as likely to benefit from a treatment comprising a dosing cycle, said method comprising detecting PD in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining. - a method comprising determining the L1 protein expression level, wherein a TIC PD-L1 protein expression level of 5% or more and less than 20% identifies said subject as likely to benefit from said treatment. .

303. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. A method of identifying a subject as likely to benefit from a treatment comprising a dosing cycle, said method comprising detecting PD in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining. - a method comprising determining the L1 protein expression level, wherein a TIC PD-L1 protein expression level of 20% or more identifies said subject as likely to benefit from said treatment.

304. The method of any one of embodiments 301-303, wherein said subject is identified as likely to benefit from treatment, said method further comprising administering treatment to said subject.

305. 305. The method of any one of embodiments 301-304, wherein said TIC is determined using the Ventana SP263 IHC assay.

306. 306. The method of any one of embodiments 267-305, wherein said subject or subject population is identified as likely to benefit from said treatment based on detected PD-Ll expression on tumor cells. .

307. 73. The method of embodiment 72, wherein said cancer is liver cancer.

308. 308. The method of embodiment 307, wherein said liver cancer is hepatocellular carcinoma (HCC).

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

310. 310. The method of embodiment 309, further comprising administering a VEGF antagonist to said subject or population of subjects.

311. A method of treating a subject or population of subjects with HCC, comprising administering to said 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, Method.

312. The method of embodiments 310 and 311, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

313. The method of any one of embodiments 309-312, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every three weeks.

314. 314. The method of embodiment 313, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 800 mg every three weeks.

315. The method of any one of embodiments 309-314, wherein said anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 600 mg every three weeks.

316. The method of any one of embodiments 309-315, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg every three weeks.

317. The method of any one of embodiments 309-316, wherein said PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every three weeks.

318. The method of embodiment 310 or 311, wherein said VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

319. 319. The method of embodiment 318, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

320. 320. The method of embodiment 319, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10.0 mg/kg every two weeks.

321. The method of any one of embodiments 309-311 and 318-320, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks.

322. The method of any one of embodiments 309-311 and 318-321, wherein said PD-1 axis binding antagonist is administered at a dose of about 20 mg to about 1600 mg every two weeks.

323. The method of embodiments 309-311, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks.

324. The method of any one of embodiments 309-311 and 323, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 4 weeks.

325. The method of any one of embodiments 309-311, 323 and 324, wherein said PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks.

326. 326. The method of any one of embodiments 309-325, wherein said HCC is locally advanced or metastatic HCC.

327. The method of any one of embodiments 309-326, wherein said HCC is unresectable HCC.

328. 328. The method of any one of embodiments 309-327, wherein said one or more subjects have been determined to have adequate liver function.

329. 329. The method of embodiment 328, wherein said adequate liver function is characterized as Child-Pugh class A.

330. The method of any one of embodiments 309-329, wherein the HCC tumor sample obtained from said one or more subjects has been determined to have a detectable PD-L1 expression level.

331. 331. The method of any one of embodiments 309-330, wherein said method comprises administering to said subject or subject population at least four dosing cycles.

332. 332. The method of embodiment 331, comprising administering at least 16 dosing cycles to said subject or subject population.

333. A method of treating a subject or subject population with HCC, said method comprising tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and about 15 mg/kg every 3 weeks. administering to said subject one or more dosing cycles of bevacizumab at a dose of

334. 334. The method of any one of embodiments 311-333, wherein said one or more subjects have no prior systemic treatment for HCC.

335. The method of any one of embodiments 309-334, wherein said treatment results in a median PFS of said subject population of at least about 5.6 months to at least about 6.83 months.

336. 73. The method of embodiment 72, wherein said cancer is bladder cancer.

337. 337. The method of embodiment 336, wherein said bladder cancer is muscle invasive bladder cancer (MIBC).

338. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent, comprising administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per dose.

339. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every three weeks and for three weeks. wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent, comprising administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg per dose.

340. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per day, wherein said treatment is perioperative treatment.

341. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every three weeks and for three weeks. administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg per day, wherein said treatment is perioperative treatment.

342. The method of embodiments 338-341, wherein said one or more subjects have a creatinine clearance of less than 60 mL/min.

343. 343. The method of any one of embodiments 338-342, wherein the one or more subjects have grade 2 or greater hearing loss.

344. 344. The method of any one of embodiments 338-343, wherein said one or more subjects have grade 2 or greater neuropathy.

345. 345. The method of any one of embodiments 338-344, wherein said one or more subjects have refused treatment with a platinum-based chemotherapeutic agent.

346. The method of any one of embodiments 338 or 342-345, wherein said platinum-based chemotherapeutic agent is cisplatin.

347. 347. The method of any one of embodiments 338-346, wherein said MIBC is surgically manipulable.

348. 348. The method of embodiment 347, wherein said method further comprises surgery.

349. 349. The method of embodiment 348, wherein at least one dosing cycle is initiated prior to said surgery.

350. The method of embodiment 348 or 349, wherein at least 1, 2, or 3 dosing cycles are completed prior to said surgery.

351. 351. The method of any one of embodiments 348-350, wherein at least one dosing cycle is initiated between 4 and 6 weeks after said surgery.

352. The method of embodiment 351, wherein 1-17 dosing cycles are completed after said surgery.

353. 353. The method of any one of embodiments 348-352, wherein said surgery is cystectomy and/or lymphadenectomy.

354. 354. The method of any one of embodiments 338-353, wherein said treatment results in a pathological complete response (pCR).

355. said treatment increases RFS time of said one or more subjects compared to baseline recurrence-free survival (RFS); increases EFS time of said one or more subjects compared to baseline disease-free survival (EFS); 355. The method of any one of embodiments 338-354, resulting in an increase in OS time of said one or more subjects compared to OS.

356. 356. The method of embodiment 355, wherein:
(a) said baseline RFS time is the median RFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline EFS time is the median EFS time of a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

357. 357. The method of any one of embodiments 338-356, wherein said treatment results in a reduction in pathological extent.

358. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per dose, wherein said subject is cisplatin ineligible.

359. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per day, wherein said treatment is perioperative treatment.

360. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and administering one or more dosing cycles of a PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg per dose, wherein said subject is cisplatin ineligible.

361. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and administering one or more dosing cycles of a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg per day, wherein said treatment is perioperative treatment.

362. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population a dose of tiragolumab between about 30 mg and about 1200 mg every three weeks and about administering one or more dosing cycles of atezolizumab at doses of 80 mg and about 1600 mg, wherein said subject is cisplatin ineligible.

363. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population a dose of tiragolumab between about 30 mg and about 1200 mg every three weeks and about administering one or more dosing cycles of atezolizumab at doses of 80 mg and about 1600 mg, wherein said treatment is perioperative treatment.

364. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. wherein said one or more subjects are cisplatin ineligible.

365. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. wherein said treatment is perioperative treatment.

366. The method of any one of embodiments 338-365, wherein said treatment results in an ORR of the subject population of at least about 13.4% to about 15%.

367. 367. The method of any one of embodiments 338-366, wherein said treatment results in a median OS for the subject population of at least about 7.9 months to about 8.6 months.

368. The method of any one of embodiments 338-367, wherein detectable PD-L1 protein expression levels are determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142.

369. Embodiment 368, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction in which 5% or more of the tumor area is occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs) The method described in .

370. 337. The method of embodiment 336, wherein the bladder cancer is urothelial carcinoma (UC).

371. 371. The method of embodiment 370, wherein said UC is metastatic urothelial carcinoma (mUC).

372. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and for three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per dose.

373. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every three weeks and for three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg per dose.

374. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and for three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg per day, wherein said subject has received prior cancer immunotherapy no way.

375. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and for three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg per dose, wherein said treatment is a second line treatment.

376. 376. The method of embodiments 372, 372 and 375, wherein said one or more subjects have not received prior cancer immunotherapy.

377. 375. The method of any one of embodiments 372-374, wherein said treatment is a second line treatment.

378. 378. The method of any one of embodiments 372-377, wherein said mUC progressed during or after platinum-containing therapy.

379. 379. According to any one of embodiments 372-378, further comprising administering a second dosing regimen to said subject or population of subjects after said one or more subjects experience disease progression or unacceptable toxicity. the method of.

380. 379. The method of embodiment 379, wherein said second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).

381. 381. The method of embodiment 380, wherein said ADC is (a) enfortumab vedotin or (b) suctuzumab govitecan.

382. (a) enfortumab vedotin administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (b) sactuzumab govitecan administered at 2 382. The method of embodiment 381, administered at a dose of 10 mg/kg weekly for weekly on/weekly off.

383. (a) enfortumab vedotin at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle, or (b) suctuzumab govitecan at 10 mg/kg 383. The method of embodiment 381 or 382, wherein the doses are administered on days 1 and 8 of each 21-day cycle.

384. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and for three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg per dose.

385. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population a dose of tiragolumab between about 30 mg and about 1200 mg every three weeks and about administering a dosing regimen comprising one or more dosing cycles of atezolizumab at doses of 80 mg and about 1600 mg.

386. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. A method comprising administering one or more dosing cycles of

387. 1. A method for treating a subject or population of subjects with mUC comprising administering to said subject or population of subjects a first dosing regimen followed by a second dosing regimen,
(a) said first dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks and PD-1 axis binding at a dose of between about 80 mg and about 1600 mg every 3 weeks; comprising one or more dosing cycles of the antagonist;
(b) said second dosing regimen comprises one or more dosing cycles of said PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks; (i) enfortumab vedotin; is administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (ii) suctuzumab govitecan is administered for 2 weeks on/1 week off administered at a dose of 10 mg/kg weekly during drug administration, wherein said second dosing regimen is administered to said subject or subject after said subject or subject population experiences disease progression or unacceptable toxicity during said first dosing regimen; A method administered to a subject population.

388. 1. A method for treating a subject or population of subjects with mUC comprising administering to said subject or population of subjects a first dosing regimen followed by a second dosing regimen,
(a) the first dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks; comprising one or more dosing cycles of
(b) said second dosing regimen comprises one or more dosing cycles of said PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks, and (i) enfortumab vedotin is , 2 weeks on/1 week off, or (ii) suctuzumab govitecan administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off and the second dosing regimen is administered to the subject after the subject experiences disease progression or unacceptable toxicity during the first dosing regimen. Method.

389. 1. A method for treating a subject or population of subjects with mUC comprising administering to said subject or population of subjects a first dosing regimen followed by a second dosing regimen,
(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of 1200 mg about every 3 weeks;
(b) said second dosing regimen comprises one or more dosing cycles of about 1200 doses of atezolizumab every 3 weeks, and (i) enfortumab vedotin 2 weeks on/1 week off or (ii) suctuzumab govitecan administered at a dose of 10 mg/kg weekly for 2 weeks on/1 week off and wherein said second dosing regimen is administered to said subject after said subject experiences disease progression or unacceptable toxicity during said first dosing regimen.

390. The method of any one of embodiments 372-389, wherein said treatment results in an ORR of the subject population of at least about 13.4% to at least about 31%.

391. 391. The method of any one of embodiments 372-390, wherein said treatment results in a median OS for the subject population of from about 7.9 months to about 16.3 months.

392. 73. The method of embodiment 72, wherein said cancer is pancreatic cancer.

393. A method of treating a subject or population of subjects with pancreatic cancer, said method comprising administering to said subject or population of subjects a dose of about 420 mg tiragolumab on days 1 and 15 of each 28-day dosing cycle; atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/m on days 1, 8 and 15 of each 28-day dosing cycle, and 1 of each 28-day dosing cycle; administering a dosing regimen comprising one or more 28-day dosing cycles of nab-paclitaxel at a dose of about 125 mg/m2 on days 8 and 15.

394. 394. The method of embodiment 392 or 393, wherein said pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. 395. The method of embodiment 394, wherein said PDAC is metastatic PDAC.

396. 396. The method of any one of embodiments 392-395, wherein said one or more subjects have had no prior systemic therapy for metastatic PDAC.

397. The method of any one of embodiments 392-396, wherein said treatment results in an ORR of the subject population of at least about 41.7% to about 46.7%.

398. Any of embodiments 392-397, wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist The method according to item 1.

399. The method of any one of embodiments 392-398, wherein said treatment results in a median PFS for the subject population of at least about 5.5 months to about 7 months.

400. The method of any one of embodiments 392-399, wherein said treatment results in a median OS for the subject population of at least about 8.5 months to about 10.6 months.

401. 73. The method of embodiment 72, wherein said cancer is esophageal cancer.

402. A method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle. and administering to said subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle. including, method.

403. A method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle. and administering to said subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle. including, method.

404. [Embodiment 321] A method for treating a subject or subject population with esophageal cancer, said method comprising anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle. and administering to said subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle. wherein said 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 subject population with esophageal cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg on day 1 of each dosing cycle and each dosing cycle administering to said subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg on day 1 of Previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. 404. The method of embodiment 402 or 403, wherein the one or more subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. 407. The method of any one of embodiments 404-406, wherein said one or more subjects have experienced disease progression or unacceptable toxicity during prior treatment.

408. 404. The method 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. 409. The method of embodiment 408, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses.

410. The method of any one of embodiments 404-409, wherein said platinum-based chemotherapeutic agent is cisplatin.

411. 411. The method of embodiment 410, wherein cisplatin is administered at a dose of about 80 mg/m2 on Day 1 of each dosing cycle.

412. The method of any one of embodiments 404-411, wherein said non-platinum chemotherapeutic agent is an antimetabolite.

413. 413. The method of embodiment 412, wherein said antimetabolite is 5-fluorouracil.

414. The method of embodiment 413, wherein 5-fluorouracil is administered at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle.

415. 415. The method of any one of embodiments 404-414, wherein said esophageal cancer is advanced or metastatic esophageal cancer.

416. The method of embodiments 402, 403, 408, and 409, wherein said one or more subjects have no prior treatment for metastatic esophageal cancer.

417. A method for treating a subject or subject population with advanced or metastatic esophageal cancer comprising: an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle, each dosing cycle a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle, a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on day 1 of each dosing cycle, and 1 of each 21-day cycle administering to the subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a non-platinum-based chemotherapeutic agent at a dose of 800 mg/m2/24 hours on Days -5, wherein said platinum-based chemotherapy A method wherein an agent is omitted from said dosing regimen after 6 doses.

418. A method for treating a subject or subject population having advanced or metastatic esophageal cancer, said method comprising administering to said subject or subject population a dose of about 600 mg of anti-TIGIT on day 1 of each dosing cycle. Antagonist antibody, a PD-1 axis binding antagonist at a dose of about 1200 mg on Day 1 of each dosing cycle, cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle, and from Day 1 of each 21-day cycle. administering a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of 800 mg/m2/24 hours on day 5, and omitting cisplatin from said dosing regimen after 6 doses. method.

419. 1. A method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering to said subject or subject population a dose of tiragolumab of about 600 mg on day 1 of each dosing cycle; Atezolizumab at a dose of about 1200 mg on Day 1 of each dosing cycle, Cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle, and 800 mg/m2/day on Days 1-5 of each 21-day cycle A method comprising administering a dosing regimen comprising one or more 21-day dosing cycles of a 24-hour dose of 5-fluorouracil, wherein cisplatin is omitted from said dosing regimen after six doses.

420. 1. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer comprising administering to said subject or population of subjects a first dosing regimen and a second dosing regimen,
(a) the first dosing regimen comprises one or more 21-day dosing cycles of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of .

421. 1. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer comprising administering to said subject or population of subjects a first dosing regimen and a second dosing regimen,
(a) the first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 800 mg/m2/24 on days 1-5 of each 21-day cycle; one or more 21-day dosing cycles of an hourly dose of a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses;
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of .

422. 1. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer comprising administering to said subject or population of subjects a first dosing regimen and a second dosing regimen,
(a) said first dosing regimen comprises cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and a dose of 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle; 1 or more 21-day dosing cycles of 5-fluorouracil in which cisplatin is omitted from the dosing regimen after 6 doses;
(b) said second dosing regimen is one or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle; A method, including

423. The method of any one of embodiments 402-422, wherein said treatment results in an ORR of the subject population of at least about 14%.

424. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (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);
HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO:5); and HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO:6). .

425. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
425. The method of embodiment 424, further comprising FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO:9); and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO:10).

426. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:
FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is E or Q);
FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
425. The method of embodiment 424, further comprising 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. 427. The method of embodiment 426, wherein X1 is E.

428. 427. The method of embodiment 426, wherein X1 is Q.

429. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain according to (a) and (b) 429. The method of any one of embodiments 424-428, comprising the described VL domain.

430. wherein said anti-TIGIT antagonist antibody:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19.

431. wherein said anti-TIGIT antagonist antibody:
The method of any one of embodiments 424-427, 429 and 430, comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19.

432. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:34,
The method of any one of embodiments 424-427 and 429-431, comprising

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 said 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 tiragolumab.

437. embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, wherein said anti-TIGIT antagonist antibody is tiragolumab, vivostolimab, etidilimab, EOS084448, SGN-TGT, or TJ-T6; 265 to 269, 286 to 288, 291, 292, 295, 296, 301 to 332, 336 to 361, 370 to 384, 387, 388, 401 to 418, 420, 421, and 424 to 436 described method.

438. 438. The method of embodiment 437, wherein said anti-TIGIT antagonist antibody has intact Fc-mediated effector functions.

439. The method of embodiment 437 or 438, wherein said anti-TIGIT antagonist antibody enhances Fc-mediated effector function.

440. The method of any one of embodiments 437-439, wherein said anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288 wherein said anti-TIGIT antagonist antibody is domvanalimab, BMS-986207, ASP8374 or COM902 , 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421.

442. The method of any one of embodiments 424-431 and 441, wherein said anti-TIGIT antagonist antibody has no Fc-mediated effector functions.

443. The method of any one of embodiments 47-442, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. 444. The method of embodiment 443, wherein the IgG class antibody is an IgG1 subclass antibody.

445. 445. The method of embodiment 444, wherein said anti-TIGIT antagonist antibody is tiragolumab, vibostolimab, etiglimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domvanalimab or BMS-986207.

446. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, wherein said IgG class antibody is an IgG4 subclass antibody , 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421.

447. 447. The method of embodiment 446, wherein said anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. an antibody fragment wherein said anti-TIGIT antagonist antibody binds to TIGIT selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv) and (Fab')2 fragment 435. The method of any one of embodiments 424-434, wherein the method is

449. The method of any one of embodiments 424-448, wherein said anti-TIGIT antagonist antibody is a monospecific antibody.

450. The method of any one of embodiments 424-448, wherein said anti-TIGIT antagonist antibody is a multispecific antibody.

451. The method of embodiment 450, wherein said multispecific antibody is a bispecific antibody.

452. The method of any one of embodiments 424-451, wherein said PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

453. The method of embodiment 452, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. 454. The method of embodiment 453, wherein said PD-Ll binding antagonist inhibits binding of PD-Ll to one or more of its ligand binding partners.

455. The method of embodiment 454, wherein said PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

456. The method of any one of embodiments 453-455, wherein said PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 , embodiment 456.

458. The method of embodiment 457, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

459. The anti-PD-L1 antagonist antibody is a HVR that:
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 RHWPGGFDY (SEQ ID NO: 22);
an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);
HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO:24); and HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25).

457. The method of embodiment 456, comprising

460. wherein said anti-PD-L1 antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or (c) a VH domain according to (a) and (b) 460. The method of embodiment 459, comprising the described VL domains.

461. wherein said anti-PD-L1 antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:27,
460. The method of embodiment 460.

462. wherein said anti-PD-L1 antagonist antibody is:
(a) (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:28; and (b) (b) a light chain comprising the amino acid sequence of SEQ ID NO:29,
462. The method of embodiment 461, comprising

463. The method of any one of embodiments 459-462, wherein said anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. The method of any one of embodiments 459-463, wherein said anti-PD-L1 antagonist antibody is a humanized antibody.

465. The method of embodiment 463 or 464, wherein said anti-PD-L1 antagonist antibody is a full length antibody.

466. Embodiment 459, wherein said anti-PD-Ll antagonist antibody is an antibody fragment that binds PD-Ll selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv and (Fab')2 fragments. 464. The method of any one of paragraphs 1-464.

467. The method of any one of embodiments 459-465, wherein said anti-PD-L1 antagonist antibody is an IgG class antibody.

468. 468. The method of embodiment 467, wherein the IgG class antibody is an IgG1 subclass antibody.

469. The method of embodiment 452, wherein said PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The method of embodiment 469, wherein said PD-1 binding antagonist inhibits binding of PD-L to one or more of its ligand binding partners.

471. The method of embodiment 470, wherein said PD-1 binding antagonist inhibits binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The method of any one of embodiments 469-471, wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21.

474. The method of any one of embodiments 469-471, wherein said PD-1 binding antagonist is an Fc fusion protein.

475. 475. The method of embodiment 474, wherein the Fc fusion protein is AMP-224.

476. of embodiments 80-112, 114-127 and 309-312, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population at a dose of between about 30 mg and about 1200 mg every three weeks. A method according to any one of paragraphs.

477. Embodiments 51, 54, 60, 62, 63, 65-67, 80-112, 114-, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 600 mg every three weeks 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. The method of any one of.

478. Embodiments 51, 54, 60, 62, 63, 65-67, 80, wherein said method comprises administering said anti-TIGIT antagonist antibody to a subject or population of subjects in graded doses based on said subject's body weight as follows: -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:
(a) is 15 kg or less and said anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks;
(b) greater than 15 kg and less than or equal to 40 kg and said anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 40 kg and said anti-TIGIT antagonist antibody is administered at about It is administered at a dose of 600 mg.

479. of embodiments 47, 48, 77, 78, 82, and 83, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every four weeks. A method according to any one of paragraphs.

480. 479. The method of any one of embodiments 47, 48, 59, 67, 323, and 479, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 840 mg every four weeks. Method.

481. The method of any one of embodiments 49, 50, and 104, comprising administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks.

482. Any one of embodiments 49, 50, 227, 251-253, 255, and 481, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 420 mg every two weeks. The method described in .

483. The method of any one of embodiments 47-482, wherein the dose of said anti-TIGIT antagonist antibody is a fixed dose.

484. Embodiments 54, 62, 63, 65-67, wherein said method comprises administering to said subject or subject population a dose of between about 900 mg and about 1500 mg every three weeks of said PD-1 axis binding antagonist. , 80-109, and 27-2698.

485. Embodiments 54, 60, 62, 63, 65-67, 80-112, 114, wherein said method comprises administering said PD-1 axis binding antagonist to said subject at a dose of about 1200 mg every three weeks ~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.

486. Any of embodiments 47, 50, 80-109, and 324, wherein said method comprises administering said PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks to said subject or population of subjects. or the method described in paragraph 1.

487. Any one of embodiments 47, 50, 59, 67, 324, and 479, wherein said method comprises administering said PD-1 axis binding antagonist to said subject at a dose of about 1680 mg every 4 weeks The method described in .

488. Embodiments 48, 49, 80-109, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of between about 600 mg and about 1200 mg every two weeks, and 481. The method according to any one of paragraphs 481 to 481.

489. Any one of embodiments 48, 49, 80-109, 227, 251-253, and 481, comprising administering said PD-1 axis binding antagonist to said subject at a dose of about 840 mg every two weeks. The method described in .

490. The method of any one of embodiments 47-489, wherein the dose of PD-1 axis binding antagonist is a fixed dose.

491. 62. The method of embodiment 60 or 61, wherein said method comprises administering pembrolizumab to said subject at a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks.

492. 192. The method of any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191, wherein the length of each of said one or more dosing cycles is 21 days.

493. The method of any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of said 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 said one or more dosing cycles is 14 days in length.

495. 495. Any one of embodiments 47-494, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. the method of.

496. 496. The method of any one of embodiments 47-495, comprising administering said PD-1 axis binding antagonist to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. .

497. The method of embodiment 321 or 493, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles.

498. The method of embodiment 322 or 493, comprising administering said PD-1 axis binding antagonist to said subject on about day 15 of each of said one or more dosing cycles.

499. The method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist prior to the anti-TIGIT antagonist antibody, or administering the anti-TIGIT antagonist antibody prior to the PD-1 axis binding antagonist. 499. The method of any one of embodiments 47-498, comprising:

500. 499. The method of embodiment 499, wherein said method comprises a first observation period after administration of said PD-1 axis binding antagonist or said anti-TIGIT antagonist antibody.

501. 500. The method of embodiment 500, wherein the first observation period is between about 30 minutes and about 60 minutes long.

502. 502. The method of embodiment 500 or 501, wherein said method comprises a second observation period after administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist.

503. 503. The method of embodiment 502, wherein the second observation period is between about 30 minutes and about 60 minutes long.

504. 504. The method of any one of embodiments 47-503, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects concurrently with said anti-TIGIT antagonist antibody.

505. 505. The method of any one of embodiments 47-504, comprising administering said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist to said subject or population of subjects intravenously.

506. 506. The method of embodiment 505, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or subject population by intravenous infusion over 30±10 minutes and/or 60±10 minutes. .

507. The method of embodiment 505 or 506, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. .

508. The method of any one of embodiments 47-114 and 116-507, wherein the tumor sample obtained from said one or more subjects has its PD-L1 expression level determined.

509. 509. The method of embodiment 508, wherein said tumor sample obtained from said one or more subjects has been determined to have a detectable PD-Ll expression level.

510. 510. The method of embodiment 509, wherein said detectable PD-Ll expression level is a detectable PD-Ll protein expression level.

511. 511. The method of embodiment 510, wherein said detectable PD-L1 protein expression level is determined by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

512. 512. The method of embodiment 511, wherein said anti-PD-Ll antibody suitable for staining is anti-PD-Ll antibody SP263, SP142, 22C3 or 28-8.

513. 513. According to embodiment 511 or 512, wherein the detectable PD-L1 protein expression level is determined using the Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, Ventana SP142 IHC assay, or pharmDx 28-8 IHC assay. Method.

514. Any of embodiments 47-109, 188, 220-265, and 307-423, wherein detectable PD-L1 protein expression levels as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 have been determined The method according to item 1.

515. Any one of embodiments 47-220, 265-338, and 370-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined The method described in .

516. Any one of embodiments 47-113, 136-187, and 220-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP22C3 has been determined The method described in .

517. According to any one of embodiments 47-114 and 116-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined. the method of.

518. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more tumor-associated immune cells (TIC) in said tumor sample.

519. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more and less than 20% TIC in said tumor sample.

520. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more TIC in said tumor sample.

521. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 20% or more TIC in said tumor sample.

522. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more and less than 50% TIC in said tumor sample.

523. 515. The method of embodiment 514, wherein said detectable PD-L1 protein expression level is 50% or more TIC in said tumor sample.

524. The method of any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or greater.

525. The method of any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 30% or greater.

526. The method of any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or more and less than 50% in said tumor sample. .

527. The method of any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or greater.

528. 516. The method of embodiment 515, wherein said PD-L1 positive tumor cell fraction is the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC).

529. 516. The method of embodiment 515, wherein the percentage of tumor area occupied by said PD-L1-expressing tumor-infiltrating IC is 1% or more.

530. 516. The method of embodiment 515, wherein the percentage of tumor area occupied by said PD-L1-expressing tumor-infiltrating IC is 5% or more.

531. 517. The method of embodiment 516, wherein said detectable PD-L1 protein expression level is a composite positive score (CPS) of 1 or more.

532. 517. The method of embodiment 516, wherein said detectable PD-L1 protein expression level is 10 or more CPS.

533. 517. The method of embodiment 516, wherein said detectable PD-L1 protein expression level is 20 or more CPS.

534. The method of any one of embodiments 528-530, wherein said IHC assay is the Ventana SP142 IHC assay.

535. 510. The method of embodiment 509, wherein said detectable PD-Ll expression level is a detectable PD-Ll nucleic acid expression level.

536. said detectable PD-L1 nucleic acid expression level has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof; 535. The method of embodiment 535.

537. 424. Any of embodiments 47-423, wherein said treatment results in an increase in said subject's OS time compared to baseline overall survival (OS) and/or said subject's PFS time compared to baseline progression-free survival (PFS) or the method described in paragraph 1.

538. 538. The method of embodiment 537, wherein:
(a) a subject whose baseline OS time has undergone a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or a treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or (b) the baseline PFS time is a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or an anti-PD-1 axis binding antagonist without a PD-1 axis binding antagonist. Method, median PFS time in a subject population that has received treatment comprising a TIGIT antagonist antibody.

539. 229. According to any one of embodiments 52, 158 and 228, wherein said one or more chemotherapeutic agents is one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. Method.

540. 539. The method of embodiment 539, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The method of embodiments 69, 92, 127, 131, 249, and 540, wherein said carboplatin is administered at a dose sufficient to achieve AUC = 5 mg/ml/min or AUC = 6 mg/ml/min .

542. The method of embodiments 69, 127, 162, 164, 166, 168, and 540, wherein said cisplatin is administered at a dose of about 75 mg/m2 or 80 mg/m2.

543. 543. The method of any one of embodiments 539-542, wherein said one or more non-platinum-based chemotherapeutic agents are antimetabolites, taxanes or topoisomerase II inhibitors.

544. The method of any one of embodiments 62, 173, 174, and 543, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The method of any one of embodiments 69, 127, 162 and 544, wherein said pemetrexed is administered at a dose of about 500 mg/m2.

546. The method of any one of embodiments 63, 64, 162, 398, and 544, wherein said gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.

547. 545. The method of embodiment 544, wherein said antimetabolite is capecitabine.

548. The method of embodiment 544 or 547, wherein said capecitabine is administered at a dose of about 1250 mg/m2.

549. The method of any one of embodiments 173, 174, 229, 230, 239, 240 and 543-548, wherein said taxane is paclitaxel or nab-paclitaxel.

550. The method of any one of embodiments 69, 162, and 549, wherein said paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.

551. The method of any one of embodiments 63, 64, 249, 398, and 549, wherein said nab-paclitaxel is administered at a dose of about 100 mg/m2.

552. Embodiments 80-91, 229, 230, 239, 241, 251- wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331 255, and the method of any one of 543-551.

553. The method of any one of embodiments 69, 92, and 552, wherein said etoposide is administered at a dose of about 100 mg/m2.

554. each of said one or more chemotherapeutic agents once every week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, every four weeks 554. The method of any one of embodiments 543-553, administered twice, or three times every four weeks.

555. 555. The method of any one of embodiments 543-554, wherein said one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.

556. 556. The method of any one of embodiments 544-555, wherein said gemcitabine is administered three times every four weeks.

557. 556. The method of any one of embodiments 544-556, wherein said gemcitabine is administered on days 1, 8 and/or 15 of one or more dosing cycles.

558. The method of any one of embodiments 544-557, wherein said capecitabine is administered daily every two weeks.

559. The method of any one of embodiments 544-558, wherein said capecitabine is administered on days 1-14 of one or more dosing cycles.

560. 559. The method of any one of embodiments 549-559, wherein said nab-paclitaxel is administered three times every four weeks.

561. 561. The method of any one of embodiments 549-560, wherein said nab-paclitaxel is administered on days 1, 8 and/or 15 of one or more dosing cycles.

562. The method of any one of embodiments 552-561, wherein said etoposide is administered on days 1-3 every 3 weeks.

563. 563. The method of any one of embodiments 552-562, wherein said etoposide is administered on days 1-3 of one or more dosing cycles.

564. 564. The method of any one of embodiments 543-563, wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

565. 564. The method of any one of embodiments 543-564, wherein said one or more chemotherapeutic agents are administered subsequent to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

566. 566. The method of any one of embodiments 543-565, wherein said one or more chemotherapeutic agents are administered intravenously or orally.

567. The method of any one of embodiments 65, 310, and 311, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

568. The method of embodiment 312 or 567, wherein said VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every three weeks.

569. The method of embodiment 318 or 568, wherein said VEGF antagonist is administered at a dose of about 15 mg/kg every three weeks.

570. The method of any one of embodiments 65, 310-312, 318-320, and 567-569, wherein said VEGF antagonist is an anti-VEGF antibody.

571. The method of embodiment 570, wherein said anti-VEGF antibody comprises the VH and VL domains of bevacizumab.

572. The method of embodiment 570 or 571, wherein said anti-VEGF antibody is bevacizumab.

573. according to any one of embodiments 65, 310-312, and 318-320, wherein said anti-TIGIT antagonist antibody is tiragolumab, said PD-1 axis binding antagonist is atezolizumab, and said VEGF antagonist is bevacizumab Method.

574. any one of embodiments 65, 310-312, 318-320, and 567-573, wherein said method comprises administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles described method.

575. The method of any one of embodiments 318-320, wherein said method comprises administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles.

576. The method of any one of embodiments 65, 310-312, and 318-320, and 567-575, wherein said VEGF antagonist is administered intravenously.

577. 577. The method of embodiment 576, wherein said VEGF antagonist is administered to said subject by intravenous infusion over 90±15 minutes.

578. Embodiment 65, 310-312, wherein said method comprises administering to said subject said PD-1 axis binding antagonist prior to said VEGF antagonist and administering said VEGF antagonist prior to said anti-TIGIT antagonist antibody. , 318-320, and 567-577.

579. 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. 578. The method of embodiment 578, comprising:

580. 579. 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. Embodiments 113, 128, 129-131, 175-182, 210-214, 221, 256, 257, 270, 289, 290, 293, 294, 297, wherein said tiragolumab and atezolizumab are combined in an IV bag prior to administration , 298, 333, 362-365, 385, 386, 389, 393, 419, and 422.

582. The method of any one of embodiments 47-581, wherein said subject is a human.

583. PD for treating a subject with cancer according to the method of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582- A kit comprising a uniaxial binding antagonist and/or an anti-TIGIT antagonist antibody.

584. Anti-TIGIT for treating a subject with cancer according to the method of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582 A kit comprising a PD-1 axis binding antagonist for use in combination with an antagonist antibody.

585. The kit of embodiment 584, further comprising an anti-TIGIT antagonist antibody.

586. The kit of any one of embodiments 583-585, wherein said anti-TIGIT antagonist antibody is tiragolumab.

587. The kit of any one of embodiments 583-586, wherein said PD-1 axis binding antagonist is a monoclonal antibody.

588. PD for treating a subject with cancer according to the method of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582- A kit comprising an anti-TIGIT antagonist antibody for use in combination with a uniaxial binding antagonist.

589. The kit of embodiment 588, wherein said kit further comprises a PD-1 axis binding antagonist.

590. The kit of embodiment 588 or 589, wherein said PD-1 axis binding antagonist is atezolizumab.

591. The kit of any one of embodiments 588-590, wherein said anti-TIGIT antagonist antibody is tiragolumab.

592. The kit of any one of embodiments 583-591, wherein said kit further comprises one or more chemotherapeutic agents.

593. 593. The kit of embodiment 592, wherein said 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 said one or more platinum-based chemotherapeutic agents is carboplatin or cisplatin.

595. The kit of embodiment 593 or 594, wherein said one or more non-platinum chemotherapeutic agents are antimetabolites, taxanes or topoisomerase II inhibitors.

596. 596. The kit of embodiment 595, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

597. The kit of embodiment 595 or 596, wherein said taxane is paclitaxel or nab-paclitaxel.

598. 598. The kit of any one of embodiments 595-597, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331.

599. The kit of any one of embodiments 583-598, further comprising said VEGF antagonist.

600. The kit of embodiment 599, wherein said VEGF antagonist is an anti-VEGF antibody.

601. The kit of embodiment 600, wherein said anti-VEGF antibody is bevacizumab.

602. A subject with cancer, wherein the method is according to any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582; or Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in methods of treating a subject population.

603. PD-1 axial binding, wherein said treating is by the method of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582 Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or subject population with cancer in combination with an antagonist.

604. Use according to embodiment 603, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

605. The use of embodiment 603, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single formulation.

Embodiment set B:
1. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment comprises administering said anti-TIGIT antagonist antibody and said PD-1 in one or more dosing cycles. comprising the use of a uniaxial binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 500 mg to about 700 mg every 3 weeks; an anti-TIGIT antagonist antibody formulated for administration at a dose of 900 mg to about 1500 mg, wherein said treatment further comprises use of a platinum-based chemotherapeutic agent every 3 weeks and a non-platinum-based chemotherapeutic agent every 3 weeks; and PD-1 axis binding antagonist.

2. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment comprises administering said anti-TIGIT antagonist antibody and said PD- in one or more dosing cycles. comprising the use of a uniaxial binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 700 mg to about 1000 mg every 4 weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of 1400 mg to 2000 mg.

3. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment comprises administering said anti-TIGIT antagonist antibody and said PD- in one or more dosing cycles. comprising the use of a uniaxial binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 600 mg every 2 weeks; said PD-1 Axis binding antagonist is administered at about An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of 600 mg to about 1200 mg.

4. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiments 2 or 3, wherein said treatment further comprises the use of one or more chemotherapeutic agents.

5. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-4, wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3);
(d) a 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).
An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-5, comprising:

7. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and (d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and the following heavy chain variable region FRs:
(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where 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).
The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of any one of embodiments 1-6, comprising:

8. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or (c) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18. , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-7, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

9. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-8, wherein said anti-TIGIT antagonist antibody is tiragolumab.

10. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to 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. Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 1-10, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody Binding antagonist.

12. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 12.

14. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-13, wherein said PD-1 axis binding antagonist is atezolizumab.

15. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21.

17. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 2-16, wherein said treatment further comprises the use of an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. Axis binding antagonist.

18. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiments 1 or 17, wherein said non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. Anti-TIGIT antagonist for use according to embodiment 18, wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid or HU-331, in particular etoposide Antibodies and PD-1 axis binding antagonists.

20. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 18 or 19, wherein said topoisomerase II inhibitor is formulated for administration at a dose of 100 mg/m2.

21. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 17-20, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. Anti-TIGIT for use according to any one of embodiments 17-21, wherein said platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

23. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 1-22, wherein said method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. wherein the induction phase comprises four initial dosing cycles, 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; an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 23.

25. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 23 or 24, wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent and/or non-platinum-based chemotherapeutic agent.

26. Antibody for use according to any one of embodiments 1-25, wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody. TIGIT antagonist antibody and PD-1 axis binding antagonist.

27. 27. An anti-TIGIT antagonist antibody for use according to any one of embodiments 1-26, wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

28. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is lung cancer.

29. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 28, wherein said lung cancer is small cell lung cancer (SCLC), in particular extensive-stage SCLC (ES-SCLC).

30. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 28, wherein said lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (Stage IIIB NSCLC).

31. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 28, wherein said lung cancer is locally advanced, unresectable or metastatic non-squamous NSCLC.

32. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 28, wherein said lung cancer is resectable lung cancer.

33. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is cervical cancer.

34. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is early triple negative breast cancer (eTNBC).

35. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is head and neck cancer.

36. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is bladder cancer.

38. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 37, wherein said cancer is urothelial carcinoma (UC), in particular metastatic urothelial carcinoma (mUC).

39. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC).

40. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 1-27, wherein said cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said method is formulated for administration at a dose of about 500 mg to about 700 mg every three weeks. a formulated anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist formulated for administration at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, comprising administering to said subject a dosing regimen comprising one or more dosing cycles comprising a non-platinum chemotherapeutic agent.

42. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said method is formulated for administration at a dose of about 700 mg to about 1000 mg every four weeks. administering to said subject a dosing regimen comprising a formulated anti-TIGIT antagonist antibody and one or more dosing cycles of a PD-1 axis binding antagonist formulated to be administered at a dose of about 1400 mg to 2000 mg every 4 weeks. an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, comprising:

43. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said method is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks. and one or more dosing cycles of a PD-1 axis binding antagonist formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks. an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, comprising administering.

44. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, said method administering (a) at a dose of about 500 mg to about 700 mg every three weeks a PD-1 axis binding antagonist formulated to be administered at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and 3 (b) said method comprises administering to said subject a dosing regimen comprising one or more weekly dosing cycles of a non-platinum chemotherapeutic agent, wherein (b) said method is administered at a dose of about 700 mg to about 1000 mg every 4 weeks; and one or more dosing cycles of a PD-uniaxial binding antagonist formulated to be administered at a dose of about 1400 mg to 2000 mg every 4 weeks. or (c) the method comprises administering to said subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every two weeks, and about 600 mg to about 600 mg every two weeks. anti-TIGIT antagonist antibody and PD-1 axis binding, comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist formulated for administration at a dose of about 1200 mg. antagonist.

45. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

46. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said 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 with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks, said PD-1 axis binding antagonist is administered 4 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 80 mg to about 2000 mg weekly.

48. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks, said PD-1 axis binding antagonist is administered 2 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 20 mg to about 1600 mg weekly.

49. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 10 mg to about 1000 mg every two weeks, said PD-1 axis binding antagonist is An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 20 mg to about 1600 mg weekly.

50. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 10 mg to about 1000 mg every two weeks, said PD-1 axis binding antagonist is An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 80 mg to about 2000 mg weekly.

51. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, said PD-1 axis binding antagonist is An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 100 mg to about 1000 mg weekly.

52. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 47-51, wherein said treatment further comprises the use of one or more chemotherapeutic agents.

53. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 52, wherein said treatment further comprises the use of platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents.

54. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, said PD-1 axis binding antagonist is administered for 3 An anti-TIGIT antagonist antibody and PD-1 formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, comprising a platinum-based chemotherapeutic agent every 3 weeks and a non-platinum-based chemotherapeutic agent every 3 weeks. Axis binding antagonist.

55. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 53 or 54, wherein said method comprises an induction phase and a maintenance phase.

56. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 55, wherein said induction phase and maintenance phase each comprise one or more dosing cycles.

57. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 55 or 56, wherein said maintenance phase does not comprise administration of a platinum-based chemotherapeutic agent.

58. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 55-57, wherein said maintenance phase does not comprise administration of a non-platinum chemotherapeutic agent.

59. said maintenance phase anti-TIGIT antagonist antibody formulated to be administered at a dose of about 200 mg to about 2000 mg every 4 weeks and formulated to be administered at a dose of about 80 mg to about 2000 mg every 4 weeks anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 58, comprising one or more dosing cycles of the PD-1 axis binding antagonist.

60. An anti-TIGIT antagonist antibody and an anti-PD-1 antagonist antibody for use in a method of treating a subject with cancer, wherein said treatment comprises one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and said anti-PD-1 antagonist antibody is administered for 3 weeks An anti-TIGIT antagonist antibody and an anti-PD-1 antagonist antibody formulated for administration at a dose of about 80 mg to about 1600 mg per dose, wherein said anti-PD-1 antagonist antibody is pembrolizumab.

61. Tiragolumab and pembrolizumab for use in a method of treating a subject with cancer, said treatment comprising the use of tiragolumab and pembrolizumab in a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, said pembrolizumab tiragolumab and pembrolizumab formulated for administration at doses between about 100 mg and about 1000 mg every 6 weeks.

62. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist antibody is formulated at a dose of between about 80 mg and about 1600 mg every 3 weeks every 3 weeks, and the antimetabolite is administered twice a day every 3 weeks for 2 weeks on/1 week off. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 10 mg/m2 and about 10000 mg/m2 per oral dose.

63. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, said PD-1 axis binding antagonist is administered for 3 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist that is gemcitabine and nab-paclitaxel at a dose of about 80 mg to about 1600 mg weekly.

64. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 52, wherein said 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 with cancer, wherein said treatment is in a dosing regimen comprising one or more dosing cycles. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist antibody is formulated for administration every 3 weeks at a dose of between about 80 mg and about 1600 mg every 3 weeks, and the VEGF antagonist is administered every 3 weeks at a dose of between about 1 mg/kg and about 35 mg/kg An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration.

66. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment comprises said anti-TIGIT antagonist antibody and a dosing regimen comprising an induction phase and a maintenance phase. comprising the use of said PD-1 axis binding antagonist;
(a) said anti-TIGIT antagonist antibody formulated for administration in said induction phase at a dose of about 30 mg to about 1200 mg every 3 weeks; said PD-1 at a dose of about 80 mg to about 1600 mg every 3 weeks; one or more dosing cycles of an axially bound antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks;
(b) said maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding antagonist every 3 weeks and a non-platinum chemotherapeutic agent every 3 weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent.

67. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, wherein said treatment comprises said anti-TIGIT antagonist antibody and a dosing regimen comprising an induction phase and a maintenance phase. comprising the use of said PD-1 axis binding antagonist;
(a) said anti-TIGIT antagonist antibody formulated for administration in said induction phase at a dose of about 30 mg to about 1200 mg every 3 weeks; said PD-1 at a dose of about 80 mg to about 1600 mg every 3 weeks; one or more dosing cycles of an axially bound antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks;
(b) said anti-TIGIT antagonist antibody formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks during said maintenance phase, and for administration at a dose of about 80 mg to about 2000 mg every 4 weeks; wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent or said non-platinum-based chemotherapeutic agent. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

68. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 56-59, 66 and 67, wherein said induction phase comprises 4-6 dosing cycles.

69. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 53-59 and 66-68, wherein
(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel, or (c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is etoposide,
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

70. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-69, wherein said cancer is a solid tumor.

71. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-70, wherein said cancer is locally advanced or metastatic.

72. the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, renal cancer, Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-71, which is melanoma, or ovarian cancer.

73. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is lung cancer.

74. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 73, wherein the lung cancer is NSCLC, particularly locally advanced unresectable NSCLC.

75. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 74, wherein said NSCLC is stage IIIB NSCLC.

76. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 73-75, wherein said lung cancer is recurrent or metastatic NSCLC.

77. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 76, wherein said NSCLC is stage IV NSCLC.

78. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 77, wherein said subject has not been previously treated for stage IV NSCLC.

79. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 73, wherein said 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, said treatment comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment comprises said anti-TIGIT antagonist antibody. an anti-TIGIT antagonist antibody that prolongs progression-free survival (PFS) of said subject compared to treatment comprising said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without and PD-1 axis binding antagonists.

81. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject population having lung cancer, said treatment comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of a chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment lasts from about 8.2 months to about 9. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist that produced a median PFS in the subject population of 2 months.

82. The treatment compared the overall survival (OS 82. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 80 or 81, which prolongs ).

83. said treatment prolongs PFS of said subject or subject population 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 an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-82.

84. said treatment reduces said PFS of said subject or subject population by at least about Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 83, extending from 3 months to about 4 months.

85. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having lung cancer, said treatment comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment comprises said anti-TIGIT antagonist antibody. an anti-TIGIT antagonist antibody and PD-1 axis binding that prolongs OS in said subject compared to treatment comprising said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without antagonist.

86. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject population having lung cancer, said treatment comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of a chemotherapeutic agent and a topoisomerase II inhibitor, said treatment for about 15.3 months to about 17.6 months. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist that yielded a median OS in the subject population of .

87. said treatment prolongs OS of said subject or subject population 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 an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 82-86.

88. said treatment reduces the OS of said subject or subject population by at least about 3 months to about 5 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; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 82-86, extended for 3 months.

89. 89. 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. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in.

90. 89. Any one of embodiments 80-89, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are further administered in one or more additional cycles following said fourth initial dosing cycle. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in.

91. An anti-TIGIT antagonist antibody and PD-1 axis binding for use according to embodiment 90, wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of said one or more additional dosing cycles. antagonist.

92. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-91, wherein said platinum-based chemotherapeutic agent is carboplatin and said topoisomerase II inhibitor is etoposide.

93. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-92, wherein said lung cancer is small cell lung cancer (SCLC).

94. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 93, wherein said SCLC is extended-stage SCLC (ES-SCLC).

95. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 94, wherein said one or more subjects are treatment naive for ES-SCLC.

96. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-95, wherein said one or more subjects do not have the presence or history of brain metastases.

97. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-96, wherein said lung cancer is not selected for PD-L1 expression.

98. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 80-96, wherein said lung cancer is selected for PD-L1 expression.

99. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 98, wherein said lung cancer is selected for PD-L1 expression by a detectable level of PD-L1 expression.

100. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 80-99, wherein said lung cancer is metastatic.

101. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 100, wherein said lung cancer has metastasized to the brain, liver, lymph nodes and/or adrenal glands.

102. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 100 or 101, wherein said lung cancer has not metastasized to the brain.

103. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 100-102, wherein said treatment results in a complete response (CR) or a partial response (PR).

104. For use according to any one of embodiments 80-103, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 2, 3 or 4 weeks. anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

105. 105. Use according to any one of embodiments 80-104, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 2000 mg every 2, 3 or 4 weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

106. Anti-TIGIT antagonist for use according to any one of embodiments 80-105, wherein said PD-1 axis binding antagonist, anti-TIGIT antagonist antibody, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered sequentially. Antibodies and PD-1 axis binding antagonists.

107. 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. an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 106.

108. 108. Anti-TIGIT antagonist for use according to any one of embodiments 80-107, wherein said anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered intravenously. Antibodies and PD-1 axis binding antagonists.

109. 109. Any one of embodiments 80-108, wherein one or more of said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are administered subcutaneously. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

110. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with SCLC, wherein said treatment comprises one or more 21-day dosing cycles of said anti-TIGIT antagonist antibody and said comprising the use of a PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg on day 1 of each dosing cycle, and atezolizumab is administered on day 1 of each dosing cycle; , carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and etoposide at each formulated to be administered at a dose of 100 mg/m on each of days 1, 2 and 3 of the dosing cycle, wherein said treatment is with atezolizumab, carboside and etoposide without said anti-TIGIT antagonist An anti-TIGIT antagonist antibody and atezolizumab that, in comparison, prolong the subject's PFS and/or OS.

111. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with SCLC, wherein said treatment comprises one or more 21-day dosing cycles of said anti-TIGIT antagonist antibody and said comprising the use of a PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 800 mg on day 1 of each dosing cycle, and atezolizumab is administered on day 1 of each dosing cycle; , carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and etoposide at each formulated to be administered at a dose of 100 mg/m on each of days 1, 2 and 3 of the dosing cycle, wherein said treatment is with atezolizumab, carboside and etoposide without said anti-TIGIT antagonist An anti-TIGIT antagonist antibody and atezolizumab that, in comparison, prolong the subject's PFS and/or OS.

112. The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg on day 1 of each additional dosing cycle and about 80 mg to about 80 mg on day 1 of each additional dosing cycle. Embodiment 110 further comprising one or more additional 21-day dosing cycles of atezolizumab formulated for administration at a dose of 1600 mg, wherein carboplatin and etoposide are omitted from each of the one or more additional dosing cycles. or an anti-TIGIT antagonist antibody and atezolizumab for use according to 111.

113. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with ES-SCLC, said treatment comprising four initial dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist , including use in one or more additional dosing cycles followed by
(a) tiragolumab formulated for the four initial dosing cycles to be administered at a dose of about 600 mg on day 1 of each initial dosing cycle, at a dose of about 1200 mg on day 1 of each initial dosing cycle; Atezolizumab formulated to administer, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle, and Days 1, 2 of each initial dosing cycle and etoposide at a dose of 100 mg/m2 on each of days 3 and
(b) said one or more additional dosing cycles are formulated to be administered at a dose of about 600 mg on day 1 of each additional dosing cycle, and on day 1 of each additional dosing cycle atezolizumab formulated for administration at a dose of about 1200 mg;
each of the four initial dosing cycles and the one or more additional dosing cycles is a 21-day dosing cycle, and the treatment is compared to a treatment comprising atezolizumab, carboplatin and etoposide without the tiragolumab; Tiragolumab and atezolizumab that prolong PFS and/or OS in a subject or subject population.

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, said treatment comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemical said anti-TIGIT antagonist antibody and said PD-1 axis binding in a dosing regimen comprising one or more dosing cycles of a first chemotherapeutic agent that is a therapeutic agent and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists, including the use of antagonists.

115. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 114, wherein said lung cancer has not been evaluated for PD-L1 expression.

116. 116. An anti-TIGIT antagonist antibody and PD-1 axis binding for use according to embodiment 114 or 115, wherein said one or more subjects have not been determined to have a PD-L1 positive tumor cell fraction of 50% or greater antagonist.

117. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 116, wherein said one or more subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. 118. An anti-tumor for use according to embodiment 116 or 117, wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and said anti-PD-L1 antibody is SP263 or 22C3. TIGIT antagonist antibody and PD-1 axis binding antagonist.

119. Antibiotic for use according to any one of embodiments 114-118, wherein said one or more subjects do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. TIGIT antagonist antibody and PD-1 axis binding antagonist.

120. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 114-119, wherein said one or more subjects have no prior systemic treatment for lung cancer.

121. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 114-120, wherein said lung cancer is locally advanced lung cancer.

122. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 114 to 121, wherein said lung cancer is NSCLC, in particular locally advanced unresectable or metastatic non-squamous NSCLC antagonist.

123. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 122, wherein said non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The dosing regimen comprises an induction phase comprising four dosing cycles, 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 in the induction phase 124. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 114-123, administered on Day 1 of each dosing cycle of.

125. wherein said dosing regimen comprises a maintenance phase following said induction phase, said maintenance phase comprising one or more dosing cycles, said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist and said non-platinum chemotherapeutic agent is administered on Day 1 of each dosing cycle of said maintenance phase.

126. 126. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 125, wherein said one or more dosing cycles of said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent.

127. Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 114-126, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed Binding antagonist.

128. Tiragolumab and atezolizumab for use in a method of treating a subject or subject population with advanced non-squamous NSCLC, said treatment comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed in a dosing regimen comprising four 21-day dosing cycles, wherein pemetrexed on day 1 of each of the four 21-day dosing cycles and said tiragolumab at about 600 mg every 3 weeks. wherein said atezolizumab is formulated to be administered at a dose of about 1200 mg every 3 weeks, and carboplatin is formulated to be administered at a dose of about 1200 mg every 3 weeks, sufficient to achieve AUC = 5 mg/ml/min every 3 weeks; or cisplatin formulated to be administered at a dose of 75 mg/m2 every 3 weeks and pemetrexed formulated to be administered at a dose of about 500 mg/m2 every 3 weeks; Atezolizumab.

129. Tiragolumab and atezolizumab for use in a method of treating a subject or subject population with advanced non-squamous NSCLC, said treatment comprising
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin;
including the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in
Tiragolumab and atezolizumab, wherein said subject or subject population has not received prior systemic therapy for said advanced non-squamous NSCLC.

130. Tiragolumab and atezolizumab for use in a method of treating a subject with advanced non-squamous NSCLC, said treatment comprising
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin;
including the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in
tiragolumab and atezolizumab, wherein said subject was naive to prior systemic therapy for said advanced non-squamous NSCLC.

131. Tiragolumab and atezolizumab for use in a method of treating a subject with advanced non-squamous NSCLC, said treatment comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist tiragolumab, atezolizumab, carboplatin or cisplatin; and pemetrexed on day 1 of each of the four 21-day dosing cycles, said tiragolumab administered at a dose of about 600 mg every 3 weeks. wherein atezolizumab is formulated to be administered at a dose of about 1200 mg every 3 weeks, cisplatin is formulated to be administered at a dose of 75 mg/m2 every 3 weeks, and pemetrexed is formulated to be administered at a dose of about Tiragolumab and atezolizumab formulated for administration at a dose of 500 mg/m2.

132. Anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 114-131, wherein said treatment prolongs PFS of said subject or population of subjects by at least about 3.5 months or about 4.7 months - uniaxial binding antagonists.

133. The anti-TIGIT antagonist antibody and PD-antibody for use according to any one of embodiments 114-132, wherein said treatment results in a median PFS of said subject population of about 12.5 months to about 14.7 months. Uniaxial binding antagonist.

134. An anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 114-133, wherein said treatment prolongs OS of said subject or population of subjects by at least about 5.5 months or about 8.0 months - uniaxial binding antagonists.

135. 135. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 114-134, wherein said treatment results in a median OS for said subject population of about 27.5 months to about 32.0 months Axis binding antagonist.

136. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects having resectable lung cancer, said treatment comprising said anti-TIGIT antibody in one or more dosing cycles. comprising the use of a TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the binding antagonist antibody is formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks.

137. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects having resectable lung cancer, said treatment comprising said anti-TIGIT antibody in one or more dosing cycles. comprising the use of a TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300 mg and about 800 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the binding antagonist antibody is formulated for administration at a dose of between about 900 mg and about 1500 mg 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 with lung cancer, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist. wherein at least one of said dosing cycles is administered at a dose between about 30 mg and about 1200 mg every 3 weeks as a neoadjuvant treatment and PD-uniaxial binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks. - uniaxial binding antagonists.

139. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject with lung cancer, said treatment comprising one or more of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist. comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in dosing cycles, wherein at least one of said dosing cycles is administered at a dose of between about 300 mg and about 800 mg every 3 weeks as a neoadjuvant treatment. wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 900 mg and about 1500 mg every three weeks. and PD-1 axis binding antagonists.

140. at least one of said dosing cycles comprises said anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks as an adjuvant treatment, wherein said PD-1 axis binding antagonist is 140. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 138 or 139, formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks.

141. at least one of said dosing cycles comprises said anti-TIGIT antagonist antibody formulated for administration at a dose of between about 500 mg and about 700 mg every three weeks as an adjuvant treatment, wherein said PD-1 axis binding antagonist is Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 140, formulated for administration at a dose of between about 900 mg and about 1500 mg every 3 weeks.

142. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 138-141, wherein said lung cancer is resectable lung cancer.

143. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 136-142, wherein said lung cancer is early stage cancer.

144. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 136-143, wherein said lung cancer is stage II, IIIA or IIIB lung cancer.

145. 145. Anti-TIGIT antagonist antibody and PD for any one of embodiments 136-144, wherein said lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations - uniaxial binding antagonists.

146. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 136-145, wherein said subject is eligible for R0 ablation for curative purposes.

147. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 136-146, wherein said subject has no prior treatment for lung cancer.

148. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 147, wherein said prior treatment is immunotherapy, chemotherapy or radiotherapy.

149. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 136-148, wherein said subject is eligible to undergo a platinum-based chemotherapy regimen.

150. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 136-149, wherein said first dosing cycle is initiated prior to surgery.

151. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 150, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to surgery.

152. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiments 150 or 151, wherein 4 dosing cycles are completed prior to surgery.

153. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 136-152, wherein at least one dosing cycle is initiated after surgery.

154. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 153, wherein 16 dosing cycles are completed after surgery.

155. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 150-154, wherein said surgery is segmentectomy, lobectomy, bilobectomy, or pneumonectomy antagonist.

156. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 136-155, wherein said method further comprises radiotherapy.

157. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 156, wherein said radiotherapy is post-operative radiotherapy.

158. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 136-157, wherein said treatment further comprises the use of one or more chemotherapeutic agents.

159. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 158, wherein said one or more chemotherapeutic agents are administered post-operatively.

160. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 159, wherein said one or more chemotherapeutic agents are administered in four dosing cycles after surgery.

161. Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 158-160, wherein said one or more chemotherapeutic agents are platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents Binding antagonist.
162. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 161, wherein
(a) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine;
(c) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel;
(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or (e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. is
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

163. 163. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 136-162, wherein said treatment results in an increase in MPR rate compared to the baseline significant pathologic response (MPR) rate Axis binding antagonist.

164. The reference MPR rate is
MPR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 164. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 163 which is .

165. 165. An anti-TIGIT antagonist antibody for use according to any one of embodiments 136-164, wherein said treatment results in a pathological complete response (pCR) and/or an increase in the pCR rate compared to the baseline pCR rate and PD-1 axis binding antagonist.

166. The reference pCR rate is
pCR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 165. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 165 which is .

167. 167. An anti-TIGIT antagonist antibody for use according to any one of embodiments 136-166, wherein said treatment results in an increase in symptom-free survival (EFS) compared to baseline EFS time and PD-1 axis binding antagonist.

168. The reference EFS rate is
EFS time in a subject population that has received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 167. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 167 which is .

169. 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 resectable lung cancer, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist. antibody and said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 600 mg every 3 weeks, said PD-1 axis binding antagonist An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the antibody is formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks.

170. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject with lung cancer, said treatment comprising one or more doses of the anti-TIGIT antagonist antibody and the -1 axis binding antagonist comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in cycles, wherein at least one of said dosing cycles administers as a neoadjuvant treatment at a dose of between about 30 mg and about 600 mg every three weeks. wherein the PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks; and PD-1 axis binding antagonist.

171. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects having resectable lung cancer, said treatment comprising about 30 mg and about 1200 mg every 3 weeks. said anti-TIGIT antagonist antibody formulated for administration at a dose between about 80 mg and about 1600 mg every 3 weeks for administration every 3 weeks at a dose of between about 80 mg and about 1600 mg every 3 weeks anti-TIGIT antagonist antibody and PD-, including the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of an antagonist antibody, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent. Uniaxial binding antagonist.

172. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject with lung cancer, said treatment comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, platinum-based chemotherapy and the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of a non-platinum chemotherapeutic agent, at least one of said dosing cycles as a neoadjuvant treatment, 3 said anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; said anti-TIGIT antagonist antibody formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks; Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists, including PD-1 axis binding antagonists, platinum-based chemotherapeutic agents, and non-platinum-based chemotherapeutic agents.

173. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects having resectable lung cancer, said treatment comprising about 30 mg and about 1200 mg every 3 weeks. said PD-1 axis binding antagonist antibody formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks. and (a) (i) a platinum-based chemotherapeutic agent at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) every 3 weeks and (b)(i) about 500 mg/m2 every three weeks, about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle. or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists, including the use of antibodies and said PD-1 axis binding antagonists.

174. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject with lung cancer, said treatment comprising tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapy comprising use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles of the agent, at least one of said dosing cycles comprising: (a) at a dose of between about 30 mg and about 600 mg every 3 weeks; (b) said PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks; c) the platinum-based chemotherapeutic agent (i) at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) for 3 weeks (d) said non-platinum-based chemotherapeutic agent (i) 500 mg/m every 3 weeks, or on day 1 of each dosing cycle and a non-platinum chemotherapeutic agent that is an antimetabolite at a dose of 1000 mg/m2 or 1250 mg/m2 on day 8, or (ii) a taxane at a dose of 100 mg/m2, 175 mg/m2 or 200 mg/m2 every 3 weeks. and wherein said treatment is a neoadjuvant treatment, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

175. Tiragolumab and atezolizumab for use in a method for treating a subject with resectable lung cancer, said treatment comprising tiragolumab at a dose of about 600 mg every 3 weeks and tiragolumab at a dose of about 1200 mg every 3 weeks. atezolizumab and
(a)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and,
(b)
(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks, or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) every 3 weeks. paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 of
tiragolumab and atezolizumab, including the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles of

176. Tiragolumab and atezolizumab for use in a method for treating a subject with lung cancer, said treatment comprising one or more dosing cycles of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent wherein at least one of said dosing cycles comprises (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; ) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks; (ii) cisplatin at a dose of about 75 mg/m2 every three weeks; A platinum-based chemotherapeutic agent that is (i) pemetrexed at a dose of 500 mg/m2 every 3 weeks, or 1000 mg/m2 or 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) 3 a non-platinum chemotherapeutic agent that is paclitaxel at doses of 100 mg/m2, 175 mg/m2 or 200 mg/m2 weekly, wherein said treatment is a neoadjuvant treatment.

177. Tiragolumab and atezolizumab for use in a method for treating a subject with non-squamous NSCLC, said treatment comprising said anti-TIGIT antagonist antibody and said PD-1 in one or more dosing cycles of tiragolumab and atezolizumab (a) at least one of said dosing cycles, as a neoadjuvant treatment, tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks and 1200 mg every 3 weeks; atezolizumab formulated for administration in doses, wherein at least one of said dosing cycles is tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks as an adjuvant treatment; tiragolumab and atezolizumab, including atezolizumab formulated for administration at a dose of about 1200 mg every three weeks.

178. Tiragolumab antibody and atezolizumab for use in a method for treating a subject with non-squamous NSCLC, said treatment comprising said anti-TIGIT antagonist antibody and said PD- tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks comprising the use of a uniaxial binding antagonist, wherein (I) at least one of said dosing cycles is a neoadjuvant treatment; (b) ) atezolizumab formulated to be administered at a dose of approximately 1200 mg every 3 weeks as a neoadjuvant treatment; (c) (i) with the goal of achieving an AUC of 5 mg/mL/min every 3 weeks (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks, and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; paclitaxel at a dose of 175 mg/m2 or about 200 mg/m2, or (iii) cisplatin at a dose of about 75 mg/m2 every three weeks and pemetrexed at a dose of about 500 mg/m2 every three weeks; At least one of the dosing cycles is tiragolumab formulated to be administered at a dose of between about 30 mg and about 1200 mg every 3 weeks as an adjuvant treatment, and at a dose of between about 80 mg and about 1600 mg every 3 weeks. Tiragolumab antibodies and atezolizumab, including atezolizumab formulated for administration.

179. Tiragolumab and atezolizumab for use in a method for treating a subject with lung cancer, said treatment comprising said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is neoadjuvant treatment, (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks, (b) neoadjuvant treatment atezolizumab formulated to be administered at a dose of approximately 1200 mg every 3 weeks as and (c)(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle, (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every three weeks, and Paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and about 1250 mg on days 1 and 8 of each dosing cycle. (II) at least one of said dosing cycles is formulated to be administered at a dose of between about 30 mg and about 1200 mg every 3 weeks as an adjuvant treatment. Tiragolumab and atezolizumab, including tiragolumab and atezolizumab formulated for administration at doses between about 80 mg and about 1600 mg every three weeks.

180. Tiragolumab and atezolizumab for use in a method for treating a subject with lung cancer, said treatment comprising said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab including the use of
(I) at least one of said dosing cycles is a neoadjuvant treatment;
(a) tiragolumab formulated for administration at a dose of about 1200 mg every 3 weeks;
(b) atezolizumab formulated for administration at a dose of about 1200 mg every three weeks as a neoadjuvant treatment;
(c)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;
(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii)3 cisplatin at a dose of about 75 mg/m2 weekly and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle;
(II) at least one of said dosing cycles comprises, as an adjuvant treatment, tiragolumab formulated for administration at a dose of between about 300 mg and about 800 mg every 3 weeks and about 900 mg and about 1500 mg every 3 weeks; Tiragolumab and atezolizumab, including atezolizumab formulated for administration at doses between.

181. Tiragolumab and atezolizumab for use in a method for treating a subject with lung cancer, said treatment comprising said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is neoadjuvant treatment, (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks, (b) neoadjuvant treatment atezolizumab formulated to be administered at a dose of approximately 1200 mg every 3 weeks as and (c)(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle, (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every three weeks, and Paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and about 1250 mg on days 1 and 8 of each dosing cycle. (II) at least one of said dosing cycles, as an adjuvant treatment, tiragolumab formulated to be administered at a dose of about 600 mg every 3 weeks as an adjuvant treatment; and Tiragolumab and atezolizumab, including atezolizumab formulated to be administered at a dose of approximately 1200 mg per dose.

182. Tiragolumab and atezolizumab for use in a method for treating a subject with resectable squamous NSCLC, said treatment comprising said anti-TIGIT antagonist antibody and said PD in one or more dosing cycles of tiragolumab and atezolizumab - tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks, comprising the use of a monoaxial binding antagonist, wherein (I) at least one of said dosing cycles is a neoadjuvant treatment, (a) b) Atezolizumab formulated to be administered at a dose of approximately 1200 mg every 3 weeks as a neoadjuvant treatment, and (c) (i) with the goal of achieving an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of approximately 1000 mg/m2 on days 1 and 8 of each dosing cycle, (ii) with the goal of achieving an AUC of 6 mg/mL/min every 3 weeks carboplatin and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and day 1 and 2 of each dosing cycle (II) at least one of said dosing cycles is formulated to be administered at a dose of between about 600 mg every 3 weeks as an adjuvant treatment. and atezolizumab formulated for administration at doses of between about 1200 mg every 3 weeks.

183. Anti-TIGIT for use according to any one of embodiments 136-182, wherein detectable PD-L1 protein expression levels as determined by an IHC assay including staining with the anti-PD-L1 antibody SP263 have been determined. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

184. 184. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 183, wherein the detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or greater.

185. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 73, 114-121, and 136-184, wherein said lung cancer is NSCLC.

186. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 185, wherein the NSCLC is squamous NSCLC.

187. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 185, wherein said NSCLC is non-squamous NSCLC.

188. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is cervical cancer.

189. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population having cervical cancer with detectable levels of PD-L1 expression, said treatment comprising comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of between about 30 mg and about 1200 mg every three weeks. wherein said PD-1 axis binding antagonist antibody is formulated for administration every 3 weeks at a dose of between about 80 mg and about 1600 mg every 3 weeks Axis binding antagonist.

190. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population having cervical cancer with detectable levels of PD-L1 expression, said treatment comprising comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of between about 300 mg and about 800 mg every three weeks. wherein said PD-1 axis binding antagonist antibody is formulated for administration every 3 weeks at a dose of between about 900 mg and about 1500 mg every 3 weeks Axis binding antagonist.

191. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - an anti-TIGIT antagonist formulated for administration at a dose of between about 30 mg and about 1200 mg every 3 weeks for said subject with L1 expression levels, based on detected PD-L1 expression on tumor cells. selecting a treatment comprising an antibody and one or more dosing cycles of a PD-1 axis binding antagonist formulated to be administered at a dose of between about 80 mg and about 1600 mg every 3 weeks; TIGIT antagonist antibody and PD-1 axis binding antagonist.

192. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-191, wherein said cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma or adenocarcinoma.

193. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-191, wherein said cervical cancer is stage IVB, metastatic, recurrent or persistent.

194. Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 189-193, wherein said cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer Binding antagonist.

195. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 189-194, wherein said one or more subjects have received at least one prior treatment.

196. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 189-195, wherein said one or more subjects have received two prior treatments.

197. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 189-196, wherein said one or more subjects have not received 3 or more prior treatments.

198. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 189-194, wherein said one or more subjects have no prior treatment.

199. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 195-198, wherein said prior treatment is chemotherapy, surgery and/or radiotherapy.

200. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189 and 192-199, wherein said treatment results in a clinical response.

201. 201. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 200, wherein said clinical response is an increase in ORR in said subject population compared to a baseline objective response rate (ORR).

202. An anti-TIGIT antagonist for use according to embodiment 201, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody Antibodies and PD-1 axis binding antagonists.

203. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 200, wherein said baseline ORR is at least about 14.6% to about 26%.

204. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 200, wherein said clinical response is CR or PR.

205. wherein said clinical response is increased in said subject's PFS time compared to baseline progression-free survival (PFS), increased in said subject's DOR time compared to baseline duration of response (DOR), or baseline overall survival (OS) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 200-204, which is an increase in OS time of said subjects compared.

206. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 205, wherein
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

207. An anti-TIGIT antagonist antibody and atezolizumab for use in a method for treating a subject having cervical cancer with detectable levels of PD-L1 expression, said treatment being at a dose of 600 mg every 3 weeks. The PD-1 axis binding antagonist formulated for administration and the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist at one or more dosing cycles of atezolizumab formulated at a dose of 1200 mg every 3 weeks. anti-TIGIT antagonist antibodies and atezolizumab, including the use of

208. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of identifying subjects with cervical cancer who are likely to benefit from treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab, comprising: the method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (c) PD-L1 expression on the detected tumor cells. Based on identifying subjects likely to benefit from treatment, including dosing cycles, anti-TIGIT antagonist antibodies and atezolizumab.

209. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of selecting a treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - an anti-TIGIT antagonist antibody formulated for administration at a dose of 600 mg every 3 weeks, based on detected PD-L1 expression on tumor cells, for said subject with L1 expression levels, and every 3 weeks selecting a treatment comprising one or more dosing cycles of atezolizumab formulated to be administered at a dose of 1200 mg to .

210. Tiragolumab and atezolizumab for use in a method for treating a subject having cervical cancer with detectable levels of PD-L1 expression, said treatment comprising tiragolumab at a dose of about 600 mg every 3 weeks; and tiragolumab and atezolizumab, including the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks.

211. Tiragolumab and atezolizumab for use in a method of treating a subject with cervical cancer, said method comprising
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) Tiragolumab formulated to be administered at a dose of 600 mg every 3 weeks and to be administered at a dose of 1200 mg every 3 weeks based on detected PD-L1 expression on tumor cells and (d) administering said treatment to said identified subject. and atezolizumab.

212. Tiragolumab and atezolizumab for use in a method of selecting treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - for said subjects with L1 expression levels, tiragolumab formulated to be administered at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detected PD-L1 expression on tumor cells; selecting a treatment comprising one or more dosing cycles of atezolizumab formulated to be administered in doses.

213. Tiragolumab and atezolizumab for use in a method of treating a subject with metastatic and/or recurrent cervical cancer, said method comprising
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) Tiragolumab formulated to be administered at a dose of 600 mg every 3 weeks and to be administered at a dose of 1200 mg every 3 weeks based on detected PD-L1 expression on tumor cells and (d) administering said treatment to said identified subject. and atezolizumab.

214. Tiragolumab and atezolizumab for use in a method of selecting treatment for a subject with metastatic and/or recurrent cervical cancer, said method comprising
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - for said subjects with L1 expression levels, tiragolumab formulated to be administered at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on detected PD-L1 expression on tumor cells; selecting a treatment comprising one or more dosing cycles of atezolizumab formulated to be administered in doses.

215. 215. For use according to any one of embodiments 189-214, wherein said subject is identified as likely to benefit from said treatment based on detected PD-L1 expression on tumor cells Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

216. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263.

217. Anti-TIGIT for use according to any one of embodiments 189-216, wherein said detectable PD-L1 expression level is 5% or more tumor-associated immune cells (TIC) in a sample from said subject Antagonist Antibodies and PD-1 Axis Binding Antagonists.

218. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-215, wherein PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.

219. Anti-TIGIT antagonist antibody for use according to any one of embodiments 189-216, wherein said detectable PD-L1 expression level is a composite positive score (CPS) of 1 or more in a sample from said subject and PD-1 axis binding antagonists.

220. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is breast cancer.

221. Tiragolumab and atezolizumab for use in a method of treating a subject or subject population having breast cancer, wherein said treatment comprises tiragolumab at a dose of about 840 mg every 4 weeks for 3 weeks on/1 week off. , atezolizumab at a dose of about 1680 mg every 4 weeks, and nab-paclitaxel at a dose of about 100 mg/m2, in a dosing regimen comprising one or more dosing cycles. Tiragolumab and atezolizumab, including use.

222. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 220 or 221, wherein said breast cancer is triple negative breast cancer (TNBC).

223. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 222, wherein said TNBC is unresectable locally advanced or metastatic TNBC.

224. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 220-223, wherein said subject has had no prior systemic therapy for metastatic breast cancer.

225. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 220-224, wherein said treatment results in an ORR of the subject population of at least about 53% to about 67.5% .

226. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 222-225, wherein said treatment results in a median OS for the subject population 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 with early stage triple negative breast cancer (eTNBC), wherein said treatment is in a dosing regimen comprising one or more dosing cycles comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 10 mg to about 1000 mg every two weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of about 20 mg to about 1600 mg of the binding antagonist every two weeks.

228. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 227, wherein said treatment further comprises use of one or more chemotherapeutic agents.

229. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 228, wherein said one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor or an alkylating agent .

230. The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a taxane, or a taxane and a platinum-based chemotherapeutic agent, and (b) the anti-TIGIT One dose of an antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 227, further comprising the above dosing cycles.

231. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 229 or 230, wherein said alkylating agent is cyclophosphamide.

232. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 231, wherein said cyclophosphamide is formulated for administration at a dose of about 600 mg/m2.

233. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 227-229, 231 and 232, wherein said treatment further comprises use of G-CSF or GM-CSF.

234. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiments 230 or 233, wherein said G-CSF is pegfilgrastim or filgrastim.

235. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 234, wherein said G-CSF is pegfilgrastim.

236. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 235, wherein said pegfilgrastim is formulated for administration at a dose of about 6 mg.

237. 237. Any one of embodiments 228, 229 and 231-236, wherein said treatment further comprises the use of one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for the uses described.

238. Embodiments 228, 229, and 231, wherein said one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once weekly, once every two weeks, or once every three weeks, respectively Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of paragraphs 1-237.

239. The platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 229-238, wherein GM-CSF is administered every two weeks.

240. Anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 229-239, wherein said taxane, or said taxane and said platinum-based chemotherapeutic agent are administered for the first 12 weeks of said dosing regimen - uniaxial binding antagonists.

241. 241. According to any one of embodiments 229-240, wherein the topoisomerase II inhibitor, alkylating agent, and G-CSF or GM-CSF are administered between weeks 13-19 of the dosing regimen. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

242. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 227-241, wherein the total length of said dosing regimen is 19 weeks.

243. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 227-242, wherein said method is neoadjuvant treatment.

244. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 227-243, wherein said dosing regimen is followed by surgery.

245. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 244, wherein said surgery is performed between 2 and 6 weeks after the last administration of said dosing regimen.

246. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 244 or 245, wherein said surgery comprises a mastectomy.

247. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 244-246, wherein said surgery comprises axillary lymph node surgery.

248. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 229-247, wherein said topoisomerase II inhibitor is doxorubicin.

249. an anti-TIGIT antagonist antibody for use according to 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; and PD-1 axis binding antagonist.

250. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 248 or 249, wherein said doxorubicin is formulated for administration at a dose of about 60 mg/m2.

251. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with eTNBC, wherein said treatment is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks and said PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
using an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a dosing regimen comprising: Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

252. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with eTNBC, wherein said treatment is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks and the PD-L1 binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
using an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a dosing regimen comprising: Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

253. An anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with eTNBC, wherein said treatment is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks and an anti-PD-L1 antagonist antibody formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
using an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a dosing regimen comprising: use.

254. Tiragolumab and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with eTNBC, wherein said treatment is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks. tiragolumab and an anti-PD-L1 antagonist antibody formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen, use.
255. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with eTNBC, wherein said anti-TIGIT treatment is formulated for administration at a dose of about 300 mg to about 600 mg every two weeks. an antagonist antibody and atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen, use.
256. Tiragolumab and atezolizumab for use in a method of treating a subject with eTNBC, wherein said treatment comprises tiragolumab at a dose of about 300 mg to about 600 mg every two weeks and a dose of about 600 mg to about 1200 mg every two weeks. of atezolizumab and
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week over the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
wherein said method further comprises surgery between 2 weeks and 6 weeks after the last dose of said dosing regimen ,use.

257. Tiragolumab and atezolizumab for use in a method of treating a subject with eTNBC, wherein said treatment comprises tiragolumab at a dose of about 420 mg every two weeks and atezolizumab at a dose of about 840 mg every two weeks;
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and the method further comprising surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen. .

258. 258. According to any one of embodiments 220-257, wherein the detectable PD-L1 protein expression level in a tumor sample from said subject is determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP 142. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in.

259. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 258, wherein the percentage of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (IC) in said tumor sample is 1% or more .

260. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 227-259, wherein said eTNBC are T2-4d TNBC when presented.

261. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 227-260, wherein said eTNBCs are cT2-cT4, cN0-cN3 and cM0 TNBCs when presented.

262. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 227-261, wherein said subject has not been previously treated for eTNBC.

263. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 227-262, wherein said treatment results in a complete pathological response (pCR).

264. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 227-263, wherein said treatment results in increased overall survival (OS) or symptom-free survival (EFS) .

265. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is head and neck cancer.

266. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 265, wherein said 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 with detectable PD-L1 expression levels, said treatment comprising one or more doses comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said PD-1 axis binding antagonist antibody is formulated for administration every three weeks at a dose of between about 80 mg and about 1600 mg every three weeks.

268. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects having SCCHN with detectable levels of PD-L1 expression, wherein said treatment comprises one or more wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300 mg and about 800 mg every three weeks. and wherein said PD-1 axis binding antagonist antibody is formulated for administration every three weeks at a dose of between about 900 mg and about 1500 mg every three weeks. .

269. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a treatment for a subject or subject population with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg every 3 weeks, based on detected PD-L1 expression, for said subject or subject population having a level of selecting a treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody formulated to be administered at a dose of between about 1200 mg.

270. Tiragolumab and atezolizumab for use in a method for treating a subject or population of subjects having SCCHN with detectable levels of PD-L1 expression, said treatment comprising tiragolumab and atezolizumab in one or more dosing cycles wherein said tiragolumab is formulated for administration at a dose of about 600 mg every 3 weeks and said atezolizumab is formulated for administration at a dose of about 1200 mg every 3 weeks .

271. Anti-TIGIT antagonist for use according to any one of embodiments 267-270, wherein the tumor sample obtained from said one or more subjects has been determined to have a detectable level of PD-L1 expression Antibodies and PD-1 axis binding antagonists.

272. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 266-271, wherein said SSCHN is human papillomavirus (HPV) positive.

273. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 266-272, wherein said SSCHN is HPV negative.

274. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 272 or 273, wherein HPV status is determined by p16 IHC, in situ hybridization or PCR.

275. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 266-274, wherein said SCCHN is recurrent and/or metastatic SCCHN.

276. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 265-275, wherein said one or more subjects have no prior treatment.

277. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 276, wherein said prior treatment is prior systemic therapy for recurrent and/or metastatic disease.

278. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 265-268 and 270-277, wherein said treatment results in CR or PR.

279. Anti-TIGIT antagonist for use according to any one of embodiments 265-268 and 270-277, wherein said treatment results in an increase in said subject population's ORR compared to a baseline objective response rate (ORR) Antibodies and PD-1 axis binding antagonists.

280. Anti-TIGIT antagonist for use according to embodiment 279, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody Antibodies and PD-1 axis binding antagonists.

281. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 279 or 280, wherein said baseline ORR is from about 19% to about 36%.

282. wherein said treatment increases PFS time of said subject or subject population compared to baseline progression-free survival (PFS), increases DOR time of said subject or subject population compared to baseline duration of response (DOR), or baseline overall survival Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 265-268 and 270-281, which results in an increase in OS time of said subject or subject population compared to duration (OS) Binding antagonist.

283. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 282, wherein
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment containing a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

284. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 282, wherein said baseline DOR time is from at least about 6.7 months to about 23.4 months.

285. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 282, wherein said baseline OS time is at least about 11.6 months to about 14.9 months.

286. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject having SCCHN with detectable levels of PD-L1 expression, said treatment comprising about 80 mg every 3 weeks. said anti-TIGIT antagonist antibody and use of said PD-1 axis binding antagonist in one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 1600 mg, said anti-TIGIT antagonist antibody being administered every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, formulated for administration at a dose of between about 30 mg and about 1200 mg per day.

287. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject having SCCHN with detectable levels of PD-L1 expression, said treatment comprising about 1200 mg of said anti-TIGIT antagonist antibody and the use of said PD-1 axis binding antagonist in one or more dosing cycles of a PD-1 axis binding antagonist at a dose, said anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, formulated for administration at .

288. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject having SCCHN with detectable levels of PD-L1 expression, said treatment comprising about 80 mg every 3 weeks. comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of a PD-L1 binding antagonist at a dose of between about 1600 mg, said anti-TIGIT antagonist antibody being administered every 3 weeks An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 30 mg and about 1200 mg.

289. Tiragolumab and atezolizumab for use in a method for treating a subject having SCCHN with detectable levels of PD-L1 expression, said treatment comprising a dose of between about 80 mg and about 1600 mg every 3 weeks. Tiragolumab and atezolizumab, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist at one or more dosing cycles of atezolizumab and tiragolumab at a dose of between about 30 mg and about 1200 mg every 3 weeks.

290. Tiragolumab and atezolizumab for use in a method for treating a subject having SCCHN with detectable PD-L1 expression levels, said treatment comprising tiragolumab at a dose of about 600 mg every 3 weeks and 3 weeks Tiragolumab and atezolizumab, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of atezolizumab at a dose of about 1200 mg per dose.
291. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) said PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and said anti-drug formulated for administration at a dose of between about 30 mg and about 1200 mg every 3 weeks; identifying a subject likely to benefit from a treatment comprising one or more dosing cycles of a TIGIT antagonist antibody; and (d) administering said treatment to said identified subject having a detectable PD-L1 expression level. an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, comprising administering.

292. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) one or more dosing cycles of said PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and said anti-TIGIT antagonist antibody formulated to be administered at a dose of about 600 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable PD-L1 expression level. and PD-1 axis binding antagonists.

293. Tiragolumab and atezolizumab for use in a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) potential to benefit from treatment comprising one or more dosing cycles of atezolizumab at doses between about 80 mg and about 1600 mg every 3 weeks and tiragolumab at doses between about 30 mg and about 1200 mg every 3 weeks; and (d) administering said treatment to said identified subject with a detectable level of PD-L1 expression.

294. Tiragolumab and atezolizumab for use in a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) identifying subjects likely to benefit from treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks; (d) tiragolumab and atezolizumab, comprising administering said treatment to said identified subject with 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 treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg and about 1200 mg every 3 weeks, based on detected PD-L1 expression, for said subjects with levels of selecting a treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody formulated to be administered at doses between the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist.

296. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and a dose of about 600 mg every 3 weeks based on detected PD-L1 expression for said subject with a level of selecting a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

297. Tiragolumab and atezolizumab for use in a method of selecting a treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. atezolizumab at a dose between about 80 mg and about 1600 mg every 3 weeks, and tiragolumab at a dose between about 30 mg and about 1200 mg every 3 weeks for said subjects with levels of selecting a treatment comprising one or more dosing cycles of tiragolumab and atezolizumab.

298. Tiragolumab and atezolizumab for use in a method of selecting a treatment for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on detected PD-L1 expression for said subject with a level tiragolumab and atezolizumab.

299. of embodiments 267-298, wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level determined by an immunohistochemistry (IHC) assay including staining with the anti-PD-L1 antibody SP263 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of claims.

300. wherein the detectable PD-L1 protein expression level is
(a) 5% or more;
(b) 5% or more and less than 20%, or (c) 20% or more tumor-associated immune cells (TIC).

301. A PD-1 axis binding antagonist formulated to administer subjects with SCCHN at doses between about 80 mg and about 1600 mg every three weeks, doses between about 30 mg and about 1200 mg every three weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a method of identifying subjects likely to benefit from treatment comprising one or more dosing cycles of a TIGIT antagonist antibody, said method being suitable for staining determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody, wherein a TIC of 5% or more PD-L1 protein expression level is determined in said subject as likely to benefit from said treatment.

302. A PD-1 axis binding antagonist formulated to administer subjects with SCCHN at doses between about 80 mg and about 1600 mg every three weeks, doses between about 30 mg and about 1200 mg every three weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a method of identifying subjects likely to benefit from treatment comprising one or more dosing cycles of a TIGIT antagonist antibody, said method being suitable for staining determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody, wherein the protein expression level of PD-L1 of TIC is greater than or equal to 5% and less than 20%. identifies said subject as likely to benefit from said treatment.

303. A PD-1 axis binding antagonist formulated to administer subjects with SCCHN at doses between about 80 mg and about 1600 mg every three weeks, doses between about 30 mg and about 1200 mg every three weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a method of identifying subjects likely to benefit from treatment comprising one or more dosing cycles of a TIGIT antagonist antibody, said method being suitable for staining determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody, wherein a PD-L1 protein expression level of 20% or more of the TICs of said subject as likely to benefit from said treatment.

304. 304. Antibiotics for use according to any one of embodiments 301-303, wherein said subject is identified as likely to benefit from treatment and said method further comprises administering treatment to said subject. TIGIT antagonist antibody and PD-1 axis binding antagonist.

305. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 301-304, wherein said TIC is determined using the Ventana SP263 IHC assay.

306. Use according to any one of embodiments 267-305, wherein said subject or subject population is identified as likely to benefit from said treatment based on detected PD-L1 expression on tumor cells. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

307. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is liver cancer.

308. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 307, wherein said liver cancer is hepatocellular carcinoma (HCC).

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with 309 hepatocellular carcinoma (HCC), said treatment comprising said anti-TIGIT antagonist antibody and said PD- wherein the anti-TIGIT antagonist antibody is formulated for administration and the PD-uniaxial binding antagonist, wherein the subject or subject population has a prior systemic history of HCC; Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist, naive to treatment.

310. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 309, wherein said 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 subject population with HCC, wherein said treatment comprises an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist and a VEGF antagonist. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists, including using said anti-TIGIT antagonist antibodies and said PD-1 axis binding antagonists in one or more dosing cycles.

312. Anti-TIGIT antagonist antibody and PD- for use according to embodiments 310 and 311, wherein said VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks. Uniaxial binding antagonist.

313. An anti-TIGIT antagonist antibody for use according to any one of embodiments 309-312, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every three weeks and PD-1 axis binding antagonist.

314. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 313, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 800 mg every three weeks.

315. Anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 309-314, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600 mg every three weeks Axis binding antagonist.

316. Anti-TIGIT antagonist for use according to any one of embodiments 309-315, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks Antibodies and PD-1 axis binding antagonists.

317. Anti-TIGIT antagonist for use according to any one of embodiments 309-316, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 900 mg to about 1500 mg every three weeks Antibodies and PD-1 axis binding antagonists.

318. Anti-TIGIT antagonist antibody and PD- for use according to embodiment 310 or 311, wherein said VEGF antagonist is formulated for administration at a dose of about 1 mg/kg to about 20 mg/kg every two weeks Uniaxial binding antagonist.

319. Anti-TIGIT antagonist antibody and PD-1 axis for use according to embodiment 318, wherein said VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 10 mg/kg every two weeks Binding antagonist.

320. Antibiotics for use according to embodiment 319, wherein said VEGF antagonist is formulated for administration at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks. TIGIT antagonist antibody and PD-1 axis binding antagonist.

321. Antibody for use according to any one of embodiments 309-311 and 318-320, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 10 mg to about 1000 mg every two weeks. TIGIT antagonist antibody and PD-1 axis binding antagonist.

322. For use according to any one of embodiments 309-311 and 318-321, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 20 mg to about 1600 mg every two weeks anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

323. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to embodiments 309-311, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks antagonist.

324. Antibiotic for use according to any one of embodiments 309-311 and 323, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 2000 mg every 4 weeks. TIGIT antagonist antibody and PD-1 axis binding antagonist.

325. For use according to any one of embodiments 309-311, 323 and 324, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 1400 mg to about 2000 mg every 4 weeks anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

326. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 309-325, wherein said HCC is locally advanced or metastatic HCC.

327. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 309-326, wherein said HCC is unresectable HCC.

328. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 309-327, wherein said one or more subjects have been determined to have adequate liver function.

329. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 328, wherein adequate liver function is characterized as Child-Pugh class A.

330. Anti-TIGIT for use according to any one of embodiments 309-329, wherein the HCC tumor sample obtained from said one or more subjects has been determined to have a detectable level of PD-L1 expression. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

331. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 309-330, wherein said method comprises administering at least four dosing cycles to a subject or population of subjects .

332. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 331, wherein said method comprises administering to the subject or population of subjects at least 16 dosing cycles.

333. Tiragolumab and atezolizumab for use in a method of treating a subject or subject population with HCC, wherein said treatment comprises tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and Tiragolumab and atezolizumab, including the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist with one or more dosing cycles of bevacizumab at a dose of about 15 mg/kg every 3 weeks.

334. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 311-333, wherein said one or more subjects have no prior systemic treatment for HCC.

335. Anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 309-334, wherein said treatment results in a median PFS of the subject population of at least about 5.6 months to at least about 6.83 months - Uniaxial binding antagonists.

336. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is bladder cancer.

337. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 336, wherein said bladder cancer is muscle invasive bladder cancer (MIBC).

338. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist , an anti-TIGIT antagonist antibody and PD-1 axis binding, formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks, wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent. antagonist.

339. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300 mg and about 800 mg every three weeks, said PD-1 axis binding antagonist is , an anti-TIGIT antagonist antibody and PD-1 axis binding, formulated for administration at a dose of between about 900 mg and about 1500 mg every 3 weeks, wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent. antagonist.

340. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment.

341. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300 mg and about 800 mg every three weeks, said PD-1 axis binding antagonist is , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 900 mg and about 1500 mg every 3 weeks, wherein said treatment is perioperative treatment.

342. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 338-341, wherein said one or more subjects have a creatinine clearance of less than 60 mL/min.

343. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 338-342, wherein said one or more subjects have grade 2 or greater hearing loss.

344. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 338-343, wherein said one or more subjects have a neuropathy of grade 2 or greater.

345. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 338-344, wherein said one or more subjects have refused treatment with a platinum-based chemotherapeutic agent.

346. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 338 or 342-345, wherein said platinum-based chemotherapeutic agent is cisplatin.

347. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 338-346, wherein the MIBC is surgically operable.

348. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 347, wherein said method further comprises surgery.

349. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 348, wherein said at least one dosing cycle is initiated prior to surgery.

350. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 348 or 349, wherein said at least 1, 2 or 3 dosing cycles are completed prior to surgery.

351. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 348-350, wherein at least one dosing cycle is initiated between 4 and 6 weeks after surgery.

352. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 351, wherein 1-17 dosing cycles are completed after surgery.

353. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 348-352, wherein said surgery is cystectomy and/or lymphadenectomy.

354. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 338-353, wherein said treatment results in a complete pathological response (pCR).

355. said treatment increases RFS time of said one or more subjects compared to baseline recurrence-free survival (RFS); increases EFS time of said one or more subjects compared to baseline disease-free survival (EFS); or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 338-354, which results in an increase in OS time in said one or more subjects compared to OS.

356. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 355, wherein
(a) said baseline RFS time is the median RFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline EFS time is the median EFS time of a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

357. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 338-356, wherein said treatment results in a reduction in pathological extent.

358. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks and wherein said subject is cisplatin ineligible.

359. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-1 axis binding antagonist , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment.

360. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-L1 binding antagonist comprising: An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks, wherein said subject is cisplatin ineligible.

361. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with MIBC, wherein said treatment comprises one or more dosing cycles of said anti-TIGIT antagonist antibody. and the use of said PD-1 axis binding antagonist, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks, said PD-L1 binding antagonist comprising: An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment.

362. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with MIBC, said treatment comprising the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is administered for 3 weeks atezolizumab is formulated to be administered at a dose of between about 80 mg and about 1600 mg every three weeks, and the subject is cisplatin insoluble; Eligible, tiragolumab and atezolizumab.

363. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with MIBC, said treatment comprising the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is administered for 3 weeks atezolizumab is formulated to be administered at a dose of between about 80 mg and about 1600 mg every three weeks, and said treatment is administered perioperatively; tiragolumab and atezolizumab, as early treatment.

364. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with MIBC, said treatment comprising the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is administered for 3 weeks tiragolumab, wherein atezolizumab is formulated to be administered at a dose of about 1200 mg every 3 weeks, and wherein the one or more subjects are cisplatin ineligible; Atezolizumab.

365. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with MIBC, said treatment comprising the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is administered for 3 weeks tiragolumab and atezolizumab formulated to be administered at a dose of about 600 mg every 3 weeks, wherein atezolizumab is formulated to be administered at a dose of about 1200 mg every 3 weeks and said treatment is perioperative treatment.

366. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 338-365, wherein said treatment results in an ORR of the subject population of at least about 13.4% to about 15% .

367. 367. Anti-TIGIT antagonist antibody and PD-antibody for use according to any one of embodiments 338-366, wherein said treatment results in a median OS for the subject population of at least about 7.9 months to about 8.6 months Uniaxial binding antagonist.

368. Anti-TIGIT for use according to any one of embodiments 338-367, wherein detectable PD-L1 protein expression levels as determined by an IHC assay including staining with the anti-PD-L1 antibody SP142 have been determined. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

369. Embodiment 368, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction in which 5% or more of the tumor area is occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs) Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use as described in .

370. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 336, wherein said bladder cancer is urothelial carcinoma (UC).

371. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 370, wherein said UC is metastatic urothelial carcinoma (mUC).

372. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with mUC, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks.

373. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with mUC, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300 mg and about 800 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 900 mg and about 1500 mg every three weeks.

374. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with mUC, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; an anti-TIGIT antagonist antibody wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks and said subject has not received prior cancer immunotherapy. and PD-1 axis binding antagonists.

375. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with mUC, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg every 3 weeks and said treatment is a secondary treatment .

376. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 372, 372 and 375, wherein said one or more subjects have not previously received cancer immunotherapy .

377. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 372-374, wherein said treatment is a second line treatment.

378. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 372-377, wherein said mUC is progressing during or after platinum-containing therapy.

379. 379. According to any one of embodiments 372-378, further comprising administering a second dosing regimen to said subject or population of subjects after said one or more subjects experience disease progression or unacceptable toxicity. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in.

380. Anti-TIGIT antagonist antibody and PD-1 for use according to embodiment 379, wherein said second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC). Uniaxial binding antagonist.

381. 380. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 380, wherein said ADC is (a) enfortumab vedotin or (b) suctuzumab govitecan.

382. (a) enfortumab vedotin is formulated for administration at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (b) suctuzumab Anti-TIGIT antagonist antibody for use according to embodiment 381 and PD- Uniaxial binding antagonist.

383. (a) enfortumab vedotin is formulated for administration at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle; Anti-TIGIT antagonist antibody and PD- for use according to embodiment 381 or 382, wherein the tecan is formulated for administration at a dose of 10 mg/kg on days 1 and 8 of each 21-day cycle. Uniaxial binding antagonist.

384. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or subject population with mUC, said treatment comprising one or more dosing cycles of the anti-TIGIT antagonist antibody comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the PD-L1 binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks.

385. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with mUC, wherein said treatment comprises tiragolumab at a dose of between about 30 mg and about 1200 mg every 3 weeks and Tiragolumab and atezolizumab, comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of atezolizumab at a dose between about 80 mg and about 1600 mg.

386. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with mUC, said treatment comprising the use of tiragolumab and atezolizumab in one or more dosing cycles, said tiragolumab Tiragolumab and atezolizumab, formulated for administration at a dose of about 600 mg every 3 weeks, said atezolizumab being formulated for administration at a dose of about 1200 mg every 3 weeks.

387. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with mUC, wherein said treatment comprises a first dosing regimen followed by a second dosing regimen using said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in
(a) said first dosing regimen is formulated for administration of said anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks and said PD-1 axis binding antagonist every 3 weeks; one or more dosing cycles formulated for administration at a dose of between about 80 mg and about 1600 mg to
(b) said second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist formulated for administration at a dose of between about 80 mg and about 1600 mg every three weeks; (i) enfortumab vedotin is formulated for administration at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (ii) Mabgovitecan is formulated for administration at a dose of 10 mg/kg weekly for 2 weeks on/1 week off, wherein said second dosing regimen is during said first dosing regimen An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist administered to said subject or subject population after said subject or subject population experiences disease progression or unacceptable toxicity.

388. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with mUC, wherein said treatment comprises a first dosing regimen followed by a second dosing regimen using said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in
(a) an anti-TIGIT antagonist antibody wherein said first dosing regimen is formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks and between about 80 mg and about 1600 mg every three weeks; one or more dosing cycles of a PD-L1 binding antagonist at a dose of
(b) said second dosing regimen comprises one or more dosing cycles of said PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks; , 2 weeks on/1 week off, or (ii) suctuzumab govitecan is formulated to be administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off; formulated to be administered at a dose of 10 mg/kg weekly with a one-week rest period, wherein said second dosing regimen is effective if said subject has disease progression or unacceptable toxicity during said first dosing regimen. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist administered to said subject after experiencing.

389. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with mUC, wherein said treatment comprises a first dosing regimen followed by said anti-TIGIT antagonist antibody in a second dosing regimen and comprising the use of said PD-1 axis binding antagonist;
(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of 1200 mg about every 3 weeks;
(b) said second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks; (ii) suctuzumab govitecan was formulated to be administered at a dose of 1.25 mg/kg weekly during drug administration, or (ii) suctuzumab govitecan was administered at 10 mg weekly for 2 weeks on/1 week off /kg, wherein the second dosing regimen is administered to the subject after the subject experiences disease progression or unacceptable toxicity during the first dosing regimen; Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

390. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 372-389, wherein said treatment results in an ORR of the subject population of at least about 13.4% to about 31% .

391. 391. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 372-390, wherein said treatment results in a median OS for said subject population of about 7.9 months to about 16.3 months Axis binding antagonist.

392. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is pancreatic cancer.

393. Tiragolumab and atezolizumab for use in a method of treating a subject or subject population having pancreatic cancer, said treatment comprising tiragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle; atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle; gemcitabine at a dose of about 1000 mg/m2 on days 1, 8 and 15 of each 28-day dosing cycle; using an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more 28-day dosing cycles comprising nab-paclitaxel at a dose of about 125 mg/m2 on days 1, 8 and 15; Tiragolumab and atezolizumab.

394. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 392 or 393, wherein said pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 394, wherein said PDAC is a metastatic PDAC.

396. An anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 392-395, wherein said one or more subjects have not received prior systemic therapy for metastatic PDAC antagonist.

397. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 392-396, wherein said treatment results in an ORR of the subject population of at least about 41.7 to about 46.7% .

398. Any of embodiments 392-397, wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to clause 1.

399. Anti-TIGIT antagonist antibody and PD-1 axis for use according to any one of embodiments 392-398, wherein said treatment results in a median OS for the subject population of at least about 5.5 months to about 7 months Binding antagonist.

400. The anti-TIGIT antagonist antibody and PD-antibody for use according to any one of embodiments 392-399, wherein said treatment results in a median OS of the subject population of at least about 8.5 months to about 10.6 months. Uniaxial binding antagonist.

401. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 72, wherein said cancer is esophageal cancer.

402. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein said treatment comprises said anti-TIGIT antagonist antibody and use of said PD-1 axis binding antagonist in a dosing regimen comprising one or more 21-day dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle; and PD-1 axis binding antagonist.

403. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein said treatment comprises said anti-TIGIT antagonist antibody and use of said PD-1 axis binding antagonist in a dosing regimen comprising one or more 21-day dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle; and PD-1 axis binding antagonist.

404. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with esophageal cancer, wherein said treatment comprises one or more treatments of the anti-TIGIT antagonist antibody for 21 days. use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising dosing cycles, wherein said anti-TIGIT antagonist antibody is administered on day 1 of each dosing cycle at a dose of between about 30 mg and about 1200 mg wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle, said subject receiving platinum-based chemotherapy an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist that has been previously treated with a drug and a non-platinum chemotherapeutic agent.

405. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with esophageal cancer, wherein said treatment comprises one or more treatments of the anti-TIGIT antagonist antibody for 21 days. use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising dosing cycles, wherein said anti-TIGIT antagonist antibody is administered on day 1 of each dosing cycle at a dose of between about 300 mg and about 800 mg wherein said PD-1 axis binding antagonist is formulated for administration at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle, said subject receiving platinum-based chemotherapy an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist that has been previously treated with a drug and a non-platinum chemotherapeutic agent.

406. An anti-TIGIT antagonist antibody and PD-1 for use according to embodiment 402 or 403, wherein said one or more subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent Axis binding antagonist.

407. Anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 404-406, wherein said one or more subjects have experienced disease progression or unacceptable toxicity during prior treatment - uniaxial binding antagonists.

408. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 402 or 403, wherein said 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 408, wherein said platinum-based chemotherapeutic agent is omitted from the dosing regimen after 6 doses.

410. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 404-409, wherein said platinum-based chemotherapeutic agent is cisplatin.

411. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 410, wherein cisplatin is formulated for administration at a dose of about 80 mg/m2 on day 1 of each dosing cycle.

412. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 404-411, wherein said non-platinum chemotherapeutic agent is an antimetabolite.

413. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 412, wherein said antimetabolite is 5-fluorouracil.

414.5-Fluorouracil is formulated for administration at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle, anti-TIGIT antagonist antibody for use according to embodiment 413 and PD-1 axis binding antagonists.

415. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 404-414, wherein said esophageal cancer is advanced or metastatic esophageal cancer.

416. An anti-TIGIT antagonist antibody for use according to any one of embodiments 402, 403, 408 and 409, wherein said one or more subjects have no prior treatment for metastatic esophageal cancer and PD-1 axis binding antagonists.

417. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein said treatment comprises said anti-TIGIT antagonist antibody and use of said PD-1 axis binding antagonist in a dosing regimen comprising one or more 21-day dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle wherein the PD-1 axis binding antagonist is formulated at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle, and the platinum-based chemotherapeutic agent is formulated at 1 of each dosing cycle. and non-platinum chemotherapeutic agents to be administered at a dose of about 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle. and the platinum-based chemotherapeutic agent is omitted from the dosing regimen after 6 doses and a PD-1 axis binding antagonist.

418. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein said treatment is performed one or more times for 21 days. use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600 mg on day 1 of each dosing cycle. wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 1200 mg on day 1 of each dosing cycle and cisplatin is formulated at a dose of about 80 mg/m on day 1 of each dosing cycle and 5-fluorouracil is formulated to be administered at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle, after 6 doses of said dosing regimen An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist wherein cisplatin is omitted from.

419. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with advanced or metastatic esophageal cancer, wherein said treatment comprises tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle , atezolizumab at a dose of approximately 1200 mg on Day 1 of each dosing cycle, cisplatin at a dose of approximately 80 mg/m2 on Day 1 of each dosing cycle, and 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle. and the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of tiragolumab and atezolizumab.

420. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, said treatment comprising a first dosing regimen and comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a second dosing regimen;
(a) the first dosing regimen comprises one or more 21-day dosing cycles of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of the PD-1 axis binding antagonist at a dose of .

421. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, said treatment comprising a first dosing regimen and comprising use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a second dosing regimen;
(a) the first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 800 mg/m2/24 on days 1-5 of each 21-day cycle; one or more 21-day dosing cycles of an hourly dose of a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses;
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of .

422. Tiragolumab and atezolizumab for use in a method for treating a subject or subject population with advanced or metastatic esophageal cancer, said treatment comprising said comprising the use of an anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist;
(a) said first dosing regimen comprises cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and a dose of 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle; 1 or more 21-day dosing cycles of 5-fluorouracil in which cisplatin is omitted from the dosing regimen after 6 doses;
(b) said second dosing regimen is one or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle; including tiragolumab and atezolizumab.

423. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 402-422, wherein said treatment results in an ORR of the subject population of at least about 14%.

424. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (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);
HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

425. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
an anti-TIGIT antagonist antibody for use according to embodiment 424, further comprising FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10); PD-1 axis binding antagonist.

426. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:
FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is E or Q);
FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14); and PD-1 axis binding antagonist.

427. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 426, wherein X1 is E.

428. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 426, wherein X1 is Q.

429. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain according to (a) and (b) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-428, comprising a VL domain as described.

430. wherein said anti-TIGIT antagonist antibody:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

431. wherein said anti-TIGIT antagonist antibody:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

432. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:34,
An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-427 and 429-431, comprising:

433. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-432, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-433, wherein the anti-TIGIT antagonist antibody is a humanized antibody.

435. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-434, wherein the anti-TIGIT antagonist antibody is a full length antibody.

436. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-427 and 429-436, wherein said anti-TIGIT antagonist antibody is tiragolumab.

437. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, wherein said anti-TIGIT antagonist antibody is tiragolumab, vivostrimab, etiglimab, EOS 084448, SGN-TGT or TJ-T 6 , 265 to 269, 286 to 288, 291, 292, 295, 296, 301 to 332, 336 to 361, 370 to 384, 387, 388, 401 to 418, 420, 421 and 424 to 436 Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for the uses described.

438. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 437, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector functions.

439. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 437 or 438, wherein said anti-TIGIT antagonist antibody enhances Fc-mediated effector function.

440. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 437-439, wherein said anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-, wherein said anti-TIGIT antagonist antibody is domvanalimab, BMS-986207, ASP8374, or COM902 288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, and 421, anti-TIGIT antagonist antibody for use according to any one of and PD-1 axis binding antagonists.

442. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 424-431 and 441, wherein said anti-TIGIT antagonist antibody has no Fc-mediated effector functions.

443. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-442, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. 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. Anti-TIGIT antagonist for use according to embodiment 444, wherein said anti-TIGIT antagonist antibody is tiragolumab, vivostolimab, etiglimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domvanalimab or BMS-986207 Antibodies and PD-1 axis binding antagonists.

446. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, wherein said IgG class antibody is an IgG4 subclass antibody , 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421.

447. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 446, wherein the anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. an antibody that binds to TIGIT, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 424-434, which is a fragment.

449. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a multispecific antibody.

451. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 450, wherein the multispecific antibody is a bispecific antibody.

452. 452. Use according to any one of embodiments 424-451, wherein said PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

453. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 452, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. 454. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 453, wherein said PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners.

455. Anti-TIGIT antagonist for use according to embodiment 454, wherein the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1 Antibodies and PD-1 axis binding antagonists.

456. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 453-455, wherein said PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 , embodiment 456. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 456.

458. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 457, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

459. The anti-PD-L1 antagonist antibody is a HVR that:
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 RHWPGGFDY (SEQ ID NO: 22);
an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);
an anti-TIGIT antagonist antibody for use according to embodiment 456 comprising a HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO:24); and a HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25); PD-1 axis binding antagonist.

460. The anti-PD-L1 antagonist antibody is
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or (c) a VH domain according to (a) and (b) An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 459 comprising the VL domain as described.

461. The anti-PD-L1 antagonist antibody is
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:27,
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 460.

462. The anti-PD-L1 antagonist antibody is
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:28; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:29,
An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 461, comprising:

463. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 459-462, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 459-463, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

465. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 463 or 464, wherein said anti-PD-L1 antagonist antibody is a full length antibody.

466. An embodiment wherein said anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of 459-464.

467. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 459-465, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

468. An 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. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 452, wherein said PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. 469. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 469, wherein said PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners.

471. Anti-TIGIT antagonist antibody for use according to embodiment 470, wherein said PD-1 binding antagonist inhibits binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2 and PD-1 axis binding antagonists.

472. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 469-471, wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21, and an anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 472.

474. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 469-471, wherein said PD-1 binding antagonist is an Fc fusion protein.

475. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 474, wherein said Fc fusion protein is AMP-224.

476. Embodiments 80-112, wherein the method comprises administering to the subject or subject population the anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30 mg and about 1200 mg every three weeks; Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of 114-127 and 309-312.

477. Embodiments 51, 54, 60, 62, 63, 65-67, wherein said method comprises administering to the subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 600 mg every three weeks; 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. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 372, 384, 387, 388, 402-404, 417, 420, 421 and 476.

478. Embodiments 51, 54, 60, 62, 63, 65-67, 80, wherein said method comprises administering said anti-TIGIT antagonist antibody to a subject or population of subjects in graded doses based on said subject's body weight as follows: -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. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of:
(a) weighing 15 kg or less and wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg every three weeks;
(b) greater than 15 kg and less than or equal to 40 kg, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 400 mg every 3 weeks; or (c) greater than 40 kg, wherein said anti-TIGIT antagonist antibody is: It is formulated for administration at a dose of approximately 600 mg every 3 weeks.

479. Embodiments 47, 48, 77, wherein the method comprises administering to the subject or subject population the anti-TIGIT antagonist antibody formulated for administration at a dose of about 700 mg to about 1000 mg every four weeks; Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of 78, 82 and 83.

480. Embodiments 47, 48, 59, 67, 323, and 479, wherein said method comprises administering to said subject said anti-TIGIT antagonist antibody formulated for administration at a dose of about 840 mg every four weeks. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of Claims.

481. Embodiments 49, 50, and 104, wherein said method comprises administering said anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every two weeks to said subject or population of subjects. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of Claims.

482. Embodiments 49, 50, 227, 251-253, 255, and 481, wherein said method comprises administering to the subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 420 mg every two weeks. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of Claims.

483. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 47-482, wherein the dose of said anti-TIGIT antagonist antibody is a fixed dose.

484. Embodiments 54, 62, wherein the method comprises administering to the subject or subject population a PD-1 axis binding antagonist formulated for administration at a dose of between about 900 mg and about 1500 mg every three weeks. , 63, 65-67, 80-109, and 27-2698.

485. Embodiments 54, 60, 62, 63, 65-, wherein said method comprises administering to said subject said PD-1 axis binding antagonist formulated for administration at a dose of about 1200 mg every three weeks 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. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 358-361, 372-375, 384, 387, 388, 402-405, 417, 420, 421, and 484.

486. Embodiments 47, 50, 80, wherein said method comprises administering said PD-1 axis binding antagonist formulated for administration at a dose of about 1400 mg to 2000 mg every 4 weeks to said subject or population of subjects. 109, and 324. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of paragraphs 1 to 324.

487. embodiments 47, 50, 59, 67, 324, wherein said method comprises administering to said subject said PD-1 axis binding antagonist formulated for administration at a dose of about 1680 mg every 4 weeks; and 479. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of 479.

488. Embodiment 48, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist formulated for administration at a dose of between about 600 mg and about 1200 mg every two weeks; 49, 80-109, and 481 anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists.

489. embodiments 48, 49, 80-109, 227, wherein said method comprises administering to said subject said PD-1 axis binding antagonist formulated for administration at a dose of about 840 mg every two weeks; 251-253, and anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of paragraphs 481-481.

490. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 47-489, wherein the dose of said PD-1 axis binding antagonist is a fixed dose.

491. 62. An anti-TIGIT antagonist antibody and PD- for use according to embodiment 60 or 61, wherein said method comprises administering pembrolizumab to said subject at a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks. A uniaxial binding antagonist or pembrolizumab.

492. 192. Anti-TIGIT for use according to any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191, wherein each of said one or more dosing cycles is 21 days in length. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

493. An anti-TIGIT antagonist antibody for use according to any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of said one or more dosing cycles is 28 days in length and PD-1 axis binding antagonists.

494. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 49, 80-109, and 309-311, wherein each of said one or more dosing cycles is 14 days in length Axis binding antagonist.

495. 495. Use according to any one of embodiments 47-494, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about day 1 of each of one or more dosing cycles. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

496. 496. according to any one of embodiments 47-495, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects on about day 1 of each of said one or more dosing cycles Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for the uses described.

497. Anti-TIGIT antagonist antibody for use according to embodiment 321 or 493, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles and PD-1 axis binding antagonists.

498. Anti-TIGIT for use according to embodiment 321 or 493, wherein said method comprises administering said PD-1 axis binding antagonist to said subject on about day 15 of each of said one or more dosing cycles Antagonist Antibodies and PD-1 Axis Binding Antagonists.

499. The method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist prior to the anti-TIGIT antagonist antibody, or administering the anti-TIGIT antagonist antibody prior to the PD-1 axis binding antagonist. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 47-498.

500. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 499, wherein said method comprises a first observation period after administration of said PD-1 axis binding antagonist or said anti-TIGIT antagonist antibody .

501. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 500, wherein the first observation period is between about 30 minutes and about 60 minutes long.

502. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to embodiment 500 or 501, wherein said method comprises a second observation period after administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist. antagonist.

503. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 502, wherein the second observation period is between about 30 minutes and about 60 minutes long.

504. Anti-TIGIT for use according to any one of embodiments 47-503, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects concurrently with said anti-TIGIT antagonist antibody. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

505. Anti-TIGIT for use according to any one of embodiments 47-504, wherein said method comprises administering said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously to said subject or population of subjects Antagonist Antibodies and PD-1 Axis Binding Antagonists.

506. Use according to embodiment 505, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or subject population by intravenous infusion over 30±10 minutes and/or 60±10 minutes. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

507. Use according to embodiment 505 or 506, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

508. an anti-TIGIT antagonist antibody for use according to any one of embodiments 47-114 and 116-507, wherein the PD-L1 expression level of a tumor sample obtained from said one or more subjects has been determined; and PD-1 axis binding antagonist.

509. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to embodiment 508, wherein said tumor sample obtained from said one or more subjects has been determined to have a detectable PD-L1 expression level antagonist.

510. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 509, wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level.

511. Anti-TIGIT for use according to embodiment 510, wherein said detectable PD-L1 protein expression level has been determined by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

512. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 511, wherein said anti-PD-L1 antibody suitable for staining is anti-PD-L1 antibody SP263, SP142, 22C3 or 28-8.

513. 513. According to embodiment 511 or 512, wherein the detectable PD-L1 protein expression level is determined using the Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, Ventana SP142 IHC assay, or pharmDx 28-8 IHC assay. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

514. Any of embodiments 47-109, 188, 220-265, and 307-423, wherein detectable PD-L1 protein expression levels as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 have been determined An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to clause 1.

515. Any one of embodiments 47-220, 265-338, and 370-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use as described in .

516. Any one of embodiments 47-113, 136-187, and 220-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP22C3 has been determined Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use as described in .

517. According to any one of embodiments 47-114 and 116-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use in.

518. Anti-TIGIT antagonist antibody and PD-1 axis for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more tumor-associated immune cells (TIC) in said tumor sample Binding antagonist.

519. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more and less than 20% TIC in said tumor sample.

520. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more TIC in said tumor sample.

521. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 20% or more TIC in said tumor sample.

522. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more and less than 50% TIC in said tumor sample.

523. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 50% or more TIC in said tumor sample.

524. Anti-TIGIT antagonist antibody for use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or more and PD-1 axis binding antagonists.

525. Anti-TIGIT antagonist antibody for use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 30% or more and PD-1 axis binding antagonists.

526. Use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or more and less than 50% in the tumor sample. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

527. Anti-TIGIT antagonist for use according to any one of embodiments 514, 516 and 517, wherein said detectable protein expression level of PD-L1 is a PD-L1 positive tumor cell fraction of 50% or more Antibodies and PD-1 axis binding antagonists.

528. Anti-TIGIT antagonist antibody and PD-1 for use according to embodiment 515, wherein said PD-L1 positive tumor cell fraction is the percentage of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (IC) Axis binding antagonist.

529. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 515, wherein the percentage of tumor area occupied by said PD-L1 expressing tumor infiltrating IC is 1% or more.

530. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 515, wherein the percentage of tumor area occupied by said PD-L1 expressing tumor infiltrating IC is 5% or more.

531. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 516, wherein said detectable PD-L1 protein expression level is a composite positive score (CPS) of 1 or greater.

532. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 516, wherein said detectable PD-L1 protein expression level is 10 or more CPS.

533. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 516, wherein said detectable PD-L1 protein expression level is 20 or more CPS.

534. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 528-530, wherein said IHC assay is the Ventana SP 142 IHC assay.

535. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 509, wherein said detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level.

536. said detectable PD-L1 nucleic acid expression level has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof; Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 535.

537. 424. Any of embodiments 47-423, wherein said treatment results in an increase in said subject's OS time compared to baseline overall survival (OS) and/or said subject's PFS time compared to baseline progression-free survival (PFS) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to claim 1.

538. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 537, wherein
(a) a subject whose baseline OS time has undergone 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 baseline PFS time is a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or an anti-PD-1 axis binding antagonist without a PD-1 axis binding antagonist. median PFS time in a subject population that has received treatment containing a TIGIT antagonist antibody;
Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

539. 229. According to any one of embodiments 52, 158 and 228, wherein said one or more chemotherapeutic agents is one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

540. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 539, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. Use according to embodiments 69, 92, 127, 131, 249, and 540, wherein said carboplatin is administered at a dose sufficient to achieve AUC = 5 mg/ml/min or AUC = 6 mg/ml/min Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for.

542. Anti-TIGIT antagonist for use according to embodiments 69, 127, 162, 164, 166, 168 and 540, wherein said cisplatin is formulated for administration at a dose of about 75 mg/m2 or 80 mg/m2 Antibodies and PD-1 axis binding antagonists.

543. Anti-TIGIT antagonist antibody and PD for use according to any one of embodiments 539-542, wherein said one or more non-platinum chemotherapeutic agents are antimetabolites, taxanes, or topoisomerase II inhibitors - uniaxial binding antagonists.

544. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 62, 173, 174 and 543, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine or 5-fluorouracil antagonist.

545. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 69, 127, 162 and 544, wherein said pemetrexed is formulated for administration at a dose of about 500 mg/m2 Axis binding antagonist.

546. For use according to any one of embodiments 63, 64, 162, 398, and 544, wherein said gemcitabine is formulated for administration at a dose of about 1000 mg/m2 or about 1250 mg/m2. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

547. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 544, wherein said antimetabolite is capecitabine.

548. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 544 or 547, wherein said capecitabine is formulated for administration at a dose of about 1250 mg/m2.

549. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 173, 174, 229, 230, 239, 240 and 543-548, wherein said taxane is paclitaxel or nab-paclitaxel antagonist.

550. an anti-TIGIT antagonist antibody for use according to any one of embodiments 69, 162 and 549, wherein said paclitaxel is formulated for administration at a dose of about 175 mg/m2 or about 200 mg/m2; and PD-1 axis binding antagonist.

551. and the anti-TIGIT antagonist antibody for use according to any one of embodiments 63, 64, 249, 398, and 549, wherein said nab-paclitaxel is formulated for administration at a dose of about 100 mg/m PD-1 axis binding antagonist.

552. Embodiments 80-91, 229, 230, 239, 241, 251-255 wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurincarboxylic acid or HU-331 and anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of 543-551.

553. Anti-TIGIT antagonist antibody and PD-1 axis binding for use according to any one of embodiments 69, 92, and 552, wherein said etoposide is formulated for administration at a dose of about 100 mg/m2 antagonist.

554. each of said one or more chemotherapeutic agents once every week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, every four weeks Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 543-553, administered twice, or three times every four weeks.

555. An anti-TIGIT antagonist antibody and PD-1 for use according to any one of embodiments 543-554, wherein said one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles Axis binding antagonist.

556. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 544-555, wherein said gemcitabine is administered three times every four weeks.

557. Anti-TIGIT antagonist antibody and PD-antibody for use according to any one of embodiments 544-556, wherein said gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles. Uniaxial binding antagonist.

558. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 544-557, wherein said capecitabine is administered daily for two weeks.

559. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 544-558, wherein said capecitabine is administered on days 1-14 of one or more dosing cycles.

560. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 549-559, wherein said nab-paclitaxel is administered three times every four weeks.

561. Anti-TIGIT antagonist antibody and PD-antibody for use according to any one of embodiments 549-560, wherein said nab-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles. Uniaxial binding antagonist.

562. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 552-561, wherein said etoposide is administered on days 1-3 every 3 weeks.

563. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 552-562, wherein said etoposide is administered on days 1-3 of one or more dosing cycles.

564. Antibodies for use according to any one of embodiments 543-563, wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. TIGIT antagonist antibody and PD-1 axis binding antagonist.

565. Anti-TIGIT for use according to any one of embodiments 543-564, wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

566. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of embodiments 543-565, wherein said one or more chemotherapeutic agents are administered intravenously or orally.

567. Antibodies for use according to any one of embodiments 65, 310 and 311, wherein said VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 25 mg/kg every three weeks. TIGIT antagonist antibody and PD-1 axis binding antagonist.

568. Anti-TIGIT antagonist antibody for use according to embodiment 312 or 567, wherein said VEGF antagonist is formulated for administration at a dose of about 10 mg/kg to about 20 mg/kg every 3 weeks Uniaxial binding antagonist.

569. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 318 or 568, wherein said VEGF antagonist is formulated for administration at a dose of about 15 mg/kg every three weeks.

570. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 65, 310-312, 318-320 and 567-569, wherein said VEGF antagonist is an anti-VEGF antibody.

571. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 570, wherein said anti-VEGF antibody comprises the VH and VL domains of bevacizumab.

572. An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 570 or 571, wherein said anti-VEGF antibody is bevacizumab.

573. according to any one of embodiments 65, 310-312, and 318-320, wherein said anti-TIGIT antagonist antibody is tiragolumab, said PD-1 axis binding antagonist is atezolizumab, and said VEGF antagonist is bevacizumab Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

574. any one of embodiments 65, 310-312, 318-320, and 567-573, wherein said method comprises administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for the uses described.

575. an anti-TIGIT antagonist antibody for use according to any one of embodiments 318-320, wherein said method comprises administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles; and PD-1 axis binding antagonist.

576. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 65, 310-312, and 318-320, and 567-575, wherein said VEGF antagonist is administered intravenously .

577. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 576, wherein said VEGF antagonist is administered to said subject by intravenous infusion over 90±15 minutes.

578. Embodiments 65, 310-312, 318-320, wherein said method comprises administering said PD-1 axis binding antagonist prior to said VEGF antagonist and administering said VEGF antagonist prior to said anti-TIGIT antagonist antibody , and an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of 567-577.

579. 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. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to embodiment 578, comprising:

580. 579. The resistance for use according to 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. TIGIT antagonist antibody and PD-1 axis binding antagonist.

581. Embodiments 113, 128, 129-131, 175-182, 210-214, 221, 256, 257, 270, 289, 290, 293, 294, 297, wherein said tiragolumab and atezolizumab are combined in an IV bag prior to administration , 298, 333, 362-365, 385, 386, 389, 393, 419, and 422.

582. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-581, wherein said subject is a human.

583. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-582, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations .

584. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 47-582, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single formulation. .

Set C of embodiments:
1. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 500 mg to about 700 mg of the anti-TIGIT every 3 weeks. One or more doses of a TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks. A use comprising administering to said subject a dosing regimen comprising cycles.

2. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 700 mg to about 1000 mg of the anti-TIGIT every four weeks. A use comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a TIGIT antagonist antibody and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks.

3. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 300 mg to about 600 mg of the anti-TIGIT antagonist every two weeks. A use comprising administering to said subject a dosing regimen comprising a TIGIT antagonist antibody and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.

4. 4. Use according to embodiment 2 or 3, wherein said method further comprises administering to said subject one or more chemotherapeutic agents.

5. Use according to any of embodiments 1-4, wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.
6. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3);
(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);
(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).
The use according to any one of embodiments 1-5, comprising

7. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and (d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and the following heavy chain variable region FRs:
(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where 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).
The use according to any one of embodiments 1-6, comprising
8. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or (c) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18. , SEQ ID NO:19.

9. Use according to any one of embodiments 1-8, wherein said anti-TIGIT antagonist antibody is tiragolumab.

10. Use according to any one of embodiments 1-9, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. Use according to any one of embodiments 1-10, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. Use according to any one of embodiments 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 , embodiment 12.

14. Use according to any one of embodiments 1-13, wherein said PD-1 axis binding antagonist is a monoclonal antibody.

15. Use according to any one of embodiments 1-11, wherein said PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21.

17. 17. Use according to any one of embodiments 2-16, wherein said method comprises administering to said subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. 18. Use according to embodiment 1 or 17, wherein said non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. 19. Use according to embodiment 18, wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid or HU-331, especially etoposide.

20. 20. Use according to embodiment 18 or 19, wherein said topoisomerase II inhibitor is administered at a dose of 100 mg/m2.

21. 21. Use according to any one of embodiments 17-20, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. Use according to any one of embodiments 17-21, wherein said platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration.

23. Use according to any one of embodiments 1-22, wherein said method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. wherein the induction phase comprises four initial dosing cycles, 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; 24. The use according to embodiment 23.

25. 25. Use according to embodiment 23 or 24, wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent and/or non-platinum-based chemotherapeutic agent.

26. 26. The use of any one of embodiments 1-25, wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody.

27. 27. The use of any one of embodiments 1-26, wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody.

28. 28. Use according to any one of embodiments 1-27, wherein said cancer is lung cancer.

29. 29. Use according to embodiment 28, wherein said lung cancer is small cell lung cancer (SCLC), in particular extensive-stage SCLC (ES-SCLC).

30. 29. Use according to embodiment 28, wherein said lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. 29. Use according to embodiment 28, wherein said lung cancer is locally advanced unresectable or metastatic non-squamous NSCLC.

32. 29. Use according to embodiment 28, wherein said lung cancer is resectable lung cancer.

33. 28. Use according to any one of embodiments 1-27, wherein said cancer is cervical cancer.

34. 28. Use according to any one of embodiments 1-27, wherein said cancer is early triple negative breast cancer (eTNBC).

35. 28. Use according to any one of embodiments 1-27, wherein said cancer is head and neck cancer.

36. Use according to any one of embodiments 1 to 27, wherein said cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. 28. Use according to any one of embodiments 1-27, wherein said cancer is bladder cancer.

38. 38. Use according to embodiment 37, wherein said cancer is urothelial carcinoma (UC), in particular metastatic urothelial carcinoma (mUC).

39. Use according to any one of embodiments 1 to 27, wherein said cancer is pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC).

40. Use according to any one of embodiments 1 to 27, wherein said cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for a method of treating a subject with cancer in combination with a PD-1 axis binding antagonist, said method comprising a dose of about 500 mg to about 700 mg every 3 weeks a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks1 A use comprising administering to said subject a dosing regimen comprising one or more dosing cycles.

42. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for a method of treating a subject with cancer in combination with a PD-1 axis binding antagonist, said method comprising a dose of about 700 mg to about 1000 mg every 4 weeks and one or more dosing cycles comprising a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks.

43. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for a method of treating a subject with cancer in combination with a PD-1 axis binding antagonist, said method comprising a dose of about 300 mg to about 600 mg every two weeks and one or more dosing cycles comprising a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.

44. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer in combination with an anti-TIGIT antagonist antibody, said method comprising: (a) said method comprising from about 500 mg to about anti-TIGIT antagonist antibody at a dose of 700 mg, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks and a non-platinum-based chemotherapeutic agent every 3 weeks. (b) the method comprises administering to said subject a dosing regimen comprising one or more dosing cycles, wherein said method comprises administering a dose of about 700 mg to about 1000 mg of anti-TIGIT antagonist antibody every 4 weeks and about administering to the subject a dosing regimen comprising one or more dosing cycles comprising a dose of 1400 mg to 2000 mg of a PD-1 axis binding antagonist, or (c) the method comprises about 300 mg to about 600 mg every two weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.

45. 45. Use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

46. 45. Use according to embodiment 44, wherein said anti-TIGIT antagonist antibody and said 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 in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 200 mg to about 1200 mg of the anti-TIGIT every four weeks. A use comprising administering to said subject a dosing regimen comprising one or more dosing cycles of a TIGIT antagonist antibody and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every four weeks.

48. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 200 mg to about 2000 mg of the anti-TIGIT every four weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a TIGIT antagonist antibody and a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every two weeks.

49. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 10 mg to about 1000 mg of the anti-TIGIT antagonist every two weeks. A use comprising administering to said subject a dosing regimen comprising a TIGIT antagonist antibody and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every two weeks.

50. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 10 mg to about 1000 mg of the anti-TIGIT antagonist every two weeks. A use comprising administering to said subject a dosing regimen comprising a TIGIT antagonist antibody and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every four weeks.

51. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 30 mg to about 1200 mg of the anti-TIGIT every 3 weeks. A use comprising administering to said subject a dosing regimen comprising a TIGIT antagonist antibody and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 100 mg to about 1000 mg every 6 weeks.

52. 52. Use according to any one of embodiments 47-51, wherein said method further comprises administering to said subject one or more chemotherapeutic agents.

53. 53. Use according to embodiment 52, wherein said method comprises administering to said 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 in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 30 mg to about 1200 mg of the anti-TIGIT every 3 weeks. One or more doses of a TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum chemotherapeutic agent every 3 weeks. A use comprising administering to said subject a dosing regimen comprising cycles.

55. 55. Use according to embodiment 53 or 54, wherein said method comprises an induction phase and a maintenance phase.

56. 56. Use according to embodiment 55, wherein said induction phase and maintenance phase each comprise one or more dosing cycles.

57. 57. Use according to embodiment 55 or 56, wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent.

58. 58. Use according to any one of embodiments 55-57, wherein said maintenance phase does not comprise administration of said non-platinum chemotherapeutic agent.

59. The maintenance phase comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at doses of about 200 mg to about 2000 mg every 4 weeks and the PD-1 axis binding antagonist at doses of about 80 mg to about 2000 mg every 4 weeks. , embodiment 58.

60. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 30 mg to about 1200 mg of the anti-TIGIT every 3 weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a TIGIT antagonist antibody and an anti-PD-1 antagonist antibody at a dose of about 80 mg to about 1600 mg every three weeks; Use wherein the antibody is pembrolizumab.

61. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising one or more dosing cycles of tiragolumab and pembrolizumab. administering a regimen to said subject, wherein said pembrolizumab is administered at a dose of between about 100 mg and about 1000 mg every 6 weeks.

62. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with cancer, said method comprising between about 30 mg and about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks, and 2 daily for 2 weeks on/1 week off. administering to said subject a dosing regimen comprising one or more dosing cycles of an antimetabolite at a dose of between about 10 mg/m2 and about 10000 mg/m2 orally.

63. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering a dose of about 30 mg to about 1200 mg of the anti-TIGIT every 3 weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every three weeks, gemcitabine and nab-paclitaxel. .

64. 53. Use according to embodiment 52, wherein said 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 in the manufacture of a medicament for a method for treating a subject with cancer, said method comprising between about 30 mg and about 1200 mg every 3 weeks a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and a VEGF antagonist at a dose of between about 1 mg/kg and about 35 mg/kg every 3 weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of

66. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase administering
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding antagonist every 3 weeks and a non-platinum chemotherapeutic agent every 3 weeks; Use, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent.

67. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase administering
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more times of said anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and said PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks; and wherein said maintenance phase does not comprise administration of said platinum-based chemotherapeutic agent or said non-platinum-based chemotherapeutic agent.

68. The use according to any one of embodiments 56-59, 66, and 67, wherein said induction phase comprises 4-6 dosing cycles.

69. The use according to any one of embodiments 53-59 and 66-68, wherein
(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel, or (c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is etoposide,
use.

70. Use according to any one of embodiments 47-69, wherein said cancer is a solid tumor.

71. 71. Use according to any one of embodiments 47-70, wherein said cancer is locally advanced or metastatic.

72. the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, renal cancer, 72. Use according to any one of embodiments 47-71, which is melanoma, or ovarian cancer.

73. 73. Use according to embodiment 72, wherein said cancer is lung cancer.

74. 74. Use according to embodiment 73, wherein said lung cancer is NSCLC, in particular locally advanced unresectable NSCLC.

75. 75. The use according to embodiment 74, wherein said NSCLC is stage IIIB NSCLC.

76. 76. Use according to any one of embodiments 73-75, wherein said lung cancer is recurrent or metastatic NSCLC.

77. 77. The use according to embodiment 76, wherein said NSCLC is stage IV NSCLC.

78. 78. Use according to embodiment 77, wherein said subject has not been previously treated for stage IV NSCLC.

79. 74. Use according to embodiment 73, wherein said lung cancer is small cell lung cancer (SCLC).

80. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having lung cancer, said method comprising an effective amount of an anti-TIGIT antagonist antibody, PD-1 administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of an axial binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment does not use said anti-TIGIT antagonist antibody. , which prolongs progression-free survival (PFS) of said subject compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor.

81. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject population having lung cancer, said method comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding administering to said subject population a dosing regimen comprising one or more dosing cycles of an antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment lasts from about 8.2 months to about 9.2 months. A use that provides a median PFS for said subject population.

82. The treatment compared the overall survival (OS ) is extended.

83. said treatment prolongs PFS of said subject or subject population 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 The use according to any one of embodiments 80-82.

84. said treatment reduces said PFS of said subject or subject population by at least about 84. Use according to embodiment 83, extending from 3 months to about 4 months.

85. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having lung cancer, said method comprising an effective amount of an anti-TIGIT antagonist antibody, PD-1 administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of an axial binding antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment does not use said anti-TIGIT antagonist antibody. , which prolongs OS in said subject compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor.

86. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject population having lung cancer, said method comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding administering to said subject population a dosing regimen comprising one or more dosing cycles of an antagonist, a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor, wherein said treatment lasts from about 15.3 months to about 17.6 months. A use that results in median OS for said subject population.

87. said treatment prolongs OS of said subject or subject population 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 87. Use according to any one of embodiments 82-86.

88. said treatment reduces the OS of said subject or subject population by at least about 3 months to about 5 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; .The use according to any one of embodiments 82-86, extended for 3 months.

89. 89. 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. Use of.

90. 89. Any one of embodiments 80-89, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are further administered in one or more additional cycles following said fourth initial dosing cycle. Use of.

91. 91. Use according to embodiment 90, wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of said one or more additional dosing cycles.

92. 92. Use according to any one of embodiments 80-91, wherein said platinum-based chemotherapeutic agent is carboplatin and said topoisomerase II inhibitor is etoposide.

93. Use according to any one of embodiments 80-92, wherein said lung cancer is small cell lung cancer (SCLC).

94. 94. Use according to embodiment 93, wherein said SCLC is extensive SCLC (ES-SCLC).

95. 95. Use according to embodiment 94, wherein said one or more subjects are treatment-naive for ES-SCLC.

96. 96. Use according to any one of embodiments 80-95, wherein said one or more subjects do not have the presence or history of brain metastases.

97. 97. Use according to any one of embodiments 80-96, wherein said lung cancer is not selected for PD-L1 expression.

98. 97. Use according to any one of embodiments 80-96, wherein said lung cancer is selected for PD-L1 expression.

99. 99. Use according to embodiment 98, wherein said lung cancer is selected for PD-L1 expression by a detectable level of PD-L1 expression.

100. 99. Use according to any one of embodiments 80-99, wherein said lung cancer is metastatic.

101. 101. Use according to embodiment 100, wherein said lung cancer has metastasized to the brain, liver, lymph nodes and/or adrenal glands.

102. 102. Use according to embodiment 100 or 101, wherein said lung cancer has never metastasized to the brain.

103. Use according to any one of embodiments 100-102, wherein said treatment results in a complete response (CR) or partial response (PR).

104. 104. Use according to any one of embodiments 80-103, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 2, 3 or 4 weeks.

105. 105. Use according to any one of embodiments 80-104, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2, 3 or 4 weeks.

106. 106. Use according to any one of embodiments 80-105, wherein said PD-1 axis binding antagonist, anti-TIGIT antagonist antibody, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered sequentially.

107. 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. 107. The use according to embodiment 106, wherein.

108. 108. Use according to any one of embodiments 80-107, wherein said anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent and topoisomerase II inhibitor are administered intravenously.

109. 109. Any one of embodiments 80-108, wherein one or more of said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are administered subcutaneously. use.

110. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with SCLC, said method comprising from about 30 mg to about Anti-TIGIT antagonist antibody at a dose of 1200 mg, atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle, dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of each dosing cycle. and one or more 21-day dosing cycles of etoposide at a dose of 100 mg/m2 on each of days 1, 2, and 3 of each dosing cycle; Use wherein treatment prolongs PFS and/or OS of said subject compared to treatment with atezolizumab, carboplatin and etoposide without said anti-TIGIT antagonist antibody.

111. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with SCLC, said method comprising from about 300 mg to about Anti-TIGIT antagonist antibody at a dose of 800 mg, atezolizumab at a dose of about 900 mg to about 1500 mg on Day 1 of each dosing cycle, dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of each dosing cycle. and one or more 21-day dosing cycles of etoposide at a dose of 100 mg/m2 on each of days 1, 2, and 3 of each dosing cycle; Use wherein treatment prolongs PFS and/or OS of said subject compared to treatment with atezolizumab, carboplatin and etoposide without said anti-TIGIT antagonist antibody.

112. One or more additions of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each additional dosing cycle 112, wherein carboplatin and etoposide are omitted from each of the one or more additional dosing cycles.

113. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population with ES-SCLC, said method comprising four initial dosing cycles followed by one or more additional and administering to said subject or subject population a dosing cycle of
(a) the four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, and 1 of each initial dosing cycle; Carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 and etoposide at a dose of 100 mg/m on each of Days 1, 2 and 3 of each initial dosing cycle including
(b) said one or more additional dosing cycles administering a dose of about 600 mg tiragolumab on day 1 of each additional dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each additional dosing cycle; including
each of the four initial dosing cycles and the one or more additional dosing cycles is a 21-day dosing cycle, and the treatment is compared to a treatment comprising atezolizumab, carboplatin and etoposide without the tiragolumab; A use that prolongs PFS and/or OS in a subject or subject population.

114. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having lung cancer, said method comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent use, including

115. 115. Use according to embodiment 114, wherein said lung cancer has not been evaluated for PD-L1 expression.

116. 116. Use according to embodiment 114 or 115, wherein said one or more subjects have not been determined to have a PD-L1 positive tumor cell fraction of 50% or greater.

117. 117. Use according to embodiment 116, wherein said one or more subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. 118. Use according to embodiment 116 or 117, wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, said anti-PD-L1 antibody being SP263 or 22C3.

119. 119. Use according to any one of embodiments 114-118, wherein said one or more subjects do not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

120. 120. Use according to any one of embodiments 114-119, wherein said one or more subjects have not received prior systemic therapy for said lung cancer.

121. Use according to any one of embodiments 114-120, wherein said lung cancer is locally advanced lung cancer.

122. Use according to any one of embodiments 114 to 121, wherein said lung cancer is NSCLC, in particular locally advanced unresectable or metastatic non-squamous NSCLC.

123. 123. Use according to embodiment 122, wherein said non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The dosing regimen comprises an induction phase comprising four dosing cycles, 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 in the induction phase 124. Use according to any one of embodiments 114-123, administered on day 1 of each dosing cycle of .

125. wherein said dosing regimen comprises a maintenance phase following said induction phase, said maintenance phase comprising one or more dosing cycles, said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist and said non-platinum chemotherapeutic agent is administered on Day 1 of each dosing cycle of said maintenance phase.

126. 126. Use according to embodiment 125, wherein said one or more dosing cycles of said maintenance phase do not comprise administration of said platinum-based chemotherapeutic agent.

127. 127. Use according to any one of embodiments 114-126, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin and said non-platinum-based chemotherapeutic agent is pemetrexed.

128. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population with advanced non-squamous NSCLC, said method comprising administering to said subject or subject population tiragolumab, atezolizumab, carboplatin or cisplatin and pemetrexed for four 21-day dosing cycles, wherein on day 1 of each of said four 21-day dosing cycles, said tiragolumab is administered at a dose of about 600 mg every 3 weeks. wherein the atezolizumab is administered at a dose of about 1200 mg every 3 weeks and the carboplatin is administered every 3 weeks at a dose sufficient to achieve AUC = 5 mg/ml/min or the cisplatin is administered every 3 weeks and wherein said pemetrexed is administered at a dose of about 500 mg/m every 3 weeks.
129. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population with advanced non-squamous NSCLC, said method comprising:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin;
administering with
Use, wherein said subject or subject population has never received prior systemic therapy for said advanced non-squamous NSCLC.

130. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with advanced non-squamous NSCLC, said method comprising:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) atezolizumab at a dose of about 1200 mg every 3 weeks, and (ii) one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/m2, wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin;
administering with
Use wherein said subject has had no prior systemic therapy for said advanced non-squamous NSCLC.

131. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with advanced non-squamous NSCLC, said method comprising administering to said subject four doses of tiragolumab, atezolizumab, carboplatin or cisplatin and pemetrexed administering a dosing regimen comprising a 21-day dosing cycle, wherein on day 1 of each of said 4 21-day dosing cycles said tiragolumab is administered at a dose of about 600 mg every 3 weeks and said atezolizumab is administered 3 times Use wherein the cisplatin is administered at a dose of about 1200 mg weekly and the pemetrexed is administered at a dose of about 500 mg/m2.

132. 132. Use according to any one of embodiments 114-131, wherein said treatment prolongs the PFS of said subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. 133. Use according to any one of embodiments 114-132, wherein said treatment results in a median PFS for said subject population of about 12.5 months to about 14.7 months.

134. 134. Use according to any one of embodiments 114-133, wherein said treatment prolongs OS of said subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. 135. Use according to any one of embodiments 114-134, wherein said treatment results in a median OS for said subject population of from about 27.5 months to about 32.0 months.

136. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising about 30 mg and about 1200 mg every 3 weeks and administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose between about 80 mg and about 1600 mg every three weeks.

137. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising about 300 mg and about 800 mg every 3 weeks and administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose between about 900 mg and about 1500 mg every three weeks.

138. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising: administering to said subject one or more dosing cycles, wherein at least one of said dosing cycles includes said anti-TIGIT antagonist antibody as a neoadjuvant treatment at a dose of between about 30 mg and about 1200 mg every three weeks; and administering said PD-1 axis binding antagonist to said subject at a dose of between about 80 mg and about 1600 mg every three weeks.

139. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising: administering to said subject one or more dosing cycles, wherein at least one of said dosing cycles includes said anti-TIGIT antagonist antibody as a neoadjuvant treatment at a dose of between about 300 mg and about 800 mg every three weeks; and administering said PD-1 axis binding antagonist to said subject at a dose of between about 900 mg and about 1500 mg every three weeks.

140. At least one of said dosing cycles comprises, as an adjuvant treatment, said anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks and said PD-1 axis binding antagonist at a dose between about 80 mg and about every three weeks. 140. Use according to embodiment 138 or 139, comprising administering to said subject at a dose of between 1600.

141. At least one of said dosing cycles comprises, as an adjuvant treatment, said anti-TIGIT antagonist antibody at a dose between about 500 mg and about 700 mg every 3 weeks and said PD-1 axis binding antagonist at a dose between about 900 mg and about 900 mg every 3 weeks. 141. Use according to embodiment 140, comprising administering to said subject at a dose of between 1500.

142. 142. Use according to any one of embodiments 138-141, wherein said lung cancer is resectable lung cancer.

143. 143. Use according to any one of embodiments 136-142, wherein said lung cancer is early stage lung cancer.

144. 144. Use according to any one of embodiments 136-143, wherein said lung cancer is stage II, IIIA or IIIB lung cancer.

145. 145. Use according to any one of embodiments 136-144, wherein said lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

146. 146. Use according to any one of embodiments 136-145, wherein said subject is eligible for R0 enucleation with curative intent.

147. 147. Use according to any one of embodiments 136-146, wherein said subject has no prior treatment for lung cancer.

148. 148. Use according to embodiment 147, wherein said prior treatment is immunotherapy, chemotherapy or radiotherapy.

149. 149. Use according to any one of embodiments 136-148, wherein said subject is eligible to receive a platinum-based chemotherapy regimen.

150. 149. Use according to any one of embodiments 136-149, wherein said first dosing cycle is initiated prior to surgery.

151. 151. Use according to embodiment 150, wherein at least 1, 2, 3 or 4 dosing cycles are completed prior to said surgery.

152. Use according to embodiment 150 or 151, wherein 4 dosing cycles are completed prior to said surgery.

153. 153. Use according to any one of embodiments 136-152, wherein at least one dosing cycle is initiated after surgery.

154. Use according to embodiment 153, wherein 16 dosing cycles are completed after said surgery.

155. 155. Use according to any one of embodiments 150-154, wherein said surgery is segmentectomy, lobectomy, bilobectomy, or pneumonectomy.

156. 156. Use according to any one of embodiments 136-155, wherein said method further comprises radiotherapy.

157. 157. Use according to embodiment 156, wherein said radiotherapy is post-operative radiotherapy.

158. 158. Use according to any one of embodiments 136-157, wherein said method further comprises administering one or more chemotherapeutic agents.

159. 159. Use according to embodiment 158, wherein said one or more chemotherapeutic agents are administered after surgery.

160. 159. Use according to embodiment 159, wherein said one or more chemotherapeutic agents are administered in four dosing cycles after said surgery.

161. 161. Use according to any one of embodiments 158-160, wherein said one or more chemotherapeutic agents are platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents.
162. 161. The use of embodiment 161, comprising:
(a) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine;
(c) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel;
(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or (e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. is
use.

163. 163. Use according to any one of embodiments 136-162, wherein said treatment results in an increased MPR rate compared to the baseline significant pathological response (MPR) rate.

164. The reference MPR rate is
MPR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 164. The use according to embodiment 163, which is.

165. 165. Use according to any one of embodiments 136-164, wherein said treatment results in a pathological complete response (pCR) and/or an increase in the pCR rate compared to the baseline pCR rate.

166. The reference pCR rate is
pCR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 165. The use according to embodiment 165, which is.

167. 167. Use according to any one of embodiments 136-166, wherein said treatment results in increased EFS time compared to baseline symptom-free survival (EFS).

168. the reference EFS time,
EFS time in a subject population that has received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 168. The use according to embodiment 167, which is.

169. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising about 30 mg and about 600 mg every 3 weeks and administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose between about 80 mg and about 1600 mg every three weeks.

170. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising: administering to said subject one or more dosing cycles, wherein at least one of said dosing cycles includes said anti-TIGIT antagonist antibody as a neoadjuvant treatment at a dose of between about 30 mg and about 600 mg every three weeks; and administering said PD-1 axis binding antagonist to said subject at a dose of between about 80 mg and about 1600 mg every three weeks.

171. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising about 30 mg and about 1200 mg every 3 weeks one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between, a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent to said subject.

172. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising: an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist; administering to said subject one or more dosing cycles of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein at least one of said dosing cycles is about 30 mg every 3 weeks as a neoadjuvant treatment; said anti-TIGIT antagonist antibody at a dose of between about 1200 mg, said PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent. Use, including administering to a subject.

173. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising about 30 mg and about 1200 mg every 3 weeks an anti-TIGIT antagonist antibody at a dose of between and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks; and (a)(i) an AUC of 5 mg/mL/min every 3 weeks. or a platinum-based chemotherapeutic agent at a dose targeted to achieve an AUC of 6 mg/mL/min; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m every three weeks; i) an antimetabolite at a dose of about 500 mg/m2 every 3 weeks, about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or (ii) about 100 mg/m2 every 3 weeks. A use comprising administering to the subject one or more dosing cycles of taxane at a dose of about 175 mg/m2, or about 200 mg/m2.

174. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising: an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, administering to said subject one or more dosing cycles of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein at least one said dosing cycle provides said subject with: (a) about 30 mg every 3 weeks; (b) the PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks; (c) the platinum-based chemotherapeutic agent (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks, or (ii) a dose of about 75 mg/m2 every 3 weeks and (d) the non-platinum-based chemotherapeutic agent, which is (i) 500 mg/m2 every three weeks, or 1000 mg/m2 on days 1 and 8 of each dosing cycle. or (ii) a dose of 100 mg/m2, 175 mg/m2 or 200 mg/m2 every three weeks with a taxane non-platinum chemotherapeutic agent. , the use wherein said treatment is a neoadjuvant treatment.

175. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with resectable lung cancer, said method comprising administering to said subject a dose of tiragolumab of about 600 mg every 3 weeks; atezolizumab at a dose of about 1200 mg weekly;
(a)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and,
(b)
(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks, or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) every 3 weeks. and one or more dosing cycles of paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2.

176. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising one or more of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent wherein at least one of said dosing cycles administers to said subject (a) a dose of tiragolumab of about 600 mg every 3 weeks; and (b) a dose of about 1200 mg every 3 weeks of (c) said platinum-based chemotherapeutic agent, (i) at a dose aimed at achieving an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; (ii) cisplatin at a dose of about 75 mg/m every 3 weeks; and (d) the non-platinum-based chemotherapeutic agent, wherein (i) every 3 weeks Pemetrexed at doses of 500 mg/m2, or 1000 mg/m2 or 1250 mg/m2 on days 1 and 8 of each dosing cycle, or (ii) doses of 100 mg/m2, 175 mg/m2 or 200 mg/m2 every 3 weeks and a non-platinum chemotherapeutic agent that is paclitaxel of , wherein said treatment is a neoadjuvant treatment.

177. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with non-squamous NSCLC, said method administering to said subject one or more dosing cycles of tiragolumab and atezolizumab (a) at least one of said dosing cycles administering to said subject a dose of about 600 mg of tiragolumab every 3 weeks and a dose of 1200 mg of atezolizumab every 3 weeks as neoadjuvant treatment; (b) use wherein at least one of the premedication cycles comprises administering to said subject a dose of about 600 mg of tiragolumab every three weeks and a dose of about 1200 mg of said atezolizumab every three weeks as an adjuvant treatment.

178. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with non-squamous NSCLC, said method administering to said subject one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is neoadjuvant treatment, and said subject is administered (a) tiragolumab at a dose of about 600 mg every 3 weeks; (b) every 3 weeks as neoadjuvant treatment (c)(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks, and pemetrexed at a dose of about 500 mg/m every 3 weeks (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; and (II) at least one of said dosing cycles as adjuvant treatment; administering an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks to use .

179. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is neoadjuvant treatment, and said subject receives (a) tiragolumab at a dose of about 600 mg every 3 weeks; atezolizumab at a dose of 1200 mg, (c)(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks, and approximately 1000 mg on days 1 and 8 of each dosing cycle. (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks, and a dose of about 175 mg/m2 or about 200 mg/m every 3 weeks; (II) paclitaxel, or (iii) cisplatin at a dose of about 75 mg/m2 every three weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; In at least one of said dosing cycles, said subject receives tiragolumab at a dose between about 30 mg and about 1200 mg every 3 weeks and atezolizumab at a dose between about 80 mg and about 1600 mg every 3 weeks as an adjuvant treatment. Use, including administering.

180. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab ,
(I) at least one of said dosing cycles is a neoadjuvant treatment, wherein said subject comprises:
(a) tiragolumab at a dose of about 1200 mg every 3 weeks;
(b) atezolizumab at a dose of about 1200 mg every 3 weeks as a neoadjuvant treatment;
(c)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;
(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, or (iii)3 administering a weekly dose of cisplatin of about 75 mg/m2 and a dose of gemcitabine of about 1250 mg/m2 on days 1 and 8 of each dosing cycle;
(II) at least one of said dosing cycles comprises, as an adjuvant treatment, giving said subject tiragolumab at a dose of between about 300 mg and about 800 mg every three weeks and a dose of between about 900 mg and about 1500 mg every three weeks; Uses, including administering atezolizumab.

181. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is neoadjuvant treatment, and said subject receives (a) tiragolumab at a dose of about 600 mg every 3 weeks; atezolizumab at a dose of 1200 mg, (c)(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks, and approximately 1000 mg on days 1 and 8 of each dosing cycle. (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks, and a dose of about 175 mg/m2 or about 200 mg/m every 3 weeks; (II) paclitaxel, or (iii) cisplatin at a dose of about 75 mg/m2 every three weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; at least one of said dosing cycles comprising administering to said subject, as an adjuvant treatment, a dose of approximately 600 mg of tiragolumab every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

182. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject with resectable squamous NSCLC, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab (I) at least one of said dosing cycles is a neoadjuvant treatment, wherein said subject is administered (a) tiragolumab at a dose of about 600 mg every three weeks, (b) as neoadjuvant treatment, Atezolizumab at a dose of approximately 1200 mg every 3 weeks, (c)(i) Carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks, and Days 1 and 8 of each dosing cycle gemcitabine at a dose of about 1000 mg/m2 daily, (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks, and about 175 mg/m2 or about 200 mg every 3 weeks. or (iii) cisplatin at a dose of about 75 mg/m2 every three weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle. (II) at least one of said dosing cycles comprises administering to said subject a dose of approximately 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks as adjuvant treatment. ,use.

183. 183. Use according to any one of embodiments 136-182, wherein the detectable PD-L1 protein expression level is determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263.

184. 184. Use according to embodiment 183, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or more.

185. Use according to any one of embodiments 73, 114-121, and 136-184, wherein said lung cancer is NSCLC.

186. 186. Use according to embodiment 185, wherein the NSCLC is squamous NSCLC.

187. 186. Use according to embodiment 185, wherein the NSCLC is non-squamous NSCLC.

188. 73. Use according to embodiment 72, wherein said cancer is cervical cancer.

189. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having cervical cancer with detectable PD-L1 expression levels, comprising: The method comprises one or more doses of an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks. A use comprising administering a cycle to said subject or population of subjects.

190. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having cervical cancer with detectable PD-L1 expression levels, comprising: The method comprises one or more dosings of an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every three weeks. A use comprising administering a cycle to said subject or population of subjects.

191. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting therapy for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - for said subject with an L1 expression level, an anti-TIGIT antagonist antibody administered every three weeks at a dose of between about 30 mg and about 1200 mg based on detected PD-L1 expression on tumor cells and about 80 mg and selecting a treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist administered every three weeks at a dose of between about 1600 mg.

192. 192. Use according to any one of embodiments 189-191, wherein said cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma.

193. 192. Use according to any one of embodiments 189-191, wherein said cervical cancer is stage IVB, metastatic, recurrent or persistent.

194. 194. Use according to any one of embodiments 189-193, wherein said cervical cancer is metastatic and/or recurrent PD-L1 positive cervical carcinoma.

195. 195. Use according to any one of embodiments 189-194, wherein said one or more subjects have received at least one prior treatment.

196. 196. Use according to any one of embodiments 189-195, wherein said one or more subjects have received two prior treatments.

197. 197. Use according to any one of embodiments 189-196, wherein said one or more subjects have not received 3 or more prior treatments.

198. 195. Use according to any one of embodiments 189-194, wherein said one or more subjects have no prior treatment.

199. 199. Use according to any one of embodiments 195-198, wherein said prior treatment is chemotherapy, surgery and/or radiotherapy.

200. Use according to any one of embodiments 189 and 192-199, wherein said treatment results in a clinical response.

201. 201. Use according to embodiment 200, wherein said clinical response is an increase in ORR in said subject population compared to a baseline objective response rate (ORR).

202. 202. Use according to embodiment 201, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

203. 201. Use according to embodiment 200, wherein said baseline ORR is at least about 14.6% to about 26%.

204. 201. Use according to embodiment 200, wherein said clinical response is CR or PR.

205. wherein said clinical response is increased in said subject's PFS time compared to baseline progression-free survival (PFS), increased in said subject's DOR time compared to baseline duration of response (DOR), or baseline overall survival (OS) 205. Use according to any one of embodiments 200-204, which is an increase in OS time for the subjects compared.

206. The use of embodiment 205, comprising:
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
use.

207. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method for treating a subject with cervical cancer with detectable PD-L1 expression levels, said method comprising: every 3 weeks A use comprising administering to said subject one or more dosing cycles of a dose of 600 mg of an anti-TIGIT antagonist antibody and one or more dosing cycles of a dose of atezolizumab of 1200 mg every three weeks.

208. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of identifying subjects with cervical cancer who are likely to benefit from treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab wherein the method comprises
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (c) PD-L1 expression on detected tumor cells. based on the likely benefit from treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. Uses, including identifying a subject.
209. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of selecting therapy for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on detected tumor cells for said subject with L1 expression level selecting a treatment comprising one or more dosing cycles of atezolizumab administered.

210. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject with cervical cancer with detectable PD-L1 expression levels, said method comprising administering to said subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

211. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with cervical cancer, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) based on detected PD-L1 expression on tumor cells, one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. and (d) administering said treatment to said identified subject.

212. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting treatment for a subject with cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks for said subjects with L1 expression levels based on detected PD-L1 expression on tumor cells selecting a treatment comprising one or more dosing cycles of

213. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with metastatic and/or recurrent cervical cancer, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on detected PD-L1 expression on tumor cells; and (d) administering said treatment to said identified subject.

214. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting treatment for a subject with metastatic and/or recurrent cervical cancer, said method comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - Tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks for said subjects with L1 expression levels based on detected PD-L1 expression on tumor cells selecting a treatment comprising one or more dosing cycles of

215. 215. Use according to any one of embodiments 189-214, wherein said subject is identified as likely to benefit from said treatment based on detected PD-Ll expression on tumor cells.

216. Use according to any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263.

217. 217. Use according to any one of embodiments 189-216, wherein said detectable PD-L1 expression level is 5% or more tumor-associated immune cells (TIC) in a sample from said subject.

218. Use according to any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody 22C3.

219. 217. Use according to any one of embodiments 189-216, wherein said detectable PD-L1 expression level is a composite positive score (CPS) of 1 or more in a sample from said subject.

220. 73. Use according to embodiment 72, wherein said cancer is breast cancer.

221. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population having breast cancer, comprising tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of nab-paclitaxel at a dose of about 100 mg/m2 with 3 weeks on/1 week off.

222. 222. Use according to embodiment 220 or 221, wherein said breast cancer is triple negative breast cancer (TNBC).

223. 223. Use according to embodiment 222, wherein said TNBC is unresectable locally advanced or metastatic TNBC.

224. 224. Use according to any one of embodiments 220-223, wherein said subject has no prior systemic therapy for metastatic breast cancer.

225. 225. Use according to any one of embodiments 220-224, wherein said treatment results in an ORR of the subject population of at least about 53% to about 67.5%.

226. 226. Use according to any one of embodiments 222-225, wherein said treatment results in a median OS for said subject population of about 25.0 months.

227. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with early triple negative breast cancer (eTNBC), said method comprising from about 10 mg to about administering to said subject a dosing regimen comprising a dose of 1000 mg of an anti-TIGIT antagonist antibody and one or more dosing cycles comprising a dose of about 20 mg to about 1600 mg of a PD-1 axis binding antagonist every two weeks; use.

228. 228. Use according to embodiment 227, wherein said method further comprises administering to said subject one or more chemotherapeutic agents.

229. 229. Use according to embodiment 228, wherein said one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a taxane, or a taxane and a platinum-based chemotherapeutic agent, and (b) the anti-TIGIT One dose of an antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) 228. Use according to embodiment 227, further comprising administering the above dosing cycle.

231. 231. Use according to embodiment 229 or 230, wherein said alkylating agent is cyclophosphamide.

232. 232. Use according to embodiment 231, wherein said cyclophosphamide is administered at a dose of about 600 mg/m2.

233. The use of any one of embodiments 227-229, 231, and 232, wherein said use further comprises administering G-CSF or GM-CSF to said subject.

234. 234. Use according to embodiment 230 or 233, wherein said G-CSF is pegfilgrastim or filgrastim.

235. 235. Use according to embodiment 234, wherein said G-CSF is pegfilgrastim.

236. 236. Use according to embodiment 235, wherein said pegfilgrastim is administered at a dose of about 6 mg.

237. Embodiments 228, 229, and 231-236, wherein said method further comprises administering said one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF to said subject Use according to any one of

238. Embodiments 228, 229, and 231, wherein said one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once weekly, once every two weeks, or once every three weeks, respectively 237. Use according to any one of clauses 1-237.

239. The platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF Or the use according to any one of embodiments 229-238, wherein GM-CSF is administered every two weeks.

240. 239. Use according to any one of embodiments 229-239, wherein said taxane, or said taxane and said platinum-based chemotherapeutic agent are administered for the first 12 weeks of said dosing regimen.

241. 240. Any one of embodiments 229-240, wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered during weeks 13 through 19 of the dosing regimen. Use of.

242. 242. Use according to any one of embodiments 227-241, wherein the total length of said dosing regimen is 19 weeks.

243. Use according to any one of embodiments 227-242, wherein said method is neoadjuvant treatment.

244. 244. Use according to any one of embodiments 227-243, wherein said dosing regimen is followed by surgery.

245. 245. Use according to embodiment 244, wherein said surgery is performed between 2 and 6 weeks after the last administration of said dosing regimen.

246. 246. Use according to embodiment 244 or 245, wherein said surgery comprises a mastectomy.

247. 247. Use according to any one of embodiments 244-246, wherein said surgery comprises axillary lymph node surgery.

248. 248. Use according to any one of embodiments 229-247, wherein said topoisomerase II inhibitor is doxorubicin.

249. 248. Use according to 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. Use according to embodiment 248 or 249, wherein doxorubicin is administered at a dose of about 60 mg/m2.

251. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering anti-TIGIT at a dose of about 300 mg to about 600 mg every two weeks. an antagonist antibody and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

252. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering anti-TIGIT at a dose of about 300 mg to about 600 mg every two weeks. an antagonist antibody and a PD-L1 binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks over weeks 13 through 19 of said dosing regimen, and for 2 weeks per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

253. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering anti-TIGIT at a dose of about 300 mg to about 600 mg every two weeks. an antagonist antibody and an anti-PD-L1 antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks over weeks 13 through 19 of said dosing regimen, and for 2 weeks per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

254. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering anti-TIGIT at a dose of about 300 mg to about 600 mg every two weeks. an antagonist antibody and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

255. 1. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising: anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks; atezolizumab at a weekly dose of about 600 mg to about 1200 mg;
(a)
(i) a taxane at a dose of about 125 mg/m2 weekly over the first 12 weeks of said dosing regimen and a platinum agent at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; (ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and for 2 weeks over weeks 13 through 19 of said dosing regimen; per G-CSF or GM-CSF, or (b)
(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; a topoisomerase II inhibitor at a dose, an alkylating agent at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

256. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering tiragolumab at a dose of about 300 mg to about 600 mg every 2 weeks and about 600 mg to about 600 mg every 2 weeks. atezolizumab at a dose of about 1200 mg;
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

257. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, said method comprising administering tiragolumab at a dose of about 420 mg every two weeks and atezolizumab at a dose of about 840 mg every two weeks. and,
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m every week for the first 12 weeks of said dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; ii) doxorubicin at a dose of about 60 mg/m every 2 weeks, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G- every 2 weeks for weeks 13 through 19 of the dosing regimen CSF or GM-CSF, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of the dosing regimen, and (ii) a dose of about 60 mg/m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin, cyclophosphamide at a dose of about 600 mg/m every 2 weeks, and G-CSF or GM-CSF every 2 weeks;
and wherein the method further comprises surgery between 2 weeks and 6 weeks after the last dose of the dosing regimen.

258. Use according to any one of embodiments 220-257, wherein the detectable PD-L1 protein expression level in a tumor sample from said subject is determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142. .

259. 259. Use according to embodiment 258, wherein the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC) in said tumor sample is 1% or more.

260. 259. Use according to any one of embodiments 227-259, wherein said eTNBC is T2-4d TNBC when presented.

261. 261. The use according to any one of embodiments 227-260, wherein said eTNBC are cT2-cT4, cN0-cN3, and cM0 TNBC when presented.

262. 262. Use according to any one of embodiments 227-261, wherein said subject has not previously been treated for eTNBC.

263. 263. Use according to any one of embodiments 227-262, wherein said treatment results in a pathological complete response (pCR).

264. 264. Use according to any one of embodiments 227-263, wherein said treatment results in increased overall survival (OS) or symptom-free survival (EFS).

265. 73. Use according to embodiment 72, wherein said cancer is head and neck cancer.

266. 266. Use according to embodiment 265, wherein said 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 in the manufacture of a medicament for treating a subject or subject population having nSCCHN with detectable PD-L1 expression levels, said method comprising , an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks, and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks. Use, including administering to a subject or population of subjects.

268. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject or subject population having nSCCHN with detectable PD-L1 expression levels, said method comprising , an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every 3 weeks, and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every 3 weeks. Use, including administering to a subject or population of subjects.

269. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting therapy for a subject or subject population with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg every 3 weeks, based on detected PD-L1 expression, for said subject or subject population having levels of selecting a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 1200 mg.

270. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having SCCHN with detectable PD-L1 expression levels, said method comprising administering to said subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

271. 271. Use according to any one of embodiments 267-270, wherein the tumor sample obtained from said one or more subjects has been determined to have a detectable level of PD-Ll expression.

272. 272. Use according to any one of embodiments 266-271, wherein said SSCHN is human papillomavirus (HPV) positive.

273. 273. Use according to any one of embodiments 266-272, wherein said SSCHN is HPV negative.

274. 274. Use according to embodiment 272 or 273, wherein HPV status is determined by p16 IHC, in situ hybridization or PCR.

275. 275. Use according to any one of embodiments 266-274, wherein said SCCHN is recurrent and/or metastatic SCCHN.

276. 276. Use according to any one of embodiments 265-275, wherein said one or more subjects have no prior treatment.

277. 277. Use according to embodiment 276, wherein said prior treatment is prior systemic treatment for recurrent and/or metastatic disease.

278. Use according to any one of embodiments 265-268 and 270-277, wherein said treatment results in CR or PR.

279. Use according to any one of embodiments 265-268 and 270-277, wherein said treatment results in an increase in ORR in said subject population compared to a baseline objective response rate (ORR).

280. 280. Use according to embodiment 279, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

281. 281. Use according to embodiment 279 or 280, wherein said baseline ORR is from about 19% to about 36%.

282. wherein said treatment increases PFS time of said subject or subject population compared to baseline progression-free survival (PFS), increases DOR time of said subject or subject population compared to baseline duration of response (DOR), or baseline overall survival Use according to any one of embodiments 265-268 and 270-281, which results in an increase in OS time of said subject or subject population compared to duration (OS).

283. 283. The use according to embodiment 282, wherein:
(a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment containing a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
use.

284. 283. Use according to embodiment 282, wherein the baseline DOR time is from at least about 6.7 months to about 23.4 months.

285. 283. Use according to embodiment 282, wherein the baseline OS time is from 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 in the manufacture of a medicament for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising: administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks. use, including

287. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising: administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every three weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every three weeks.

288. Use of an anti-TIGIT antagonist antibody and a PD-L1 binding antagonist in the manufacture of a medicament for a method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising: every 3 weeks administering to said subject one or more dosing cycles of a PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg of and an anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg every three weeks including, use.

289. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising: administering one or more dosing cycles of atezolizumab at a dose between about 80 mg and about 1600 mg every 3 weeks and tiragolumab at a dose between about 30 mg and about 1200 mg every 3 weeks.

290. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising: administering one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

291. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable PD-L1 expression level.

292. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) may benefit from treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable level of PD-L1 expression.

293. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) potential to benefit from treatment comprising one or more dosing cycles of atezolizumab at doses between about 80 mg and about 1600 mg every 3 weeks and tiragolumab at doses between about 30 mg and about 1200 mg every 3 weeks; and (d) administering said treatment to said identified subject having a detectable level of PD-L1 expression.

294. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCCHN, said method comprising:
(a) obtaining a tumor sample from said subject;
(b) detecting the protein expression level of PD-L1 in said tumor sample by an IHC assay using an anti-PD-L1 antibody suitable for staining;
(c) identifying subjects likely to benefit from treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks; (d) a use comprising administering said treatment to said identified subject having a detectable PD-L1 expression level.

295. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks, and about 30 mg and about 1200 mg every 3 weeks, based on detected PD-L1 expression, for said subjects with levels of selecting a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at an intermediate dose.

296. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. 1 of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks, based on detected PD-L1 expression, for said subjects with levels of Selecting a treatment that includes one or more dosing cycles.

297. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. atezolizumab at doses between about 80 mg and about 1600 mg every 3 weeks, and tiragolumab at doses between about 30 mg and about 1200 mg every 3 weeks, for said subjects with levels of selecting a treatment comprising one or more dosing cycles of

298. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting therapy for a subject with SCCHN, said method comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD-L1 expression. treatment comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on detected PD-L1 expression for said subject with a level use, including selecting

299. Embodiment 267- wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level determined by an immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP263 298. Use according to any one of clauses 298-298.

300. the detectable PD-L1 protein expression level in the tumor sample is
(a) 5% or more;
299. Use according to embodiment 299, wherein (b) 5% or more and less than 20%, or (c) 20% or more tumor-associated immune cells (TIC).

301. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying subjects likely to benefit from a treatment comprising a dosing cycle, said method comprising an anti-TIGIT antibody suitable for staining. determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using a PD-L1 antibody, wherein a PD-L1 protein expression level of 5% or more TIC indicates said subject. A use that identifies a likely person to benefit from said treatment.

302. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying subjects likely to benefit from a treatment comprising a dosing cycle, said method comprising an anti-TIGIT antibody suitable for staining. determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using a PD-L1 antibody, wherein the protein expression level of PD-L1 of 5% or more and less than 20% of the TIC is , identifying said subject as likely to benefit from said treatment.

303. Subjects with SCCHN were given one or more doses of a PD-1 axis binding antagonist at doses between about 80 mg and about 1600 mg every 3 weeks, anti-TIGIT antagonist antibodies at doses between about 30 mg and about 1200 mg every 3 weeks. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying subjects likely to benefit from a treatment comprising a dosing cycle, said method comprising an anti-TIGIT antibody suitable for staining. determining the protein expression level of PD-L1 in a tumor sample from said subject by an IHC assay using a PD-L1 antibody, wherein 20% or more of said PD-L1 protein expression level of TIC indicates said subject. A use that identifies a likely person to benefit from said treatment.

304. 304. Use according to any one of embodiments 301-303, wherein said subject is identified as likely to benefit from treatment and said method further comprises administering treatment to said subject.

305. 305. Use according to any one of embodiments 301-304, wherein said TIC is determined using the Ventana SP263 IHC assay.

306. Use according to any one of embodiments 267-305, wherein said subject or subject population is identified as likely to benefit from said treatment based on detected PD-L1 expression on tumor cells. .

307. 73. Use according to embodiment 72, wherein said cancer is liver cancer.

308. 308. Use according to embodiment 307, wherein said liver cancer is hepatocellular carcinoma (HCC).

309. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population having hepatocellular carcinoma (HCC), wherein said subject or subject population is treated with the anti-TIGIT antagonist antibody and administering one or more dosing cycles of a PD-1 axis binding antagonist, wherein said subject or population of subjects has no prior systemic treatment for HCC.

310. 309. Use according to embodiment 309, further comprising administering to said subject or population of subjects a VEGF antagonist.

311. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population with HCC One or more of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist to said subject or population of subjects.

312. Use according to embodiments 310 and 311, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

313. 313. Use according to any one of embodiments 309-312, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every three weeks.

314. 314. Use according to embodiment 313, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 800 mg every three weeks.

315. 315. Use according to any one of embodiments 309-314, wherein said anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 600 mg every three weeks.

316. 316. Use according to any one of embodiments 309-315, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg every three weeks.

317. 317. Use according to any one of embodiments 309-316, wherein said PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every three weeks.

318. Use according to embodiment 310 or 311, wherein said VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

319. 319. Use according to embodiment 318, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

320. 320. Use according to embodiment 319, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg or about 10.0 mg/kg every two weeks.

321. The use of any one of embodiments 309-311 and 318-320, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks.

322. Use according to any one of embodiments 309-311 and 318-321, wherein said PD-1 axis binding antagonist is administered at a dose of about 20 mg to about 1600 mg every two weeks.

323. Use according to embodiments 309-311, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks.

324. Use according to any one of embodiments 309-311 and 323, wherein said PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 4 weeks.

325. The use of any one of embodiments 309-311, 323, and 324, wherein said PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks.

326. 326. Use according to any one of embodiments 309-325, wherein said HCC is locally advanced or metastatic HCC.

327. 327. Use according to any one of embodiments 309-326, wherein said HCC is unresectable HCC.

328. 328. Use according to any one of embodiments 309-327, wherein said one or more subjects have been determined to have adequate liver function.

329. 329. Use according to embodiment 328, wherein said adequate liver function is characterized as Child-Pugh class A.

330. 329. Use according to any one of embodiments 309-329, wherein the HCC tumor sample obtained from said one or more subjects has been determined to have a detectable PD-L1 expression level.

331. 331. Use according to any one of embodiments 309-330, wherein said method comprises administering to said subject or subject population at least four dosing cycles.

332. 332. Use according to embodiment 331, comprising administering at least 16 dosing cycles to said subject or population of subjects.

333. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population with HCC, said method comprising administering tiragolumab at a dose of about 600 mg every 3 weeks, a dose of about 1200 mg every 3 weeks and one or more dosing cycles of bevacizumab at a dose of about 15 mg/kg every 3 weeks to said subject.

334. 334. Use according to any one of embodiments 311-333, wherein said one or more subjects have no prior systemic treatment for HCC.

335. 335. Use according to any one of embodiments 309-334, wherein said treatment results in a median PFS of said subject population of at least about 5.6 months to at least about 6.83 months.

336. 73. Use according to embodiment 72, wherein said cancer is bladder cancer.

337. 337. Use according to embodiment 336, wherein said bladder cancer is muscle invasive bladder cancer (MIBC).

338. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks. wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

339. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every 3 weeks. wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

340. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks. A use, including, wherein said treatment is a perioperative treatment.

341. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg every 3 weeks. wherein said treatment is a perioperative treatment.

342. Use according to embodiments 338-341, wherein said one or more subjects have a creatinine clearance of less than 60 mL/min.

343. 343. Use according to any one of embodiments 338-342, wherein said one or more subjects have a hearing loss of grade 2 or greater

344. 344. Use according to any one of embodiments 338-343, wherein said one or more subjects have grade 2 or greater neuropathy.

345. 345. Use according to any one of embodiments 338-344, wherein said one or more subjects have refused treatment with a platinum-based chemotherapeutic agent.

346. Use according to any one of embodiments 338 or 342-345, wherein said platinum-based chemotherapeutic agent is cisplatin.

347. 347. Use according to any one of embodiments 338-346, wherein said MIBC is surgically manipulable.

348. 348. Use according to embodiment 347, wherein said method further comprises surgery.

349. 349. Use according to embodiment 348, wherein at least one dosing cycle is initiated prior to said surgery.

350. 349. Use according to embodiment 348 or 349, wherein at least 1, 2, or 3 dosing cycles are completed prior to said surgery.

351. 351. Use according to any one of embodiments 348-350, wherein at least one dosing cycle is initiated between 4 and 6 weeks after said surgery.

352. Use according to embodiment 351, wherein 1-17 dosing cycles are completed after said surgery.

353. 353. Use according to any one of embodiments 348-352, wherein said surgery is cystectomy and/or lymphadenectomy.

354. 354. Use according to any one of embodiments 338-353, wherein said treatment results in a pathological complete response (pCR).

355. said treatment increases RFS time of said one or more subjects compared to baseline recurrence-free survival (RFS); increases EFS time of said one or more subjects compared to baseline disease-free survival (EFS); 355. Use according to any one of embodiments 338-354, resulting in an increase in OS time of said one or more subjects compared to OS.
356. 356. The use according to embodiment 355, comprising:
(a) said baseline RFS time is the median RFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline EFS time is the median EFS time of a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment containing a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
use.

357. 357. Use according to any one of embodiments 338-356, wherein said treatment results in a reduction in pathological extent.

358. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks. and wherein said subject is cisplatin ineligible.

359. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks. A use, including, wherein said treatment is a perioperative treatment.

360. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks , use wherein said subject is cisplatin ineligible.

361. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population for 3 weeks administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every three weeks and a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg every three weeks , the use wherein said treatment is a perioperative treatment.

362. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population about 30 mg and about 1200 mg every three weeks tiragolumab at a dose of between and one or more dosing cycles of atezolizumab at a dose of about 80 mg and about 1600 mg every 3 weeks, wherein said subject is cisplatin ineligible.

363. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population about 30 mg and about 1200 mg every three weeks and one or more dosing cycles of between about 80 mg and about 1600 mg of atezolizumab every three weeks, wherein said treatment is perioperative treatment.

364. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population about 600 mg every 3 weeks A dose of tiragolumab and one or more dosing cycles of atezolizumab at a dose of about 1200 mg every three weeks, wherein said one or more subjects are cisplatin ineligible.

365. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population about 600 mg every 3 weeks A dose of tiragolumab and one or more dosing cycles of a dose of atezolizumab of about 1200 mg every three weeks, wherein said treatment is perioperative treatment.

366. 366. Use according to any one of embodiments 338-365, wherein said treatment results in an ORR of the subject population of at least about 13.4% to about 15%.

367. 367. Use according to any one of embodiments 338-366, wherein said treatment results in a median OS for the subject population of at least about 7.9 months to about 8.6 months.

368. Use according to any one of embodiments 338-367, wherein detectable PD-L1 protein expression levels are determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142.

369. Embodiment 368, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction in which 5% or more of the tumor area is occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs) Use as described.

370. 337. Use according to embodiment 336, wherein the bladder cancer is urothelial carcinoma (UC).

371. 371. Use according to embodiment 370, wherein said UC is metastatic urothelial carcinoma (mUC).

372. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising about 30 mg and about 1200 mg every 3 weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks to said subject or population of subjects. use, including

373. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising about 300 mg and about 800 mg every 3 weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 900 mg and about 1500 mg every three weeks to said subject or population of subjects. use, including

374. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising about 30 mg and about 1200 mg every 3 weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks to said subject or population of subjects. and wherein said subject has no prior cancer immunotherapy.

375. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising about 30 mg and about 1200 mg every 3 weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks to said subject or population of subjects. and wherein said treatment is a second line treatment.

376. Use according to embodiments 372, 372 and 375, wherein said one or more subjects have not received prior cancer immunotherapy.

377. 375. Use according to any one of embodiments 372-374, wherein said treatment is a second line treatment.

378. 378. Use according to any one of embodiments 372-377, wherein said mUC progressed during or after platinum-containing therapy.

379. 379. According to any one of embodiments 372-378, further comprising administering a second dosing regimen to said subject or population of subjects after said one or more subjects experience disease progression or unacceptable toxicity. Use of.

380. 379. Use according to embodiment 379, wherein said second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).

381. 381. Use according to embodiment 380, wherein said ADC is (a) enfortumab vedotin or (b) suctuzumab govitecan.

382. (a) enfortumab vedotin administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (b) sactuzumab govitecan administered at 2 382. Use according to embodiment 381, administered at a dose of 10 mg/kg weekly for weekly on/weekly off.

383. (a) enfortumab vedotin at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle, or (b) suctuzumab govitecan at 10 mg/kg Use according to embodiment 381 or 382, wherein doses are administered 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 in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising about 30 mg and about 1200 mg every 3 weeks and one or more dosing cycles of a PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg every 3 weeks to said subject or population of subjects. use, including

385. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising administering to said subject or subject population about 30 mg every 3 weeks A use comprising administering a dosing regimen comprising one or more dosing cycles of tiragolumab at a dose of between about 1200 mg and atezolizumab at a dose of between about 80 mg and about 1600 mg every three weeks.

386. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with mUC, said method comprising administering to said subject or subject population for 3 weeks administration of one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks.

387. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having mUC, comprising administering to said subject or subject population a first dosing regimen and administering a subsequent second dosing regimen;
(a) said first dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks and PD-1 axis binding at a dose of between about 80 mg and about 1600 mg every 3 weeks; comprising one or more dosing cycles of the antagonist;
(b) said second dosing regimen comprises one or more dosing cycles of said PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks; (i) enfortumab vedotin; is administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (ii) suctuzumab govitecan is administered for 2 weeks on/1 week off administered at a dose of 10 mg/kg weekly during drug administration, wherein said second dosing regimen is administered to said subject or subject after said subject or subject population experiences disease progression or unacceptable toxicity during said first dosing regimen; A use administered to a target population.

388. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having mUC, comprising administering to said subject or subject population a first dosing regimen and administering a subsequent second dosing regimen;
(a) said first dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of between about 80 mg and about 1600 mg every 3 weeks; comprising one or more dosing cycles of
(b) said second dosing regimen comprises one or more dosing cycles of said PD-L1 binding antagonist at a dose between about 80 mg and about 1600 mg every three weeks; , 2 weeks on/1 week off, or (ii) suctuzumab govitecan administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off and the second dosing regimen is administered to the subject after the subject experiences disease progression or unacceptable toxicity during the first dosing regimen. use.

389. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or population of subjects with mUC, wherein said subject or population of subjects is administered a first dosing regimen followed by a second dosing regimen including doing
(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of 1200 mg about every 3 weeks;
(b) said second dosing regimen comprises one or more dosing cycles of about 1200 doses of atezolizumab every 3 weeks, and (i) enfortumab vedotin 2 weeks on/1 week off or (ii) suctuzumab govitecan administered at a dose of 10 mg/kg weekly for 2 weeks on/1 week off and wherein said second dosing regimen is administered to said subject after said subject experiences disease progression or unacceptable toxicity during said first dosing regimen.

390. 389. Use according to any one of embodiments 372-389, wherein said treatment results in an ORR of the subject population of at least about 13.4% to at least about 31%.

391. 391. Use according to any one of embodiments 372-390, wherein said treatment results in a median OS for the subject population of about 7.9 months to about 16.3 months.

392. 73. Use according to embodiment 72, wherein said cancer is pancreatic cancer.

393. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population having pancreatic cancer, said method comprising administering to said subject or subject population on Day 1 of each 28-day dosing cycle and Tiragolumab at a dose of about 420 mg on day 15, atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, and doses of about 1000 mg/m2 on days 1, 8 and 15 of each 28-day dosing cycle and one or more 28-day dosing cycles of nab-paclitaxel at a dose of about 125 mg/m2 on days 1, 8 and 15 of each 28-day dosing cycle.

394. 394. Use according to embodiment 392 or 393, wherein said pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. 395. Use according to embodiment 394, wherein said PDAC is a metastatic PDAC.

396. 396. Use according to any one of embodiments 392-395, wherein said one or more subjects have not received prior systemic therapy for metastatic PDAC.

397. 397. Use according to any one of embodiments 392-396, wherein said treatment results in an ORR of the subject population of at least about 41.7% to about 46.7%.

398. Any of embodiments 392-397, wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist Use as set forth in paragraph 1.

399. Use according to any one of embodiments 392-398, wherein said treatment results in a median PFS for the subject population of at least about 5.5 months to about 7 months.

400. 399. Use according to any one of embodiments 392-399, wherein said treatment results in a median OS for the subject population of at least about 8.5 months to about 10.6 months.

401. 73. Use according to embodiment 72, wherein said cancer is esophageal cancer.

402. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising: An anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of the cycle and one or more PD-1 axis binding antagonists at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle. administering to said subject or subject population a dosing regimen comprising a 21-day dosing cycle of

403. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising: anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of the cycle and one or more PD-1 axis binding antagonists at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle administering to said subject or subject population a dosing regimen comprising a 21-day dosing cycle of

404. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having esophageal cancer, said method comprising: one or more 21-day dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 30 mg and about 1200 mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 80 mg and about 1600 mg on day 1 of each dosing cycle to said subject or population of subjects, wherein said 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 in the manufacture of a medicament for a method for treating a subject or subject population having esophageal cancer, said method comprising: one or more 21-day dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 300 mg and about 800 mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900 mg and about 1500 mg on day 1 of each dosing cycle to said subject or population of subjects, wherein said subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. 404. Use according to embodiment 402 or 403, wherein said one or more subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. 407. Use according to any one of embodiments 404-406, wherein said one or more subjects have experienced disease progression or unacceptable toxicity during prior treatment.

408. 404. Use according to embodiment 402 or 403, wherein said 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. 409. Use according to embodiment 408, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses.

410. 409. Use according to any one of embodiments 404-409, wherein said platinum-based chemotherapeutic agent is cisplatin.

411. 411. Use according to embodiment 410, wherein cisplatin is administered at a dose of about 80 mg/m2 on day 1 of each dosing cycle.

412. Use according to any one of embodiments 404-411, wherein said non-platinum chemotherapeutic agent is an antimetabolite.

413. 413. Use according to embodiment 412, wherein said antimetabolite is 5-fluorouracil.

414. Use according to embodiment 413, wherein 5-fluorouracil is administered at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle.

415. Use according to any one of embodiments 404-414, wherein said esophageal cancer is advanced or metastatic esophageal cancer.

416. Use according to embodiments 402, 403, 408 and 409, wherein said one or more subjects have no prior treatment for metastatic esophageal cancer.

417. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with advanced or metastatic esophageal cancer, comprising 1 day of each dosing cycle anti-TIGIT antagonist antibody at a dose between about 30 mg and about 1200 mg in the eye, PD-1 axis binding antagonist at a dose between about 80 mg and about 1600 mg on day 1 of each dosing cycle, on day 1 of each dosing cycle One or more 21-day dosing cycles of a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 and a non-platinum-based chemotherapeutic agent at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle administering to a subject or population of subjects a dosing regimen comprising said platinum-based chemotherapeutic agent is omitted from said dosing regimen after six doses.

418. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising: or to the subject population, anti-TIGIT antagonist antibody at a dose of about 600 mg on day 1 of each dosing cycle, PD-1 axis binding antagonist at a dose of about 1200 mg on day 1 of each dosing cycle, day 1 of each dosing cycle A dosing regimen comprising one or more 21-day dosing cycles of cisplatin at a dose of about 80 mg/m2 on days 1-5 of each 21-day cycle and 5-fluorouracil at a dose of 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. wherein cisplatin is omitted from said dosing regimen after 6 doses.

419. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering to said subject or subject population each dosing cycle tiragolumab at a dose of about 600 mg on Day 1 of each dosing cycle, atezolizumab at a dose of about 1200 mg on Day 1 of each dosing cycle, cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle, and each 21-day cycle of administering a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of 800 mg/m2/24 hours on days 1-5; The method wherein cisplatin is omitted.

420. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having advanced or metastatic esophageal cancer, said subject or subject population comprising: administering a first dosing regimen and a second dosing regimen;
(a) the first dosing regimen comprises one or more 21-day dosing cycles of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of a PD-1 axis binding antagonist.

421. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method for treating a subject or subject population having advanced or metastatic esophageal cancer, said subject or subject population comprising: administering a first dosing regimen and a second dosing regimen;
(a) the first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 800 mg/m2/24 on days 1-5 of each 21-day cycle; one or more 21-day dosing cycles of an hourly dose of a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses;
(b) said second dosing regimen comprises a dose of the anti-TIGIT antagonist antibody between about 30 mg and about 1200 mg on day 1 of each dosing cycle and between about 80 mg and about 1600 mg on day 1 of each dosing cycle; one or more 21-day dosing cycles of a PD-1 axis binding antagonist.
422. Use of tiragolumab and atezolizumab in the manufacture of a medicament for a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein said subject or population of subjects comprises a first dosing regimen and a second administering a dosing regimen of
(a) said first dosing regimen comprises cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and a dose of 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle; 1 or more 21-day dosing cycles of 5-fluorouracil in which cisplatin is omitted from the dosing regimen after 6 doses;
(b) said second dosing regimen is one or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle; including, use.

423. Use according to any one of embodiments 402-422, wherein said treatment results in an ORR of the subject population of at least about 14%.

424. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (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);
HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). .

425. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
425. Use according to embodiment 424, further comprising FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The anti-TIGIT antagonist antibody has the following heavy chain variable region FRs:
FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is E or Q);
FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
425. The method of embodiment 424, further comprising 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. 427. The use according to embodiment 426, wherein X1 is E.

428. 427. The use according to embodiment 426, wherein X1 is Q.

429. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain according to (a) and (b) Use according to any one of embodiments 424-428, comprising a VL domain as described.

430. wherein said anti-TIGIT antagonist antibody:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19.

431. wherein said anti-TIGIT antagonist antibody:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19.

432. wherein said anti-TIGIT antagonist antibody:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:34,
The use according to any one of embodiments 424-427 and 429-431, comprising

433. Use according to any one of embodiments 424-432, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. Use according to any one of embodiments 424-433, wherein said anti-TIGIT antagonist antibody is a human antibody.

435. Use according to any one of embodiments 424-434, wherein the anti-TIGIT antagonist antibody is a full length antibody.

436. Use according to any one of embodiments 424-427 and 429-436, wherein the anti-TIGIT antagonist antibody is tiragolumab.

437. embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, wherein said anti-TIGIT antagonist antibody is tiragolumab, vivostolimab, etidilimab, EOS084448, SGN-TGT, or TJ-T6; 265 to 269, 286 to 288, 291, 292, 295, 296, 301 to 332, 336 to 361, 370 to 384, 387, 388, 401 to 418, 420, 421, and 424 to 436 Use as indicated.

438. 438. Use according to embodiment 437, wherein said anti-TIGIT antagonist antibody has intact Fc-mediated effector functions.

439. Use according to embodiment 437 or 438, wherein said anti-TIGIT antagonist antibody enhances Fc-mediated effector function.

440. The use according to any one of embodiments 437-439, wherein said anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288 wherein said anti-TIGIT antagonist antibody is domvanalimab, BMS-986207, ASP8374 or COM902 , 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421.

442. Use according to any one of embodiments 424-431 and 441, wherein said anti-TIGIT antagonist antibody has no Fc-mediated effector functions.

443. Use according to any one of embodiments 47-442, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. Use according to embodiment 443, wherein the IgG class antibody is an IgG1 subclass antibody.

445. 445. Use according to embodiment 444, wherein said anti-TIGIT antagonist antibody is tiragolumab, vibostolimab, etiglimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domvanalimab or BMS-986207.

446. Embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, wherein said IgG class antibody is an IgG4 subclass antibody , 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421.

447. 447. Use according to embodiment 446, wherein said anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. an antibody fragment wherein said anti-TIGIT antagonist antibody binds to TIGIT selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv) and (Fab')2 fragment 435. Use according to any one of embodiments 424-434, wherein the

449. Use according to any one of embodiments 424-448, wherein said anti-TIGIT antagonist antibody is a monospecific antibody.

450. Use according to any one of embodiments 424-448, wherein said anti-TIGIT antagonist antibody is a multispecific antibody.

451. 451. Use according to embodiment 450, wherein said multispecific antibody is a bispecific antibody.

452. 452. Use according to any one of embodiments 424-451, wherein said PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

453. 453. Use according to embodiment 452, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. 454. Use according to embodiment 453, wherein said PD-Ll binding antagonist inhibits binding of PD-Ll to one or more of its ligand binding partners.

455. 455. Use according to embodiment 454, wherein said PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

456. Use according to any one of embodiments 453-455, wherein said PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 , embodiment 456.

458. Use according to embodiment 457, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

459. The anti-PD-L1 antagonist antibody is a HVR that:
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 RHWPGGFDY (SEQ ID NO: 22);
an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);
457. The method of embodiment 456, comprising an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO:24); and a HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25).

460. wherein said anti-PD-L1 antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or (c) a VH domain according to (a) and (b) 460. The method of embodiment 459, comprising the described VL domains.

461. wherein said anti-PD-L1 antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:27,
460. The method of embodiment 460.

462. wherein said anti-PD-L1 antagonist antibody is:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:28; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:29,
462. The method of embodiment 461, comprising

463. Use according to any one of embodiments 459-462, wherein said anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. Use according to any one of embodiments 459-463, wherein said anti-PD-L1 antagonist antibody is a humanized antibody.

465. Use according to embodiment 463 or 464, wherein said anti-PD-L1 antagonist antibody is a full length antibody.

466. Embodiment 459, wherein said anti-PD-Ll antagonist antibody is an antibody fragment that binds PD-Ll selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv and (Fab')2 fragments. 464. Use according to any one of clauses 1-464.

467. Use according to any one of embodiments 459-465, wherein said anti-PD-L1 antagonist antibody is an IgG class antibody.

468. 468. Use according to embodiment 467, wherein the IgG class antibody is an IgG1 subclass antibody.

469. 453. Use according to embodiment 452, wherein said PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. 469. Use according to embodiment 469, wherein said PD-1 binding antagonist inhibits binding of PD-L to one or more of its ligand binding partners.

471. 471. Use according to embodiment 470, wherein said PD-1 binding antagonist inhibits binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. Use according to any one of embodiments 469-471, wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, canrelizumab, cintilimab, tislelizumab, tripalimab, dostarimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, gimberelimab, valsutilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, budicarimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21.

474. Use according to any one of embodiments 469-471, wherein said PD-1 binding antagonist is an Fc fusion protein.

475. 475. Use according to embodiment 474, wherein the Fc fusion protein is AMP-224.

476. of embodiments 80-112, 114-127 and 309-312, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population at a dose of between about 30 mg and about 1200 mg every three weeks. Use according to any one of the paragraphs.

477. Embodiments 51, 54, 60, 62, 63, 65-67, 80-112, 114-, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 600 mg every three weeks 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, Use according to any one of 388, 402-404, 417, 420, 421 and 476.

478. Embodiments 51, 54, 60, 62, 63, 65-67, 80, wherein said method comprises administering said anti-TIGIT antagonist antibody to a subject or population of subjects in graded doses based on said subject's body weight as follows: -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:
(a) is 15 kg or less and said anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks;
(b) greater than 15 kg and less than or equal to 40 kg and said anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 40 kg and said anti-TIGIT antagonist antibody is administered at about It is administered at a dose of 600 mg.

479. of embodiments 47, 48, 77, 78, 82, and 83, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every four weeks. Use according to any one of the paragraphs.

480. 479. The method of any one of embodiments 47, 48, 59, 67, 323, and 479, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 840 mg every four weeks. use.

481. The use of any one of embodiments 49, 50, and 104, comprising administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks.

482. Any one of embodiments 49, 50, 227, 251-253, 255, and 481, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 420 mg every two weeks. Use as described.

483. Use according to any one of embodiments 47-482, wherein the dose of said anti-TIGIT antagonist antibody is a fixed dose.

484. Embodiments 54, 62, 63, 65-67, wherein said method comprises administering to said subject or subject population a dose of between about 900 mg and about 1500 mg every three weeks of said PD-1 axis binding antagonist. , 80-109, and 27-2698.

485. Embodiments 54, 60, 62, 63, 65-67, 80-112, 114, wherein said method comprises administering said PD-1 axis binding antagonist to said subject at a dose of about 1200 mg every three weeks ~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.

486. Any of embodiments 47, 50, 80-109, and 324, wherein said method comprises administering said PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks to said subject or population of subjects. or the use described in paragraph 1.

487. Any one of embodiments 47, 50, 59, 67, 324, and 479, wherein said method comprises administering said PD-1 axis binding antagonist to said subject at a dose of about 1680 mg every 4 weeks Use as described.

488. Embodiments 48, 49, 80-109, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of between about 600 mg and about 1200 mg every two weeks, and 481. Use according to any one of clauses 481 to 481.

489. Any one of embodiments 48, 49, 80-109, 227, 251-253, and 481, comprising administering said PD-1 axis binding antagonist to said subject at a dose of about 840 mg every two weeks. Use as described in section.

490. 489. Use according to any one of embodiments 47-489, wherein the dose of said PD-1 axis binding antagonist is a fixed dose.

491. 62. Use according to embodiment 60 or 61, wherein said method comprises administering pembrolizumab to said subject at a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks.

492. 192. Use according to any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191, wherein each of said one or more dosing cycles is 21 days in length.

493. The use according to any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of said one or more dosing cycles is 28 days in length.

494. The use according to any one of embodiments 49, 80-109, and 309-311, wherein each of said one or more dosing cycles is 14 days in length.

495. 495. Any one of embodiments 47-494, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. Use of.

496. 496. Use according to any one of embodiments 47-495, comprising administering said PD-1 axis binding antagonist to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. .

497. Use according to embodiment 321 or 493, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles.

498. Use according to embodiment 321 or 493, comprising administering said PD-1 axis binding antagonist to said subject on about day 15 of each of said one or more dosing cycles.

499. The method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist prior to the anti-TIGIT antagonist antibody, or administering the anti-TIGIT antagonist antibody prior to the PD-1 axis binding antagonist. 498. Use according to any one of embodiments 47-498, comprising

500. 499. Use according to embodiment 499, wherein said method comprises a first observation period after administration of said PD-1 axis binding antagonist or said anti-TIGIT antagonist antibody.

501. 500. The use according to embodiment 500, wherein said first observation period is between about 30 minutes and about 60 minutes long.

502. Use according to embodiment 500 or 501, wherein said method comprises a second observation period after administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist.

503. 503. The use according to embodiment 502, wherein the second observation period is between about 30 minutes and about 60 minutes long.

504. 504. Use according to any one of embodiments 47-503, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects simultaneously with said anti-TIGIT antagonist antibody.

505. 505. Use according to any one of embodiments 47-504, comprising administering said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist to said subject or population of subjects intravenously.

506. Use according to embodiment 505, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or subject population by intravenous infusion over 30±10 minutes and/or 60±10 minutes. .

507. Use according to embodiment 505 or 506, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. .

508. Use according to any one of embodiments 47-114 and 116-507, wherein the PD-L1 expression level of a tumor sample obtained from said one or more subjects has been determined.

509. 509. Use according to embodiment 508, wherein said tumor sample obtained from said one or more subjects has been determined to have a detectable PD-L1 expression level.

510. 509. Use according to embodiment 509, wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level.

511. 511. Use according to embodiment 510, wherein said detectable PD-L1 protein expression level is determined by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

512. 512. Use according to embodiment 511, wherein said anti-PD-Ll antibody suitable for staining is anti-PD-Ll antibody SP263, SP142, 22C3 or 28-8.

513. 513. According to embodiment 511 or 512, wherein the detectable PD-L1 protein expression level is determined using the Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, Ventana SP142 IHC assay, or pharmDx 28-8 IHC assay. use.

514. Any of embodiments 47-109, 188, 220-265, and 307-423, wherein detectable PD-L1 protein expression levels as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 have been determined Use as set forth in paragraph 1.

515. Any one of embodiments 47-220, 265-338, and 370-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined Use as described.

516. Any one of embodiments 47-113, 136-187, and 220-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP22C3 has been determined Use as described.

517. According to any one of embodiments 47-114 and 116-423, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined. Use of.

518. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more tumor-associated immune cells (TIC) in said tumor sample.

519. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 5% or more and less than 20% TIC in said tumor sample.

520. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more TIC in said tumor sample.

521. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 20% or more TIC in said tumor sample.

522. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 10% or more and less than 50% TIC in said tumor sample.

523. 515. Use according to embodiment 514, wherein said detectable PD-L1 protein expression level is 50% or more TIC in said tumor sample.

524. Use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or greater.

525. Use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 30% or more.

526. Use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or more and less than 50% in said tumor sample. .

527. Use according to any one of embodiments 514, 516 and 517, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or more.

528. 516. Use according to embodiment 515, wherein said PD-L1 positive tumor cell fraction is the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC).

529. 516. Use according to embodiment 515, wherein the percentage of tumor area occupied by said PD-L1-expressing tumor-infiltrating IC is 1% or more.

530. 516. Use according to embodiment 515, wherein the percentage of tumor area occupied by said PD-L1-expressing tumor-infiltrating IC is 5% or more.

531. 517. Use according to embodiment 516, wherein said detectable PD-L1 protein expression level is a composite positive score (CPS) of 1 or more.

532. 517. Use according to embodiment 516, wherein said detectable PD-L1 protein expression level is 10 or more CPS.

533. 517. Use according to embodiment 516, wherein said detectable PD-L1 protein expression level is 20 or more CPS.

534. Use according to any one of embodiments 528-530, wherein said IHC assay is the Ventana SP142 IHC assay.

535. 509. Use according to embodiment 509, wherein said detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level.

536. said detectable PD-L1 nucleic acid expression level has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof; A use according to embodiment 535.

537. 424. Any of embodiments 47-423, wherein said treatment results in an increase in said subject's OS time compared to baseline overall survival (OS) and/or said subject's PFS time compared to baseline progression-free survival (PFS) or the use described in paragraph 1.

538. 538. The use according to embodiment 537, comprising:
(a) a subject whose baseline OS time has undergone 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 baseline PFS time is a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or an anti-PD-1 axis binding antagonist without a PD-1 axis binding antagonist. median PFS time in a subject population that has received treatment containing a TIGIT antagonist antibody;
peptide.

539. 229. According to any one of embodiments 52, 158 and 228, wherein said one or more chemotherapeutic agents is one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. use.

540. 539. Use according to embodiment 539, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. Use according to embodiments 69, 92, 127, 131, 249, and 540, wherein said carboplatin is administered at a dose sufficient to achieve AUC = 5 mg/ml/min or AUC = 6 mg/ml/min .

542. Use according to embodiments 69, 127, 162, 164, 166, 168 and 540, wherein said cisplatin is administered at a dose of about 75 mg/m2 or 80 mg/m2.

543. 543. Use according to any one of embodiments 539-542, wherein said one or more non-platinum chemotherapeutic agents are antimetabolites, taxanes or topoisomerase II inhibitors.

544. Use according to any one of embodiments 62, 173, 174, and 543, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. Use according to any one of embodiments 69, 127, 162 and 544, wherein said pemetrexed is administered at a dose of about 500 mg/m2.

546. Use of any one of embodiments 63, 64, 162, 398, and 544, wherein said gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.

547. 545. Use according to embodiment 544, wherein said antimetabolite is capecitabine.

548. Use according to embodiment 544 or 547, wherein said capecitabine is administered at a dose of about 1250 mg/m2.

549. The use according to any one of embodiments 173, 174, 229, 230, 239, 240 and 543-548, wherein said taxane is paclitaxel or nab-paclitaxel.

550. 549. Use according to any one of embodiments 69, 162, and 549, wherein said paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.

551. Use according to any one of embodiments 63, 64, 249, 398, and 549, wherein said nab-paclitaxel is administered at a dose of about 100 mg/m2.

552. Embodiments 80-91, 229, 230, 239, 241, 251- wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331 255, and use according to any one of 543-551.

553. 553. Use according to any one of embodiments 69, 92, and 552, wherein said etoposide is administered at a dose of about 100 mg/m2.

554. each of said one or more chemotherapeutic agents once every week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, every four weeks Use according to any one of embodiments 543-553, administered twice, or three times every four weeks.

555. 555. Use according to any one of embodiments 543-554, wherein said one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.

556. 556. Use according to any one of embodiments 544-555, wherein said gemcitabine is administered three times every four weeks.

557. 556. Use according to any one of embodiments 544-556, wherein said gemcitabine is administered on days 1, 8 and/or 15 of one or more dosing cycles.

558. The use according to any one of embodiments 544-557, wherein said capecitabine is administered daily every two weeks.

559. Use according to any one of embodiments 544-558, wherein said capecitabine is administered on days 1-14 of one or more dosing cycles.

560. 559. Use according to any one of embodiments 549-559, wherein said nab-paclitaxel is administered three times every four weeks.

561. 561. Use according to any one of embodiments 549-560, wherein said nab-paclitaxel is administered on days 1, 8 and/or 15 of one or more dosing cycles.

562. 562. Use according to any one of embodiments 552-561, wherein said etoposide is administered on days 1-3 every 3 weeks.

563. 563. Use according to any one of embodiments 552-562, wherein said etoposide is administered on days 1-3 of one or more dosing cycles.

564. 564. Use according to any one of embodiments 543-563, wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

565. 564. Use according to any one of embodiments 543-564, wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

566. 566. Use according to any one of embodiments 543-565, wherein said one or more chemotherapeutic agents are administered intravenously or orally.

567. Use according to any one of embodiments 65, 310, and 311, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

568. Use according to embodiment 312 or 567, wherein said VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every three weeks.

569. Use according to embodiment 318 or 568, wherein said VEGF antagonist is administered at a dose of about 15 mg/kg every three weeks.

570. Use according to any one of embodiments 65, 310-312, 318-320, and 567-569, wherein said VEGF antagonist is an anti-VEGF antibody.

571. 571. Use according to embodiment 570, wherein said anti-VEGF antibody comprises the VH and VL domains of bevacizumab.

572. Use according to embodiment 570 or 571, wherein said anti-VEGF antibody is bevacizumab.

573. according to any one of embodiments 65, 310-312, and 318-320, wherein said anti-TIGIT antagonist antibody is tiragolumab, said PD-1 axis binding antagonist is atezolizumab, and said VEGF antagonist is bevacizumab use.

574. Any one of embodiments 65, 310-312, 318-320, and 567-573, wherein said use comprises administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles. Use of.

575. 321. Use according to any one of embodiments 318-320, wherein said method comprises administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles.

576. Use according to any one of embodiments 65, 310-312, and 318-320, and 567-575, wherein said VEGF antagonist is administered intravenously.

577. 577. Use according to embodiment 576, wherein said VEGF antagonist is administered to said subject by intravenous infusion over 90±15 minutes.

578. Embodiment 65, 310-312, wherein said use comprises administering said PD-1 axis binding antagonist prior to said VEGF antagonist and administering said VEGF antagonist prior to said anti-TIGIT antagonist antibody to said subject , 318-320, and 567-577.

579. 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. 578. The use according to embodiment 578, comprising:

580. 579. The use according to 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 long.

581. Embodiments 113, 128, 129-131, 175-182, 210-214, 221, 256, 257, 270, 289, 290, 293, 294, 297, wherein said tiragolumab and atezolizumab are combined in an IV bag prior to administration , 298, 333, 362-365, 385, 386, 389, 393, 419, and 422.

582. Use according to any one of embodiments 47-581, wherein said subject is a human.

583. Use according to any one of embodiments 47-582, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

584. Use according to any one of embodiments 47-582, wherein said anti-TIGIT antagonist antibody and said 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, these descriptions and examples should not be construed as limiting the scope of the invention. do not have. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims (503)

A method of treating a subject with cancer, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a dose of about 900 mg to about 1500 mg every three weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. A method of treating a subject with cancer, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and PD at a dose of about 1400 mg to 2000 mg every 4 weeks. - A method comprising administering a dosing regimen comprising one or more dosing cycles of a monoaxial binding antagonist. A method of treating a subject with cancer, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a dose of about 600 mg to about 1200 mg every two weeks. administering a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist. 4. The method of claim 2 or 3, wherein said method further comprises administering one or more chemotherapeutic agents to said subject. A method according to any one of claims 1 to 4, wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO:3);
(d) a 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).
The method according to any one of claims 1 to 5, comprising The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and (d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and the following heavy chain variable region FRs:
(a) FR-H1 comprising the amino acid sequence of X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where 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).
The method of any one of claims 1-6, further comprising The anti-TIGIT antagonist antibody is
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or (c) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18. , comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19. The method of any one of claims 1-8, wherein the anti-TIGIT antagonist antibody is tiragolumab. The method of any one of claims 1-9, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist. The method of any one of claims 1-10, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody. The method of any one of claims 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 13. The method of claim 12. 14. The method of any one of claims 1-13, wherein the PD-1 axis binding antagonist is atezolizumab. The method of any one of claims 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, camrelizumab, cintilimab, tislelizumab, tripalimab, dostarlimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, Jimverelimab, Valsutilimab, Genolimuzumab, BI754091, Cetrelimab, YBL-006, BAT1306, HX008, Budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21. 17. The method of any one of claims 2-16, wherein said method comprises administering to said 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 said non-platinum chemotherapeutic agent is a topoisomerase II inhibitor. 19. The method of claim 18, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331, especially etoposide. 20. The method of claim 18 or 19, wherein said topoisomerase II inhibitor is administered at a dose of 100 mg/ ^m2 . A method according to any one of claims 17 to 20, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin, especially carboplatin. 22. The method of any one of claims 17-21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration. 23. The method of any one of claims 1-22, wherein the method comprises a dosing regimen comprising an induction phase and a maintenance phase. wherein the induction phase comprises four initial dosing cycles, 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; 24. The method of claim 23, wherein 25. The method of claim 23 or 24, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent and/or non-platinum-based chemotherapeutic agent. 26. The method of any one of claims 1-25, wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody. 27. The method of any one of claims 1-26, wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody. 28. The method of any one of claims 1-27, wherein the cancer is lung cancer. 29. The method of claim 28, wherein said lung cancer is small cell lung cancer (SCLC), in particular extensive-stage SCLC (ES-SCLC). 29. The method of claim 28, wherein said lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC). 29. The method of claim 28, wherein said lung cancer is locally advanced unresectable or metastatic non-squamous NSCLC. 29. The method of claim 28, wherein said lung cancer is resectable lung cancer. 28. The method of any one of claims 1-27, wherein the cancer is cervical cancer. 28. The method of any one of claims 1-27, wherein the cancer is early triple negative breast cancer (eTNBC). 28. The method of any one of claims 1-27, wherein the cancer is head and neck cancer. A method according to any one of claims 1 to 27, wherein said cancer is liver cancer, in particular hepatocellular carcinoma (HCC). 28. The method of any one of claims 1-27, wherein the cancer is bladder cancer. 38. A method according to claim 37, wherein said cancer is urothelial carcinoma (UC), in particular metastatic urothelial carcinoma (mUC). A method according to any one of the preceding claims, wherein said cancer is pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC). Method according to any one of the preceding claims, wherein said cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer. A kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject with cancer according to the method of any one of claims 1-40. 42. The kit of Claim 41, wherein said kit further comprises one or more chemotherapeutic agents. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with cancer, said method being any one of claims 1-40, Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject with cancer in combination with a PD-1 axis binding antagonist, said treatment being a method according to any one of claims 1-40. is due to use. 45. Use according to claim 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations. 45. Use according to claim 44, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single formulation. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis at a dose of about 1400 mg to 2000 mg every 4 weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis at a dose of about 600 mg to about 1200 mg every two weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a binding antagonist. 49. The method of claim 47 or 48, wherein said method further comprises administering one or more chemotherapeutic agents to said subject. 50. The method of claim 49, wherein said method comprises administering a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent to said subject. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, PD-1 axis at a dose of about 900 mg to about 1500 mg every three weeks. administering to said subject a dosing regimen comprising one or more dosing cycles comprising a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. 52. The method of claim 50 or 51, wherein said method comprises an induction phase and a maintenance phase. 53. The method of claim 52, wherein the induction phase and maintenance phase each comprise one or more dosing cycles. 54. The method of claim 52 or 53, wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent. The method of any one of claims 52-54, wherein said maintenance phase does not include administration of said non-platinum chemotherapeutic agent. said maintenance phase comprising one or more dosing cycles of the anti-TIGIT antagonist antibody at doses of about 700 mg to about 1000 mg every 4 weeks and the PD-1 axis binding antagonist at doses of about 1400 mg to 2000 mg every 4 weeks; 56. The method of claim 55. A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and an anti-PD- administering to said subject a dosing regimen comprising one or more dosing cycles of an antagonist antibody, wherein said anti-PD-1 antagonist antibody is pembrolizumab. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein said pembrolizumab is administered about every 6 weeks. The method, administered at a dose of 300 mg to about 500 mg. A method for treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks for 2 weeks on/1 week off for 3 weeks. PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, and one or more antimetabolites at a dose of about 10 mg/m ² to about 10000 mg/m ² orally twice daily every 3 weeks. administering to said subject a dosing regimen comprising a dosing cycle of A method of treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, PD-1 axis at a dose of about 900 mg to about 1500 mg every three weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of the binding antagonist, gemcitabine and nab-paclitaxel. 50. The method of claim 49, wherein said one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel. A method for treating a subject with cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose between about 500 mg and about 700 mg every three weeks, between about 900 mg and about 1500 mg every three weeks. administering to said subject a dosing regimen comprising a dose of a PD-1 axis binding antagonist and one or more dosing cycles of a VEGF antagonist at a dose between about 1 mg/kg and about 35 mg/kg every three weeks. ,Method. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase,
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding antagonist every 3 weeks and a non-platinum chemotherapeutic agent every 3 weeks; The maintenance period does not include administration of the platinum-based chemotherapeutic agent,
Method. A method of treating a subject with cancer, said method comprising administering to said subject a dosing regimen comprising an induction phase and a maintenance phase,
(a) the induction phase comprises an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, platinum-based every 3 weeks; chemotherapeutic agents, and one or more dosing cycles of non-platinum chemotherapeutic agents every 3 weeks;
(b) said maintenance phase comprises one or more additions of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks; comprising a dosing cycle, wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent;
Method. 65. The method of any one of claims 53-56, 63, and 64, wherein the induction phase comprises 4-6 dosing cycles. (a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel, or (c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum-based chemotherapeutic agent is etoposide,
The method of any one of claims 50-56 and 63-65. 67. The method of any one of claims 47-66, wherein said cancer is a solid tumor. 68. The method of any one of claims 47-67, wherein the cancer is locally advanced or metastatic. the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, renal cancer, 69. The method of any one of claims 47-68, which is melanoma or ovarian cancer. 70. The method of claim 69, wherein said cancer is lung cancer. 71. The method of claim 70, wherein said 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. 71. The method of claim 70, wherein said lung cancer is small cell lung cancer (SCLC). A method of treating a subject or population of subjects having lung cancer, said method comprising administering an effective amount of 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. said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor, wherein said treatment comprises administering to said subject or subject population in a dosing regimen comprising cycles, wherein said treatment is without said anti-TIGIT antagonist antibody. A method of prolonging progression-free survival (PFS) of said subject compared to treatment with an agent. A method of treating a subject population with lung cancer, said method 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. administering to said subject population with a dosing regimen comprising: said treatment resulting in a median PFS of said subject population of from about 8.2 months to about 9.2 months. said treatment compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody, overall survival of said subject or subject population ( OS) is extended. wherein said treatment reduced PFS of said subject or subject population 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; 80. The method of any one of claims 77-79, extending. said treatment reduces said PFS of said subject or subject population at least as compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody 81. The method of claim 80, extending from about 3 months to about 4 months. A method of treating a subject or population of subjects having lung cancer, said method comprising administering an effective amount of 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. said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor, wherein said treatment comprises administering to said subject or subject population in a dosing regimen comprising cycles, wherein said treatment is without said anti-TIGIT antagonist antibody. A method of prolonging OS in said subject compared to treatment with an agent. A method of treating a subject population with lung cancer, said method 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. administering to said subject population with a dosing regimen comprising: said treatment resulting in a median OS of said subject population of from about 15.3 months to about 17.6 months. said treatment reduces the OS of said subject or subject population 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; 84. The method of any one of claims 79-83, extending. Said treatment reduced the OS of said subject or subject population by at least about 3 months to about 5. The method of any one of claims 79-83, extended for 3 months. 86. 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. described method. 87. 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 following the fourth initial dosing cycle. the method of. 88. The method of claim 87, wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of said one or more additional dosing cycles. 89. The method of any one of claims 77-88, wherein said platinum-based chemotherapeutic agent is carboplatin and said topoisomerase II inhibitor is etoposide. 90. The method of any one of claims 77-89, wherein said lung cancer is small cell lung cancer (SCLC). 91. The method of claim 90, wherein the SCLC is extensive SCLC (ES-SCLC). 92. The method of claim 91, wherein said subject(s) is treatment naive for ES-SCLC. 93. The method of any one of claims 77-92, wherein said subject(s) has no presence or history of brain metastases. 94. The method of any one of claims 77-93, wherein said lung cancer is not selected for PD-Ll expression. 94. The method of any one of claims 77-93, wherein said lung cancer is selected for PD-Ll expression. 96. The method of claim 95, wherein said lung cancer is selected for PD-L1 expression by a detectable level of PD-L1 expression. 97. The method of any one of claims 77-96, wherein said lung cancer is metastatic. 98. The method of claim 97, wherein said lung cancer has metastasized to the brain, liver, lymph nodes and/or adrenal glands. 99. The method of claim 97 or 98, wherein said lung cancer has never metastasized to the brain. 99. The method of any one of claims 77-99, wherein said treatment results in a complete response (CR) or partial response (PR). A method for treating a subject or subject population with SCLC, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 900 mg to about 1500 mg, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and on Days 1, 2, and 2 of each dosing cycle. atezolizumab comprising administering to said subject or subject population one or more 21-day dosing cycles of etoposide at a dose of 100 mg/ ^m2 on each of day 3, wherein said treatment is without said anti-TIGIT antagonist antibody. , prolonging PFS and/or OS of said subject or subject population compared to treatment with carboplatin and etoposide. A method for treating a subject or subject population with ES-SCLC, said method administering to said subject or subject population four initial dosing cycles followed by one or more additional dosing cycles. including
(a) the four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, and 1 of each initial dosing cycle; Carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 and etoposide at a dose of 100 mg/m2 on each of Days 1, 2 and ³ of each initial dosing cycle. administering
(b) said one or more additional dosing cycles administering a dose of about 600 mg tiragolumab on day 1 of each additional dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each additional dosing cycle; including
each of the four initial dosing cycles and the one or more additional dosing cycles is a 21-day dosing cycle, and the treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without the tiragolumab; A method of prolonging PFS and/or OS of a subject or subject population. 1. A method of treating a subject or population of subjects having lung cancer, said method comprising: an anti-TIGIT antagonist antibody; a PD-1 axis binding antagonist; a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent; administering to said subject or population of subjects a dosing regimen comprising one or more dosing cycles of a second chemotherapeutic agent that is a therapeutic agent. 104. The method of claim 103, wherein said lung cancer has not been evaluated for PD-L1 expression. 105. The method of claim 103 or 104, wherein said subject(s) have not been determined to have a PD-L1 positive tumor cell fraction of 50% or greater. 106. The method of claim 105, wherein said subject(s) 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 said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, said anti-PD-L1 antibody being SP263 or 22C3. 108. The method of any one of claims 103-107, wherein said subject(s) does 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 said subject(s) has never received prior systemic therapy for said lung cancer. 110. The method of any one of claims 103-109, wherein said lung cancer is locally advanced lung cancer. A method according to any one of claims 103 to 110, wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic non-squamous NSCLC. 112. The method of claim 111, wherein said non-squamous NSCLC is stage IV non-squamous NSCLC. The dosing regimen comprises an induction phase comprising four dosing cycles, 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 in the induction phase 113. The method of any one of claims 103-112, administered on day 1 of each dosing cycle of. wherein said dosing regimen comprises a maintenance phase following said induction phase, said maintenance phase comprising one or more dosing cycles, said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist and said non-platinum chemotherapeutic agent 114. The method of claim 113, wherein is administered on Day 1 of each dosing cycle of said maintenance phase. 115. The method of claim 114, wherein said one or more dosing cycles of said maintenance phase do not include administration of said 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. A method of treating a subject or subject population with advanced non-squamous NSCLC, said method comprising administering to said subject or subject population four 21-day dosing cycles of tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed. wherein on day 1 of each of said four 21-day dosing cycles said tiragolumab is administered at a dose of about 600 mg every 3 weeks and said atezolizumab is administered at a dose of about 1200 mg every 3 weeks and said carboplatin is administered every 3 weeks at a dose sufficient to achieve AUC = 5 mg/ml/min or said cisplatin is administered at a dose of 75 mg/ ^m2 every 3 weeks , wherein said pemetrexed is administered at a dose of about 500 mg/m ² every 3 weeks. 1. A method of treating a subject or subject population having advanced non-squamous NSCLC, said method comprising:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 weeks and (ii) tiragolumab at a dose of about 600 mg every 3 ^weeks , atezolizumab at a dose of about 1200 mg every 3 weeks, and every 3 weeks. one or more maintenance dosing cycles of pemetrexed at a dose of about 500 mg/ ^m2 , wherein said one or more 21-day maintenance dosing cycles do not include administration of carboplatin including
The method, wherein said subject or subject population has not received prior systemic therapy for said advanced non-squamous NSCLC. 119. The method of any one of claims 103-118, wherein said treatment prolongs PFS of said subject or population of subjects by at least about 3.5 months or about 4.7 months. 119. The method of any one of claims 103-118, wherein said treatment results in a median PFS for said subject population of about 12.5 months to about 14.7 months. 119. The method of any one of claims 103-118, wherein said treatment prolongs OS of said subject or population of subjects by at least about 5.5 months or about 8.0 months. 119. The method of any one of claims 103-118, wherein said treatment results in a median OS for said subject population of from about 27.5 months to about 32.0 months. A method for treating a subject with resectable lung cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and a dose of about 900 mg to about 1500 mg every three weeks. administering to said subject one or more dosing cycles of a PD-1 axis binding antagonist of. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, at least one of said anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and said PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks as a neoadjuvant treatment. A method comprising administering to a subject. at least one of said dosing cycles comprises, as an adjuvant treatment, said anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and said PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks; 125. The method of claim 124, comprising administering to said subject a dose. 126. The method of claim 124 or 125, wherein said 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, IIIA or IIIB lung cancer. The method of any one of claims 123-128, wherein the subject is eligible for R0 resection with curative intent. 130. The method of any one of claims 123-129, wherein the subject has no prior treatment for lung cancer. 131. The method of claim 130, wherein said prior treatment is immunotherapy, chemotherapy, or radiation therapy. The method of any one of claims 123-131, wherein said subject is eligible to undergo 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 said surgery. 135. The method of claim 133 or 134, wherein four dosing cycles are completed prior to said 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 said surgery. 138. The method of any one of claims 133-137, wherein the surgery is segmentectomy, lobectomy, bilobectomy, or pneumonectomy. The method of any one of claims 123-138, wherein said method further comprises radiotherapy. 140. The method of claim 139, wherein said radiation therapy is postoperative radiation therapy. 141. The method of any one of claims 123-140, further comprising administering one or more chemotherapeutic agents. 142. The method of claim 141, wherein said one or more chemotherapeutic agents are administered post-operatively. 143. The method of claim 142, wherein said one or more chemotherapeutic agents are administered in four dosing cycles after said surgery. 144. The method of any one of claims 141-143, wherein said one or more chemotherapeutic agents are platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents. (a) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine;
(c) the platinum-based chemotherapeutic agent is carboplatin, and the non-platinum-based chemotherapeutic agent is paclitaxel;
(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or (e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. 145. The method of claim 144, wherein 146. The method of any one of claims 123-145, wherein said treatment results in an increase in MPR rate as compared to baseline significant pathologic response (MPR) rate. The reference MPR rate is
MPR rates in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel and bevacizumab 147. The method of claim 146, wherein 148. The method of any one of claims 123-147, wherein said treatment results in a pathological complete response (pCR) and/or an increase in pCR rate compared to a baseline pCR rate. The reference pCR rate is
pCR rates in subject populations who have received (a) treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, and/or (b) treatment with cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab 149. The method of claim 148, wherein 149. The method of any one of claims 123-149, wherein said treatment results in an increase in EFS compared to baseline symptom-free survival (EFS) time. the reference EFS time,
EFS time in subject populations who have received (a) treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody and/or (b) treatment comprising cisplatin and docetaxel or cisplatin, docetaxel and bevacizumab 151. The method of claim 150, wherein A method for treating a subject with resectable lung cancer, said method comprising administering to said subject tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks;
(a)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or 6 mg/mL/min every 3 weeks, or (ii) a dose of about 75 mg/ ^m2 every 3 weeks cisplatin, and
(b)
(i) pemetrexed at a dose of about 500 mg/ ^m2 every 3 weeks, or gemcitabine at a dose of about 1000 mg/ ^m2 or about 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle, or (ii) paclitaxel at a dose of about 175 mg/ ^m2 or about 200 mg/ ^m2 every 3 weeks;
A method comprising administering one or more dosing cycles of 1. A method for treating a subject with lung cancer, said method comprising administering to said subject one or more dosing cycles of tiragolumab and atezolizumab,
(I) at least one of said dosing cycles is a neoadjuvant treatment, wherein said subject comprises:
(a) tilacolumab at a dose of about 1200 mg every 3 weeks;
(b) atezolizumab at a dose of about 1200 mg every 3 weeks as a neoadjuvant treatment;
(c)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/ ^m2 on days 1 and 8 of each dosing cycle;
(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/ ^m2 or about 200 mg/ ^m2 every 3 weeks, or (iii) ) administering cisplatin at a dose of about 75 mg/ ^m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/ ^m2 on days 1 and 8 of each dosing cycle;
(II) at least one of said dosing cycles administering tiragolumab at a dose of about 500 mg to about 700 mg every 3 weeks and atezolizumab at a dose of about 900 mg to about 1500 mg every 3 weeks as an adjuvant treatment; including,
Method. 154. The method of any one of claims 123-153, wherein detectable PD-L1 protein expression levels are determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263. 155. The method of claim 154, wherein the detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or greater. The method of any one of claims 70, 103-110, and 123-155, wherein said lung cancer is NSCLC. 157. The method of claim 156, wherein said NSCLC is squamous NSCLC. 157. The method of claim 156, wherein said NSCLC is non-squamous NSCLC. 70. The method of claim 69, wherein said cancer is cervical cancer. A method for treating a subject or subject population having cervical cancer with detectable levels of PD-L1 expression, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks. and administering to said subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks. A method of selecting treatment for a subject with cervical cancer, comprising:
(a) detecting protein expression levels of PD-L1 on tumor cells from a tumor sample of said subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - anti-TIGIT antagonist antibody administered every three weeks at a dose of about 500 mg to about 700 mg and about 900 mg to about 1500 mg for said subject with L1 expression levels, based on detected PD-L1 expression on tumor cells A method comprising selecting a treatment comprising one or more dosing cycles of a PD-1 axis binding antagonist administered every three weeks at a dose of 162. The method of claim 160 or 161, wherein said cervical cancer is squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma. 163. The method of any one of claims 160-162, wherein said cervical cancer is stage IVB, metastatic, recurrent or persistent. 164. The method of any one of claims 160-163, wherein said cervical cancer is metastatic and/or recurrent PD-L1 positive cervical carcinoma. 165. The method of any one of claims 160-164, wherein said subject(s) has received at least one prior treatment. 166. The method of any one of claims 160-165, wherein said subject(s) has received two prior treatments. 167. The method of any one of claims 160-166, wherein said subject(s) has never had 3 or more prior treatments. 165. The method of any one of claims 160-164, wherein said subject(s) has no prior treatment. 169. The method of any one of claims 165-168, wherein said prior treatment is chemotherapy, surgery and/or radiotherapy. The method of any one of claims 160 and 162-169, wherein said treatment results in a clinical response. 171. The method of claim 170, wherein said clinical response is an increase in ORR in said subject population compared to a baseline objective response rate (ORR). 172. The method of claim 171, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. 171. The method of claim 170, wherein the reference ORR is at least about 14.6% to about 26%. 171. The method of claim 170, wherein said clinical response is CR or PR. wherein said clinical response is increased in said subject's PFS compared to baseline progression-free survival (PFS) time, increased in said subject's DOR compared to baseline duration of response (DOR) time, or baseline overall survival (OS) time 175. The method of any one of claims 170-174, wherein the subject's OS is increased compared to (a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment containing a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
176. The method of claim 175. A method for treating a subject having cervical cancer with detectable levels of PD-L1 expression, said method comprising administering to said subject tiragolumab at a dose of about 600 mg every 3 weeks and administering one or more dosing cycles of atezolizumab at a dose of about 1200 mg. 178. The method of any one of claims 160-177, wherein said subject is identified as likely to benefit from said treatment based on detected PD-Ll expression on tumor cells. The method of any one of claims 160-178, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263. 179. The method of any one of claims 160-179, wherein the detectable PD-Ll expression level is 5% or more tumor-associated immune cells (TIC) in a sample from the subject. The method of any one of claims 160-178, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody 22C3. 179. The method of any one of claims 160-179, wherein the detectable PD-Ll expression level is a composite positive score (CPS) of 1 or more in a sample from the subject. 70. The method of claim 69, wherein said cancer is breast cancer. A method of treating a subject or subject population having breast cancer, comprising tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and about 100 mg/ml for 3 weeks on/1 week off. administering to said subject or subject population a dosing regimen comprising one or more dosing cycles of ^two doses of nab-paclitaxel. 185. The method of claim 183 or 184, wherein said breast cancer is triple negative breast cancer (TNBC). 186. The method of claim 185, wherein said TNBC is unresectable locally advanced or metastatic TNBC. 187. The method of any one of claims 183-186, wherein said subject(s) has no prior systemic therapy for metastatic breast cancer. 188. The method of any one of claims 183-187, wherein said treatment results in an ORR of said subject population of at least about 53% to at least about 67.5%. The method of any one of claims 183-188, wherein said treatment results in a median OS for said subject population of about 25.0 months. A method of treating a subject with early triple-negative breast cancer (eTNBC), said method comprising an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a dose of about 600 mg to 1200 mg every two weeks. administering to said subject a dosing regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist of. 191. The method of claim 190, further comprising administering one or more chemotherapeutic agents to said subject. 192. The method of claim 191, wherein said one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent. The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a taxane, or a taxane and a platinum-based chemotherapeutic agent, and (b) the anti-TIGIT One dose of an antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) 191. The method of claim 190, further comprising administering the following dosing cycles. 194. The method of claim 192 or 193, wherein said alkylating agent is cyclophosphamide. 195. The method of claim 194, wherein said cyclophosphamide is administered at a dose of about 600 mg/ ^m2 . 196. The method of any one of claims 190-192, 194, and 195, wherein said method further comprises administering G-CSF or GM-CSF to said subject. 197. The method of claim 193 or 196, wherein said G-CSF is pegfilgrastim or filgrastim. 198. The method of claim 197, wherein said G-CSF is pegfilgrastim. 199. The method of claim 198, wherein said pegfilgrastim is administered at a dose of about 6 mg. of claims 191, 192 and 194-199, wherein said method further comprises administering said one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF to said subject. A method according to any one of paragraphs. Claims 191, 192 and 194- wherein said 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 200. The method according to any one of clauses 200 to 200. The platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF Or the method of any one of claims 192-201, wherein GM-CSF is administered every two weeks. 203. The method of any one of claims 192-202, wherein said taxane, or said taxane and said platinum-based chemotherapeutic agent are administered for the first 12 weeks of said dosing regimen. 204. any one of claims 192-203, wherein said topoisomerase II inhibitor, said alkylating agent, and said G-CSF or GM-CSF are administered during weeks 13 through 19 of said dosing regimen described method. The method of any one of claims 190-204, wherein the total length of said dosing regimen is 19 weeks. The method of any one of claims 190-205, wherein said method is neoadjuvant treatment. 207. The method of any one of claims 190-206, wherein said dosing regimen is followed by surgery. 208. The method of claim 207, wherein said surgery is performed between 2 and 6 weeks after the last administration of said dosing regimen. 209. The method of claim 207 or 208, wherein said surgery comprises a mastectomy. The method of any one of claims 207-209, wherein said surgery comprises axillary lymph node surgery. The method of any one of claims 192-210, wherein said topoisomerase II inhibitor is doxorubicin. 211. 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 of claim 211 or 212, wherein doxorubicin is administered at a dose of about 60 mg/ ^m2 . A method of treating a subject with eTNBC, said method comprising tiragolumab at a dose of about 420 mg every two weeks and atezolizumab at a dose of about 840 mg every two weeks;
(a)
(i) nab-paclitaxel at a dose of about 125 mg/m ² weekly and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks over the first 12 weeks of said dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/ ^m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/ ^m2 every 2 weeks, and every 2 weeks for weeks 13 through 19 of the dosing regimen; G-CSF or GM-CSF of, or (b)
(i) nab-paclitaxel at a dose of about 125 mg/ ^m2 weekly for the first 12 weeks of the dosing regimen, and (ii) about 60 mg/ ^m2 every two weeks for weeks 13-19 of the dosing regimen. doxorubicin at a dose of , cyclophosphamide at a dose of about 600 mg/m ² every 2 weeks, and G-CSF or GM-CSF every 2 weeks
administering to said subject with a dosing regimen comprising
The method further comprising surgery between 2 weeks and 6 weeks after the last administration of the dosing regimen. 215. The method of any one of claims 184-214, wherein the detectable PD-Ll protein expression level in a tumor sample from said subject is determined by an IHC assay comprising staining with the anti-PD-Ll antibody SP142. . 216. The method of claim 215, wherein the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC) in said tumor sample is 1% or more. 217. The method of any one of claims 190-216, wherein said eTNBC is T2-4d TNBC at presentation. 218. The method of any one of claims 190-217, wherein the eTNBCs are cT2-cT4, cN0-cN3, and cM0 TNBCs when presented. The method of any one of claims 190-218, wherein the subject has no previous treatment for eTNBC. The method of any one of claims 190-219, wherein said treatment results in a pathological complete response (pCR). 221. The method of any one of claims 190-220, wherein said treatment results in increased overall survival (OS) or symptom-free survival (EFS). 70. The method of claim 69, wherein said cancer is 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). 3. A method for treating a subject or subject population having SCCHN with detectable PD-L1 expression levels, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks; administering to said subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg weekly. A method of selecting a treatment for a subject or subject population with SCCHN, comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject or subject population by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) detectable PD. - for said subject or population of subjects with L1 expression levels, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, and about 500 mg every 3 weeks, based on detected PD-L1 expression; selecting a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of ~700 mg;
method including. A method for treating a subject having SCCHN with detectable PD-L1 expression levels, said method comprising tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. administering to said subject one or more dosing cycles of 227. The method of any one of claims 224-226, wherein the tumor sample obtained from the subject(s) has been determined to have a detectable PD-L1 expression level. The method of any one of claims 223-227, wherein said SSCHN is human papillomavirus (HPV) positive. The method of any one of claims 223-228, wherein said SSCHN is HPV negative. 230. The method of claim 228 or 229, wherein HPV status is determined by p16 IHC, in situ hybridization or PCR. The method of any one of claims 223-230, wherein said SCCHN is recurrent and/or metastatic SCCHN. 232. The method of any one of claims 222-231, wherein said subject(s) has no prior treatment. 233. The method of claim 232, wherein said prior therapy is prior systemic therapy for recurrent and/or metastatic disease. The method of any one of claims 222-224 and 226-233, wherein said treatment results in CR or PR. The method of any one of claims 222-224 and 226-233, wherein said treatment results in an increase in ORR in said subject population compared to a baseline objective response rate (ORR). 236. The method of claim 235, wherein said reference ORR is the median ORR of a subject population that has undergone treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. 237. The method of claim 235 or 236, wherein said reference ORR is at least about 19% to about 36%. wherein said treatment increases PFS of said subject or subject population compared to baseline progression-free survival (PFS) time, increases DOR of said subject or subject population compared to baseline duration of response (DOR) time, or baseline overall survival 238. The method of any one of claims 222-224 and 226-237, wherein the method results in an increase in OS of the subject or population of subjects compared to duration (OS) time. (a) said baseline PFS time is the median PFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline DOR time is the median DOR time of a subject population that has been treated with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. is the median OS time in a subject population that has received treatment containing a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
239. The method of claim 238. 239. The method of claim 238, wherein the baseline DOR time is from at least about 6.7 months to about 23.4 months. 239. The method of claim 238, wherein the baseline OS time is at least about 11.6 months to about 14.9 months. 224- wherein said detectable PD-L1 expression level is a detectable PD-L1 protein expression level determined by an immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP263 241. The method according to any one of paragraphs 241 to 241. wherein the detectable PD-L1 protein expression level is in a tumor sample,
(a) 5% or more,
(b) greater than or equal to 5% and less than 20%, or (c) greater than or equal to 20% tumor-associated immune cells (TIC)
243. The method of claim 242, wherein 244. The method of any one of claims 224-243, wherein said subject or subject population is identified as likely to benefit from said treatment based on detected PD-Ll expression on tumor cells. . 70. The method of claim 69, wherein said cancer is liver cancer. 246. The method of claim 245, wherein said liver cancer is hepatocellular carcinoma (HCC). A method of treating a subject or population of subjects with hepatocellular carcinoma (HCC), comprising administering to said subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. wherein said subject or subject population has no prior systemic treatment for HCC. 248. The method of claim 247, further comprising administering a VEGF antagonist to said subject or population of subjects. A method of treating a subject or population of subjects with HCC, comprising administering to said 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, Method. The method of claims 248 and 249, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks. The method of any one of claims 247-250, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 500 mg to about 700 mg every three weeks. The method of any one of claims 247-251, wherein said PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every three weeks. 249. The method of claim 248 or 249, wherein said VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks. 254. The method of claim 253, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks. 255. The method of claim 254, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10.0 mg/kg every two weeks. The method of any one of claims 247-249 and 253-255, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 800 mg every two weeks. The method of any one of claims 247-249 and 253-256, wherein said PD-1 axis binding antagonist is administered at a dose of about 200 mg to about 1200 mg every two weeks. The method of claims 247-249, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 700 mg to about 1000 mg every four weeks. The method of any one of claims 247-249 and 258, wherein said PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks. The method of any one of claims 247-259, wherein said HCC is locally advanced or metastatic HCC. The method of any one of claims 247-260, wherein said HCC is unresectable HCC. The method of any one of claims 247-261, wherein said subject(s) has been determined to have adequate liver function. 263. The method of claim 262, wherein said adequate liver function is characterized as Child-Pugh class A. 264. The method of any one of claims 247-263, wherein the HCC tumor sample obtained from the subject(s) has been determined to have a detectable PD-L1 expression level. 265. The method of any one of claims 247-264, wherein said method comprises administering to said subject or subject population at least 4 dosing cycles. 262. The method of claim 261, comprising administering at least 16 dosing cycles to the subject or subject population. A method of treating a subject or subject population with HCC, said method comprising tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and about 15 mg/kg every 3 weeks. administering to said subject one or more dosing cycles of bevacizumab at a dose of The method of any one of claims 249-267, wherein said subject(s) has no prior systemic treatment for HCC. The method of any one of claims 247-268, wherein said treatment results in a median PFS for said subject population of at least about 5.6 months to at least about 6.83 months. 70. The method of claim 69, wherein said cancer is bladder cancer. 271. The method of claim 270, wherein the bladder cancer is muscle invasive bladder cancer (MIBC). A method for treating a subject or subject population with MIBC, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and about 900 mg to about 900 mg every 3 weeks. A method comprising administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1500 mg, wherein said subject is ineligible for treatment with a platinum-based chemotherapeutic agent. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and about 900 mg to about 900 mg every 3 weeks. A method comprising administering one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1500 mg, wherein said treatment is perioperative treatment. 274. The method of claim 272 or 273, wherein said subject(s) has a creatinine clearance of less than 60 mL/min. 275. The method of any one of claims 272-274, wherein said subject(s) has grade 2 or greater hearing loss. 276. The method of any one of claims 272-275, wherein said subject(s) has grade 2 or greater neuropathy. 277. The method of any one of claims 272-276, wherein said subject(s) has refused treatment with a platinum-based chemotherapeutic agent. The method of any one of claims 272 or 274-277, wherein said platinum-based chemotherapeutic agent is cisplatin. 279. The method of any one of claims 272-278, wherein said MIBC is surgically manipulable. 280. The method of claim 279, further comprising surgery. 281. The method of claim 280, wherein at least one dosing cycle is initiated prior to said surgery. 281. The method of claim 280, wherein at least 1, 2, or 3 dosing cycles are completed prior to said surgery. 283. The method of any one of claims 280-282, wherein at least one dosing cycle is initiated between 4 and 6 weeks after said surgery. 284. The method of claim 283, wherein 1-17 dosing cycles are completed after said surgery. 285. The method of any one of claims 280-284, wherein said surgery is cystectomy and/or lymphadenectomy. The method of any one of claims 272-285, wherein said treatment results in a pathological complete response (pCR). said treatment increases RFS of said subject(s) compared to baseline recurrence free survival (RFS) time, increases EFS of said subject(s) compared to baseline disease free survival (EFS) time; or results in an increase in OS of said subject(s) compared to baseline overall survival (OS) time. (a) said baseline RFS time is the median RFS time of a subject population that has received treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
(b) said baseline EFS time is the median EFS time of a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody, or (c) said baseline OS time. 288. The method of claim 287, wherein is the median OS time in a subject population that has received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. 289. The method of any one of claims 272-288, wherein said treatment results in a reduction in pathological extent. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. wherein said subject(s) is cisplatin ineligible. A method for treating a subject or subject population with MIBC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. wherein said treatment is perioperative treatment. 292. The method of any one of claims 272-291, wherein said treatment results in an ORR of the subject population of at least about 13.4% to at least about 15%. 293. The method of any one of claims 272-292, wherein said treatment results in a median OS for said subject population of from about 7.9 months to about 8.6 months. 294. The method of any one of claims 272-293, wherein the detectable PD-L1 protein expression level as determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined. 294, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction in which 5% or more of the tumor area is occupied by PD-L1-expressing tumor-infiltrating immune cells (ICs); The method described in . 271. The method of claim 270, wherein said bladder cancer is urothelial carcinoma (UC). 297. The method of claim 296, wherein said UC is metastatic urothelial carcinoma (mUC). A method for treating a subject or subject population with mUC, said method comprising administering to said subject or subject population an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and administering a dosage regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg. 300. The method of claim 298, wherein said subject(s) has received no prior cancer immunotherapy. 300. The method of claim 298 or 299, wherein said treatment is a second line treatment. 301. The method of any one of claims 298-300, wherein said mUC progressed during or after platinum-containing therapy. 302. The method of any one of claims 298-301, further comprising administering to said subject or subject population with a second dosing regimen after said subject or subject population experiences disease progression or unacceptable toxicity. . 303. The method of claim 302, wherein said 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 said ADC is (a) enfortumab vedotin or (b) sacituzumab govitecan. (a) enfortumab vedotin administered at a dose of 1.25 mg/kg weekly for 2 weeks on/1 week off, or (b) sacituzumab govitecan administered for 2 weeks 305. The method of claim 304, administered at a dose of 10 mg/kg weekly for on/one week off. A method for treating a subject or subject population having mUC, said method comprising administering to said subject or subject population tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. A method comprising administering one or more dosing cycles of 1. A method for treating a subject or population of subjects with mUC comprising administering to said subject or population of subjects a first dosing regimen followed by a second dosing regimen,
(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of 1200 mg about every 3 weeks;
(b) said second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin 2 weeks on/1 week off or (ii) sacituzumab govitecan administered at a dose of 10 mg/kg weekly for 2 weeks on/1 week off. , wherein said second dosing regimen is administered to said subject or subject population after said subject or subject population experiences disease progression or unacceptable toxicity during said first dosing regimen. 308. The method of any one of claims 298-307, wherein said treatment results in an ORR of the subject population of at least about 13.4% to at least about 31%. 309. The method of any one of claims 298-308, wherein said treatment results in a median OS for the subject population of from about 7.9 months to about 16.3 months. 70. The method of claim 69, wherein said cancer is pancreatic cancer. A method of treating a subject or population of subjects with pancreatic cancer, said method comprising administering to said subject or population of subjects a dose of about 420 mg tiragolumab on days 1 and 15 of each 28-day dosing cycle; atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/ ^m2 on days 1, 8 and 15 of each 28-day dosing cycle, and each 28-day dosing cycle. administering in a dosing regimen comprising one or more 28-day dosing cycles of nab-paclitaxel at a dose of about 125 mg/m ² on days 1, 8 and 15 of . 312. The method of claim 310 or 311, wherein said pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). 313. The method of claim 312, wherein said PDAC is metastatic PDAC. 314. The method of any one of claims 310-313, wherein said subject(s) has no prior systemic therapy for metastatic PDAC. The method of any one of claims 310-314, wherein said treatment results in an ORR of the subject population of at least about 41.7% to about 46.7%. 316. Any of claims 310-315, wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. or the method described in paragraph 1. The method of any one of claims 310-316, wherein said treatment results in a median PFS for the subject population of at least about 5.5 months to about 7 months. The method of any one of claims 310-317, wherein said treatment results in a median OS for the subject population of at least about 8.5 months to about 10.6 months. 70. The method of claim 69, wherein said cancer is esophageal cancer. A method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on day 1 of each dosing cycle; and administering to said subject or subject population in a dosing regimen comprising one or more 21-day dosing cycles of a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on day 1 of each dosing cycle. A method for treating a subject or subject population with esophageal cancer, said method comprising administering an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on day 1 of each dosing cycle and 1 of each dosing cycle. administering to said subject or subject population a dosing regimen comprising one or more 21-day dosing cycles of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg per day, wherein said subject(s) is Previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 321. The method of claim 320, wherein said subject(s) has 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 said subject(s) has experienced disease progression or unacceptable toxicity during prior treatment. 321. 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 said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses. The method of any one of claims 321-325, wherein said platinum-based chemotherapeutic agent is cisplatin. 327. The method of claim 326, wherein cisplatin is administered at a dose of about 80 mg/ ^m2 on Day 1 of each dosing cycle. The method of any one of claims 321-327, wherein said non-platinum chemotherapeutic agent is an antimetabolite. 329. The method of claim 328, wherein said antimetabolite is 5-fluorouracil. 329. The method of claim 329, wherein 5-fluorouracil is administered at a dose of 800 mg/ ^m2 /24 hours on days 1-5 of each 21-day cycle. The method of any one of claims 321-330, wherein said esophageal cancer is advanced or metastatic esophageal cancer. 332. The method of claim 320 or 331, wherein said subject(s) has no prior treatment for metastatic esophageal cancer. 1. A method for treating a subject or subject population with advanced or metastatic esophageal cancer, said method comprising administering to said subject or subject population a dose of tiragolumab of about 600 mg on day 1 of each dosing cycle; Atezolizumab at a dose of about 1200 mg on Day 1 of each dosing cycle, Cisplatin at a dose of about 80 mg/ ^m2 on Day 1 of each dosing cycle, and 800 mg/m on Days 1-5 of each 21-day cycle A method comprising administering a ^2/24 hour dose of 5-fluorouracil in a dosing regimen comprising one or more 21 day dosing cycles, wherein cisplatin is omitted from said dosing regimen after 6 doses. 1. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer comprising administering to said subject or population of subjects a first dosing regimen and a second dosing regimen,
(a) said first dosing regimen comprises cisplatin at a dose of about 80 mg/m ² on Day 1 of each dosing cycle and 800 mg/m ² /24 hours on Days 1-5 of each 21-day cycle; and omitting cisplatin from the dosing regimen after 6 doses of 5-fluorouracil for one or more 21-day dosing cycles
(b) said second dosing regimen is one or more 21-day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle; including,
Method. The method of any one of claims 321-334, wherein said treatment results in an ORR of said subject population of at least about 14%. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVR):
HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (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);
HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). The anti-TIGIT antagonist antibody comprises the following light chain variable region framework regions (FR):
FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10)
337. The method of claim 336, further comprising: The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:
FR-H1 comprising the amino acid sequence of X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), in which 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)
337. The method of claim 336, further comprising: 339. The method of claim 338, wherein _X1 is E. 339. The method of claim 338, wherein _X1 is Q. wherein said anti-TIGIT antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain according to (a) and (b) 341. The method of any one of claims 336-340, comprising the VL domain of claim 336-340. wherein said anti-TIGIT antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17 or 18; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19. wherein said anti-TIGIT antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:19. wherein said anti-TIGIT antagonist antibody is:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:34. The method of any one of claims 336-344, wherein said anti-TIGIT antagonist antibody is a monoclonal antibody. The method of any one of claims 336-345, wherein said anti-TIGIT antagonist antibody is a human antibody. The method of any one of claims 336-346, wherein said anti-TIGIT antagonist antibody is a full length antibody. The method of any one of claims 336-347, wherein said anti-TIGIT antagonist antibody has intact Fc-mediated effector functions. The method of any one of claims 336-339 and 341-348, wherein said anti-TIGIT antagonist antibody is tiragolumab. The anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab') ₂ fragment. , the method of any one of claims 336-346. The method of any one of claims 336-349, wherein said anti-TIGIT antagonist antibody is an IgG class antibody. 352. The method of claim 351, wherein said IgG class antibody is an IgG1 subclass antibody. 353. The method of any one of claims 336-352, wherein said PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. 354. The method of claim 353, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist. 355. The method of claim 354, wherein the PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners. 356. The method of embodiment 355, wherein said PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1. The method of any one of claims 354-356, wherein said PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody. The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, emvaforimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502 , cosibelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 or HS-636 358. The method of claim 357. 359. The method of claim 358, wherein said anti-PD-L1 antagonist antibody is atezolizumab. The anti-PD-L1 antagonist antibody is a HVR that:
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 RHWPGGFDY (SEQ ID NO: 22);
an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);
HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO:24); and HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25). wherein said anti-PD-L1 antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or (c) a VH domain according to (a) and (b) 361. The method of claim 360, comprising a VL domain as described. wherein said anti-PD-L1 antagonist antibody is:
362. The method of claim 361, comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:27. wherein said anti-PD-L1 antagonist antibody is:
363. The method of claim 362, comprising (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:28; and (b) a light chain comprising the amino acid sequence of SEQ ID NO:29. The method of any one of claims 360-363, wherein said anti-PD-L1 antagonist antibody is a monoclonal antibody. The method of any one of claims 360-364, wherein said anti-PD-L1 antagonist antibody is a humanized antibody. The method of claim 364 or 365, wherein said anti-PD-L1 antagonist antibody is a full-length antibody. 4. The anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. 365. The method of any one of paragraphs 360-365. The method of any one of claims 360-366, wherein said anti-PD-L1 antagonist antibody is an IgG class antibody. 369. The method of claim 368, wherein said IgG class antibody is an IgG1 subclass antibody. 354. The method of claim 353, wherein said PD-1 axis binding antagonist is a PD-1 binding antagonist. 371. The method of claim 370, wherein said PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners. 372. The method of claim 371, wherein said PD-1 binding antagonist inhibits binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2. The method of any one of claims 370-372, wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody. The anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiplimab, BGB-108, prorgolimab, camrelizumab, cintilimab, tislelizumab, tripalimab, dostarlimab, retifantlimab, sasanlimab, penplimab, CS1003, HLX10, SCT - I10A, Jimverelimab, Valsutilimab, Genolimuzumab, BI754091, Cetrelimab, YBL-006, BAT1306, HX008, Budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM48ENUM38ENUM48ENUM40001 , STI-1110, AK-103 or hAb21. The method of any one of claims 370-372, wherein said PD-1 binding antagonist is an Fc fusion protein. 376. The method of claim 375, wherein said Fc fusion protein is AMP-224. Claims 77-101, 103-116, 119-122, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of between about 500 mg and about 700 mg every three weeks. and the method of any one of 247-249. 57, 59, 60, 62-64, 101, 123-151, 160, 161, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 600 mg every three weeks , 224, 225, 247-255, 272-289, 298-305, 320-332 and 377. 84. Any one of claims 77, 78, 82 and 83, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every four weeks. described method. 379. The method of any one of claims 47, 56, 64, 258 and 379, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 840 mg every four weeks. 257. Any one of claims 77, 78, 82, 83 and 256, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks. The method described in section. The method of any one of claims 48, 190-213, 215-221, 256 and 381, comprising administering said anti-TIGIT antagonist antibody to said subject at a dose of about 420 mg every two weeks. 383. The method of any one of claims 47-382, wherein the dose of said anti-TIGIT antagonist antibody is a fixed dose. 77-100, 103-116, 119-122, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of about 900 mg to about 1500 mg every three weeks; 243-245. 59, 60, 62-64, 123-151, 160, 161, 224, 225, 247 comprising administering said PD-1 axis binding antagonist to said subject at a dose of about 1200 mg every three weeks 258, 272-289, 298-305, 320-332 and 384. 84. Any one of claims 77, 78, 82 and 83, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of about 1400 mg to 2000 mg every four weeks. described method. The method of any one of claims 47, 56, 64, 259 and 386, comprising administering said PD-1 axis binding antagonist to said subject at a dose of about 1680 mg every four weeks. 258. Any of claims 77, 78, 82, 83 and 257, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of about 600 mg to about 1200 mg every two weeks. The method according to item 1. any one of claims 48, 190-213, 215-221, 257 and 388, comprising administering said PD-1 axis binding antagonist to said subject at a dose of about 840 mg every two weeks. Method. The method of any one of claims 47-389, wherein the dose of PD-1 axis binding antagonist is a fixed dose. 59. The method of claim 58, wherein said method comprises administering pembrolizumab to said subject at a fixed dose of about 400 mg every 6 weeks. 162. The method of any one of claims 51, 57, 59, 60, 62, 77, 78, 82, 83, 103 and 161, wherein the length of each of said one or more dosing cycles is 21 days. . The method of any one of claims 47, 56, 64, 77, 184-189 and 253-259, wherein each of said one or more dosing cycles is 28 days in length. 394. Any one of claims 47-393, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. the method of. 395. The method of any one of claims 47-394, comprising administering said PD-1 axis binding antagonist to said subject or population of subjects on about day 1 of each of said one or more dosing cycles. . 257. The method of claim 256, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles. 258. The method of claim 257, comprising administering said PD-1 axis binding antagonist to said subject on about day 15 of each of said one or more dosing cycles. 398. The method of any one of claims 47-397, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects prior to said anti-TIGIT antagonist antibody. 399. The method of claim 398, comprising a first observation period following administration of said PD-1 axis binding antagonist. 400. The method of claim 399, wherein the first observation period is about 30 minutes to about 60 minutes long. 401. The method of claim 399 or 400, wherein said method comprises a second observation period following administration of said anti-TIGIT antagonist antibody. 402. The method of claim 401, wherein the second observation period is about 30 minutes to about 60 minutes long. 398. The method of any one of claims 47-397, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects concurrently with said anti-TIGIT antagonist antibody. 404. The method of any one of claims 47-403, comprising intravenously administering said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist to said subject or population of subjects. 405. The method of claim 404, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or subject population by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. . 406. The method of claim 404 or 405, wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or subject population by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. . 407. The method of any one of claims 47-103 and 105-406, wherein the PD-Ll expression level of a tumor sample obtained from said subject(s) has been determined. 408. The method of claim 407, wherein said tumor sample obtained from said subject(s) has been determined to have a detectable PD-Ll expression level. 409. The method of claim 408, wherein said detectable PD-Ll expression level is a detectable PD-Ll protein expression level. 409. The method of claim 409, wherein said detectable PD-L1 protein expression level is determined by an immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining. 411. The method of claim 410, wherein said anti-PD-Ll antibody suitable for staining is anti-PD-Ll antibody SP263, SP142, 22C3 or 28-8. 412. of claim 410 or 411, wherein the detectable PD-Ll protein expression level is determined using the Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, Ventana SP142 IHC assay, or pharmDx 28-8 IHC assay. Method. Claims 47-102, 159, 181-223 and 245-335, wherein the detectable PD-L1 protein expression level is determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263. Method. The method of any one of claims 47-189, 222-269 and 296-335, wherein the detectable PD-L1 protein expression level is determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142. The method of any one of claims 47-189 and 222-335, wherein the detectable PD-L1 protein expression level is determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C3. 336. The method of any one of claims 47-103 and 105-335, wherein the detectable PD-Ll protein expression level is determined by an IHC assay comprising staining with anti-PD-Ll antibody 28-8. 414. The method of claim 413, wherein said detectable PD-L1 protein expression level is 5% or more tumor-associated immune cells (TIC) in said tumor sample. 414. The method of claim 413, wherein said detectable PD-Ll protein expression level is 5% or more and less than 20% TIC in said tumor sample. 414. The method of claim 413, wherein said detectable PD-L1 protein expression level is 10% or more TIC in said tumor sample. 414. The method of claim 413, wherein said detectable PD-L1 protein expression level is 20% or more TIC in said tumor sample. 414. The method of claim 413, wherein said detectable PD-L1 protein expression level is 10% or more and less than 50% TIC in said tumor sample. 414. The method of claim 413, wherein said detectable PD-L1 protein expression level is 50% or more TIC in said tumor sample. The method of any one of claims 413, 415 and 416, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or greater. The method of any one of claims 413, 415 and 416, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 30% or greater. Any one of claims 413, 415 and 416, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 1% or more and less than 50% in said tumor sample. Method. The method of any one of claims 413, 415 and 416, wherein said detectable PD-L1 protein expression level is a PD-L1 positive tumor cell fraction of 50% or greater. 415. The method of claim 414, wherein said PD-L1 positive tumor cell fraction is the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC). 415. The method of claim 414, wherein the PD-L1-expressing tumor-infiltrating IC accounts for 1% or more of the tumor area. 415. The method of claim 414, wherein the PD-L1-expressing tumor-infiltrating IC accounts for 5% or more of the tumor area. 416. The method of claim 415, wherein said detectable PD-L1 protein expression level is a composite positive score (CPS) of 1 or more. 416. The method of claim 415, wherein said detectable PD-L1 protein expression level is 10 or more CPS. 416. The method of claim 415, wherein said detectable PD-L1 protein expression level is 20 or more CPS. The method of any one of claims 427-429, wherein said IHC assay is the Ventana SP142 IHC assay. 409. The method of claim 408, wherein said detectable PD-Ll expression level is a detectable PD-Ll nucleic acid expression level. said detectable PD-L1 nucleic acid expression level has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof; 435. The method of claim 434. 336. Any of claims 47-335, wherein said treatment results in an increase in said subject's OS compared to baseline overall survival (OS) time and/or said subject's PFS compared to baseline progression free survival (PFS) time. or the method described in paragraph 1. (a) a subject whose baseline OS time has undergone a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or a treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or (b) the baseline PFS time is a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or an anti-PD-1 axis binding antagonist without a PD-1 axis binding antagonist. median PFS time in a subject population that has received treatment containing a TIGIT antagonist antibody;
437. The method of claim 436. 191. according to any one of claims 49, 141 and 190, wherein said one or more chemotherapeutic agents is one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents Method. 439. The method of claim 438, wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin. 439. The method of claims 66, 89, 116, 145, 212 and 439, wherein said carboplatin is administered at a dose sufficient to achieve AUC = 5 mg/ml/min or AUC = 6 mg/ml/min. 66, 116, 145, 147, 149, 151, 278, and 326, wherein said cisplatin is administered at a dose of about 75 mg/ ^m2 or 80 mg/ ^m2 . 442. The method of any one of claims 438-441, wherein said one or more non-platinum chemotherapeutic agents is an antimetabolite, taxane or topoisomerase II inhibitor. 443. The method of claim 59 or 442, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine or 5-fluorouracil. 444. The method of any one of claims 66, 116, 145 and 443, wherein said pemetrexed is administered at a dose of about 500 mg/ ^m2 . 444. The method of any one of claims 60, 61, 145, 316, and 443, wherein said gemcitabine is administered at a dose of about 1000 m ^<2> or about 1250 mg/m ^<2> . 444. The method of claim 59 or 443, wherein said antimetabolite is capecitabine. 447. The method of claims 443 or 446, wherein said capecitabine is administered at a dose of about 1250 mg/ ^m2 . The method of any one of claims 193, 202, 203 and 442-447, wherein said taxane is paclitaxel or nab-paclitaxel. 449. The method of any one of claims 66, 145 and 448, wherein said paclitaxel is administered at a dose of about 175 mg/ ^m2 or about 200 mg/ ^m2 . The method of any one of claims 60, 61, 212, 316 and 448, wherein said nab-paclitaxel is administered at a dose of about 100 mg/ ^m2 . Claims 77, 78, 82, 83, 192, 193 and 442- wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331 450. The method of any one of clauses 450 to 450. 452. The method of any one of claims 66, 89 and 451, wherein said etoposide is administered at a dose of about 100 mg/ ^m2 . each of said one or more chemotherapeutic agents once every week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, every four weeks The method of any one of claims 438-452, administered twice, or three times every four weeks. The method of any one of claims 438-453, wherein said one or more chemotherapeutic agents is administered on Day 1 of one or more dosing cycles. The method of any one of claims 443-454, wherein said gemcitabine is administered three times every four weeks. 456. The method of any one of claims 443-455, wherein said gemcitabine is administered on days 1, 8 and/or 15 of one or more dosing cycles. The method of any one of claims 443-456, wherein said capecitabine is administered daily for two weeks. The method of any one of claims 443-457, wherein said capecitabine is administered on days 1-14 of one or more dosing cycles. The method of any one of claims 448-458, wherein said nab-paclitaxel is administered three times every four weeks. The method of any one of claims 448-459, wherein the nab-paclitaxel is administered on days 1, 8 and 15 of one or more dosing cycles. The method of any one of claims 451-460, wherein said etoposide is administered on days 1-3 every 3 weeks. The method of any one of claims 451-461, wherein said etoposide is administered on days 1-3 of one or more dosing cycles. 463. The method of any one of claims 438-462, wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. 464. The method of any one of claims 438-463, wherein said one or more chemotherapeutic agents are administered subsequent to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. The method of any one of claims 438-464, wherein said one or more chemotherapeutic agents are administered intravenously or orally. The method of any one of claims 62, 248 and 249, wherein said VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks. 467. The method of claim 250 or 466, wherein said VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every three weeks. 468. The method of claim 467, wherein said VEGF antagonist is administered at a dose of about 15 mg/kg every 3 weeks. The method of any one of claims 62, 248-250, 253-255 and 466-468, wherein said VEGF antagonist is an anti-VEGF antibody. 469. The method of claim 469, wherein said anti-VEGF antibody is bevacizumab. The method of any one of claims 62, 248-250 and 253-255, wherein said anti-TIGIT antagonist antibody is tiragolumab, said PD-1 axis binding antagonist is atezolizumab, and said VEGF antagonist is bevacizumab. . Claims 62, 248-250, 253-255 and 466-471, wherein said method comprises administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles. the method of. The method of any one of claims 253-255, wherein said method comprises administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein said VEGF antagonist is administered intravenously. 475. The method of claim 474, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90±15 minutes. Claims 62, 248-250, wherein said method comprises administering said PD-1 axis binding antagonist prior to said VEGF antagonist and administering said VEGF antagonist prior to said anti-TIGIT antagonist antibody to said subject. , 253-255, and 466-475. 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. 477. The method of claim 476, comprising: 478. The method of claim 477, wherein the first observation period, the second observation period, and the third observation period are each about 30 minutes to about 120 minutes long. of claims 102, 117, 118, 152, 153, 177, 184, 214, 226, 267, 290, 291, 306, 307, 311, 333 and 334, wherein tiragolumab and atezolizumab are combined in an IV bag prior to administration A method according to any one of paragraphs. 479. The method of any one of claims 47-479, wherein said subject is a human. A kit comprising a PD-1 axis binding antagonist and/or an anti-TIGIT antagonist antibody for treating a subject with cancer according to the method of any one of claims 47-160, 162-224 and 226-480 . PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody to treat a subject with cancer according to the method of any one of claims 47-160, 162-224 and 226-480 kit, including 483. The kit of claim 482, further comprising an anti-TIGIT antagonist antibody. The kit of any one of claims 481-483, wherein said anti-TIGIT antagonist antibody is tiragolumab. The kit of any one of claims 481-484, wherein said PD-1 axis binding antagonist is atezolizumab. Anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject with cancer according to the method of any one of claims 47-160, 162-224 and 226-480 kit, including The kit of claim 486, wherein said kit further comprises a PD-1 axis binding antagonist. The kit of claim 486 or 487, wherein said PD-1 axis binding antagonist is atezolizumab. The kit of any one of claims 486-488, wherein said anti-TIGIT antagonist antibody is tiragolumab. The kit of any one of claims 486-489, further comprising one or more chemotherapeutic agents. 491. The kit of claim 490, wherein said 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 said one or more platinum-based chemotherapeutic agents is carboplatin or cisplatin. 493. The kit of claim 491 or 492, wherein said one or more non-platinum chemotherapeutic agents are antimetabolites, taxanes or topoisomerase II inhibitors. 494. The kit of claim 493, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil. 495. The kit of claim 493 or 494, wherein said taxane is paclitaxel or nab-paclitaxel. 496. The kit of any one of claims 493-495, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, orintricarboxylic acid, or HU-331. The kit of any one of claims 481-496, further comprising said VEGF antagonist. 498. The method of claim 497, wherein said VEGF antagonist is an anti-VEGF antibody. 499. The method of claim 498, wherein said anti-VEGF antibody is bevacizumab. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cancer, said method according to any of claims 47-160, 162-224 and 226-480 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, which is the method of claim 1. 226. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or subject population with cancer in combination with a PD-1 axis binding antagonist, said treatment comprising claims 47-160, 162-224 and 226 480. Use according to any one of claims 1-480. 502. The use of claim 501, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations. 502. The use of claim 501, wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single formulation.

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