CA3165187A1 - Methods for treatment of cancer with an anti-tigit antagonist antibody - Google Patents

Abstract

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

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

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METHODS FOR TREATMENT OF CANCER WITH AN ANTI-TIGIT ANTAGONIST ANTIBODY
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. Patent Application No. 62/966,448, filed on January 27, 2020; U.S. Patent Application No. 62/985,822, filed on March 5, 2020; U.S.
Patent Application No.
62/994,272, filed on March 24, 2020; International Application No.
PCT/U52020/024526, filed on March 24, 2020; U.S. Patent Application No. 63/059,054, filed on July 30, 2020; U.S.
Patent Application No.
63/059,960, filed on July 31, 2020; U.S. Patent Application No. 63/074,807, filed on September 4, 2020;
U.S. Patent Application No. 63/074,827, filed on September 4, 2020;
International Application No.
PCT/US2020/049415, filed on September 4, 2020; U.S. Patent Application No.
63/085,890, filed on September 30, 2020; U.S. Patent Application No. 63/105,198, filed on October 23, 2020; U.S. Patent Application No. 63/114,517, filed on November 16, 2020; U.S. Patent Application No. 63/124,693, filed on December 11,2020; and U.S. Patent Application No. 63/127,109, filed on December 17, 2020, the entire contents of each of which are incorporated herein by reference in their entirety.
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 25, 2021, is named 50474-206W02_Sequence_Listing_1_25_2021_5125 and is 30,641 bytes in size.
FIELD OF THE INVENTION
The present invention relates to methods, uses, and compositions for the treatment of cancer.
More specifically, the invention concerns the treatment of patients having cancer with an anti-TIGIT
antagonist antibody (e.g., treatment with an anti-TIGIT antagonist antibody as a monotherapy or a combination therapy).
BACKGROUND OF THE INVENTION
Cancers are characterized by the uncontrolled growth of cell subpopulations.
Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. Cancer care thus represents a significant and ever-increasing societal burden.
Thus, there is an unmet need in the field for the development of efficacious immunotherapies and methods of dosing the same for the treatment of cancers.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.
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 for treating a subject having a cancer according to the methods provided herein.
In another aspect, the invention provides an anti-TIGIT antagonist antibody and a PD-1 axis .. binding antagonist for use in a method of treating a subject having a cancer, wherein the method is according to the methods provided herein.
In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the methods provided herein.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 mg every three weeks, wherein the anti-PD-1 antagonist antibody is pembrolizumab.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles

2 of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of between about 300 mg to about 500 mg every six weeks.
In another aspect, the invention provides a method for treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, and an antimetabolite at a dose of between about 10 mg/m2 to about 10000 mg/m2 twice a day orally every three weeks for 2-weeks on/1-week off.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, gemcitabine, and nab-paclitaxel.
In another aspect, the invention provides a method for treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, and a VEGF antagonist at a dose of between about 1 mg/kg to about 35 mg/kg every three weeks.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein (a) the induction phase comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks; and (b) the maintenance phase comprises one or more additional dosing cycles of the anti-TIGIT antagonist antibody every three weeks, the PD-1 axis binding antagonist every three weeks, and the non-platinum-based chemotherapeutic agent every three weeks, and wherein the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent.
In another aspect, the invention provides a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein (a) the induction phase comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks; and (b) the maintenance phase comprises one or more additional dosing cycles of the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and the PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks, wherein the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic agent.

3 In another aspect, the invention provides a method of treating a subject or population of subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment extends progression-free survival (PFS) of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.
In another aspect, the invention provides a method of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment results in a median PFS of the population of subjects of about 8.2 months to about 9.2 months.
In another aspect, the invention provides a method of treating a subject or population of subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase ll inhibitor, wherein the treatment extends OS of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase ll inhibitor without the anti-TIGIT antagonist antibody.
In another aspect, the invention provides a method of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment results in a median OS of the population of subjects of about 15.3 months to about 17.6 months.
In another aspect, the invention provides a method for treating a subject or population of subjects having SCLC, the method comprising administering to the subject or population of subjects one or more 21-day dosing cycles of 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 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 a dose of 100 mg/m2on each of Days 1, 2, and 3 of each dosing cycle, wherein the treatment extends PFS and/or OS of the subject or population of subjects as compared to treatment with atezolizumab, carboplatin, and etoposide without the anti-TIGIT
antagonist antibody.
In another aspect, the invention provides a method for treating a subject or population of subjects having ES-SCLC, the method comprising administering to the subject or population of subjects four initial dosing cycles followed by one or more additional dosing cycles, wherein (a) the four initial dosing cycles comprise administering 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, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle, and etoposide at a dose of

4 100 mg/m2on each of Days 1, 2, and 3 of each initial dosing cycle; and (b) the one or more additional dosing cycles comprise administering tiragolumab at a dose of about 600 mg 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, wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment extends PFS and/or OS of the subject or population of subjects as compared to treatment with atezolizumab, carboplatin, and etoposide without the tiragolumab.
In another aspect, the invention provides a method of treating a subject or population of subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent which is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent which is a non-platinum-based chemotherapeutic agent.
In another aspect, the invention provides a method of treating a subject or population of subjects having an advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the tiragolumab is administered at a dose of about 600 mg every three weeks, the atezolizumab is administered at a dose of about 1200 mg every three weeks, the carboplatin is administered at a dose sufficient to achieve an AUC = 5 mg/ml/min every three weeks or the cisplatin is administered at a dose of 75 mg/m2 every three weeks, and the pemetrexed is administered at a dose of about 500 mg/m2 every three weeks on Day 1 of each of the four 21-day dosing cycles.
In another aspect, the invention provides a method of treating a subject or population of subjects having an advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects (i) four induction phase dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve an AUC = 5 mg/ml/min every three weeks, and pemetrexed at a dose of about 500 mg/m2 every three weeks; and (ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and pemetrexed at a dose of about 500 mg/m2 every three weeks, wherein the one or more 21-day dosing cycles of the maintenance phase do not comprise administration of the carboplatin, wherein the subject or population of subjects have received no prior systemic therapy for the advanced non-squamous NSCLC.
In another aspect, the invention provides a method for treating a subject having a resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.
In another aspect, the invention provides a method for treating a subject having a lung cancer, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of between about 500 mg to

5 about 700 mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks as a neoadjuvant treatment.
In another aspect, the invention provides a method for treating a subject having a resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and (a) (i) carboplatin at a dose targeted to achieve an AUG of 5 mg/mL/min or an AUG of 6 mg/mUmin every three weeks; or (ii) cisplatin at a dose of about 75 mg/m2 every three weeks; and (b) (i) pemetrexed at a dose of about 500 mg/m2 every three 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 three weeks.
In another aspect, the invention provides a method for treating a subject having a lung cancer, the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) at least one of the dosing cycles is a neoadjuvant treatment and comprises administering to the subject (a) tiragolumab at a dose of about 1200 mg every three weeks; (b) atezolizumab at a dose of about 1200 mg every three weeks as a neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mUmin every three 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 AUG of 6 mg/mUmin every three weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every three 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; and (II) at least one of the dosing cycles comprises administering to the subject tiragolumab at a dose of between about 500 mg to about 700 mg every three weeks and atezolizumab at a dose of between about 900 mg to about 1500 mg every three weeks as an adjuvant treatment.
In another aspect, the invention provides a method for treating a subject or population of subjects having a cervical cancer with a detectable expression level of PD-L1, the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.
In another aspect, the invention provides a method of selecting a therapy for a subject having a cervical cancer, the method comprising (a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from the subject by an INC assay using an anti-PD-L1 antibody suitable for staining;
and (b) selecting for the subject having a detectable expression level of PD-L1 a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist administered at a dose of between about 900 mg to about 1500 mg every three weeks based on PD-L1 expression on tumor cells having been detected.
In another aspect, the invention provides a method for treating a subject having a cervical cancer with a detectable expression level of PD-L1, the method comprising administering to the subject 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.

6 In another aspect, the invention provides a method of treating a subject or population of subjects having a breast cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of tiragolumab at a dose of about 840 mg every four weeks, atezolizumab at a dose of about 1680 mg every four weeks, and nab-paclitaxel at a dose of about 100 mg/m2 for 3-weeks on/1 -week off.
In another aspect, the invention provides a method of treating a subject having an early triple-negative breast cancer (eTNBC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks.
In another aspect, the invention provides a method of treating a subject having an eTNBC, the method comprising administering to the subject a dosing regimen 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 every week and carboplatin at a dose targeted to achieve an AUC of 5 mg/mUmin every three weeks for the first 12 weeks of the dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/m2 every two weeks, cyclophosphamide at a dose of about 600 mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of the dosing regimen; or (b) (i) nab-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/m2 every two weeks, cyclophosphamide at a dose of about 600 mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of the dosing regimen;
wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.
In another aspect, the invention provides a method for treating a subject or population of subjects having an SCCHN with a detectable expression level of PD-L1, the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1 500 mg every three weeks.
In another aspect, the invention provides a method of selecting a therapy for a subject or population of subjects having an SCCHN, the method comprising: (a) detecting a protein expression level .. of PD-L1 in a tumor sample from the subject or population of subjects by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) selecting for the subject or population of subjects having a detectable expression level of PD-L1 a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks based on PD-L1 expression having been detected.
In another aspect, the invention provides a method for treating a subject having an SCCHN with a detectable expression level of PD-L1, the method comprising administering to the subject 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.

7 In another aspect, the invention provides a method of treating a subject or population of subjects having a hepatocellular carcinoma (HOC), the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects have received no prior systemic treatment for HCC.
In another aspect, the invention provides a method of treating a subject or population of subjects having an HOC, the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF
antagonist.
In another aspect, the invention provides a method of treating a subject or population of subjects having an HCC, the method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and bevacizumab at a dose of about 15 mg/kg every three weeks.
In another aspect, the invention provides a method for treating a subject or population of subjects having an MIBC, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, wherein 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 population of subjects having an MIBC, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, wherein the treatment is a perioperative treatment.
In another aspect, the invention provides a method for treating a subject or population of subjects having an MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks, wherein the subject or subjects are cisplatin ineligible.
In another aspect, the invention provides a method for treating a subject or population of subjects having an !MSC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks, wherein the treatment is a perioperative treatment.
In another aspect, the invention provides a method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.
In another aspect, the invention provides a method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks.

8 In another aspect, the invention provides a method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein (a) the first dosing regimen comprises one or more 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; and (b) the second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg every three weeks and (i) enfortumab vedotin is administered at a dose of 1.25 mg/kg every week for 2-weeks on/1 week off or (ii) sacituzumab govitecan is administered at a dose of 10 mg/kg every week for 2-weeks on/1 week off, wherein the second dosing regimen is administered to the subject or population of subjects after the subject or population of subjects have experienced disease progression or unacceptable toxicity during the first dosing regimen.
In another aspect, the invention provides a method of treating a subject or population of subjects having a pancreatic cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of 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, and nab-paclitaxel at a dose of about 125 mg/m20n Days 1, 8, and 15 of each 28-day dosing cycle.
In another aspect, the invention provides a method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg on Day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg on Day 1 of each dosing cycle.
In another aspect, the invention provides a method for treating a subject or population of subjects having an esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg on Day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg on Day 1 of each dosing cycle, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
In another aspect, the invention provides a method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of 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 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 the dosing regimen after six doses.
In another aspect, the invention provides a method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the

9 subject or population of subjects a first dosing regimen and a second dosing regimen, wherein (a) the first dosing regimen comprises one or more 21-day dosing cycles of cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing 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 the dosing regimen after six doses; and (b) the second dosing regimen comprises 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.
In another aspect, the invention provides a kit comprising a PD-1 axis binding antagonist and/or an anti-TIGIT antagonist antibody for treating a subject having a 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 for treating a subject having a cancer according to the methods provided herein.
In another aspect, the invention provides a kit comprising an anti-TIGIT
antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to the methods provided herein.
In another aspect, the invention provides an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having a cancer, wherein the method is according to the methods provided herein.
In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or population of subjects having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the methods provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase lb 04W dosing expansion).
FIG. 2 is a flow chart of a phase lb trial schema. EOCG = Eastern Cooperative Oncology Group;
IHC = immunohistochemistry; PD-L1+ = programmed death-ligand 1 positive; Q4W =
every 4 weeks;
RECIST v1.1 = Response Criteria in Solid Tumors, Version 1.1; TFI = treatment-free interval; TNBC =
triple-negative breast cancer.
FIG. 3 is a flow chart of a phase la study design. CRC = colorectal cancer, DLT = dose-limiting toxicity, GC = gastric cancer, HNSCC = head and neck squamous cell carcinoma, IV = intravenous, MAD
= maximum administered dose, MSI = microsatellite instability, MSS =
microsatellite-stable, MTD =
maximum tolerated dose, NSCLC = non¨small cell lung cancer, OC = ovarian cancer, PD = progression of disease, PK = pharmacokinetic, RCC = renal cell carcinoma, TNBC = triple-negative breast cancer, UBC = urothelial bladder cancer.
FIG. 4 is a flow chart of the phase lb tiragolumab and atezolizumab expansion cohorts, serial biopsy cohort, and 04W dosing expansion cohort study design. CIT = cancer immunotherapy; DLT =
dose-limiting toxicity; HNSCC = head and neck squamous cell carcinoma, IV =
intravenous, MAD =
maximum administered dose, MSI = microsatellite instability, MSS =
microsatellite-stable, N/ITD =

maximum tolerated dose, NSCLC = non-small cell lung cancer, PD = progression of disease; PD 1 =
programmed death-1; PD-L1 = programmed death ligand 1; PK = pharmacokinetic, TIGIT = 1-cell Immunoreceptor with Ig and ITIM domains. Note: Limited to patients with PD-L1 selected and/or TIGIT-selected tumors, aAdvanced, incurable, refractory tumors. Tiragolumab IV and atezolizumab 1200 mg IV
every 3 weeks. Will only enroll following IMC review of safety data from Phase la. 3+3 dose escalation with DLT window of 21 days. Other intermediate doses of tiragolumab may be studied if they do not exceed the MTD. To gain further safety, PK, and PD data, patients may be backfill-enrolled if they consent to optional serial biopsies. Evaluation of dose levels exceeding 1200 mg tiragolumab will require a protocol amendment with a supporting rationale. bExpansion may begin at doses MID or MAD. GUp to approximately half of patients in each cohort will be those who consent to optional serial biopsies.
Patients with tumors for which anti-PD-L1/PD-1 agents are approved by local regulatory authorities (e.g., NSCLC melanoma, renal cell carcinoma) may only be enrolled in an expansion cohort (indication-specific or serial biopsy) if a clinical trial of an investigational agent in combination with an anti-PD-L1 is considered an acceptable treatment option. dLimited to patients who consent to optional serial biopsies (acceptable samples include core needle, excisional, incisional, punch, and/or foreceps biopsies). eln the 04W dosing expansion cohort, a safety run-in of approximately 3 patients will be completed. All relevant safety data from the safety run-in will be thoroughly reviewed by an IMC and by the investigators before enrollment is continued.
FIG. 5 is a flow chart of the phase lb chemotherapy expansion cohorts study design.
FIG. 6 is a flow chart of the phase lb non-chemotherapy expansion cohorts study design.
FIG. 7 is a flow chart showing the conditions for continuing study treatment beyond progression.
ECOG = Eastern Cooperative Oncology Group; RECIST = Response Evaluation Criteria in Solid Tumors.
FIG. 8 is a flow chart showing crossover from phase la to phase lb. AE =
adverse event, DLT =
dose-limiting toxicity, PD = progression of disease.
FIG. 9 is a graph showing the pharmacokinetics of tiragolumab.
FIG. 10 is a series of graphs showing the pharmacodynamics of tiragolumab.
FIG. 11 is a graph showing all adverse events 10% in a phase la tiragolumab dose-escalation study. *Grade 5 AEs were malignant neoplasm progression (n=3), not related to tiragolumab.
FIG. 12 is a graph showing all adverse events 10% in phase lb tiragolumab and atezolizumab dose-escalation study. *Grade 5 AEs were malignant neoplasm progression (n=12) and pulmonary embolism (n=2), not related to study drug(s).
FIG. 13 is a graph showing tumor size reduction in phase la tiragolumab dose-escalation study.
FIG. 14 is a graph showing tumor size reduction in phase lb tiragolumab and atezolizumab dose-escalation study.
FIG. 15 is a graph showing CIT-naive PD-L1-positive NSCLC tumor size reduction in phase lb tiragolumab and atezolizumab dose-escalation study.
FIG. 16 is a graph showing CIT-naive PD-L1-positive NSCLC tumor size reduction over time in phase lb tiragolumab and atezolizumab dose-escalation study.
FIG. 17 is a flow chart of a phase III trial schema. 1L = first-line; CE =
carboplatin and etoposide;
ECOG PS = Eastern Cooperative Oncology Group performance status; ES-SCLC =
extensive-stage small cell lung cancer; LDH = lactase dehydrogenase; RECIST = Response Evaluation Criteria in Solid Tumors; ITT= intent-to-treat; PP = primary population.
FIG. 18 is a schematic diagram of the study design showing the parameters for the selection of subjects, stratification criteria, randomization into treatment arms, and treatment endpoints.
FIG. 19 is a schematic diagram showing the design of the G042501 Phase II
clinical trial.
Patients with resectable Stage II, IIIA, or select IIIB (T3N2) non-small cell lung cancer (NSCLC) who do not have an activating EGFR mutation (EGFR-), do not have an ALKfusion oncogene (ALK-), and have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, are selected. Cohort A
consists of PD-L1 high patients. Patients in Cohort A are treated with atezolizumab (Atezo) and tiragolumab (Tira) every three weeks (Q3W) for 4 cycles. Cohort B consists of patients having any PD-L1 status. Patients in Cohort B are treated with Atezo, Tira, and platinum-based doublet chemotherapy (Chemo) Q3W for 4 cycles. Chest computed tomography (CT) is performed after Cycle 2 and Cycle 4.
Surgery is performed for patients in both cohorts, and major pathological response (MPR) and pathological complete response (pCR) are assessed. Following surgery, patients in Cohort A are treated with Atezo and Tira 03W for 16 cycles or Chemo 03W for 4 cycles. Patients in Cohort B are treated with Atezo and Tira 03W for 16 cycles. Postoperative radiotherapy (PORT) is optional for R1/R2 resections and/or ypN2 prior to adjuvant administration. Survival follow-up is performed.
FIG. 20 is a flow chart showing patient enrollment in the G042501 Phase II
clinical trial. For Cohort A (PD-L1 high patients; PD-L1 tumor proportion score (TPS) 50%), a safety lead-in is performed using 6 patients. If surgical safety criteria are not met, enrollment of Cohort A is halted. If surgical safety criteria are met, enrollment of Cohort A is continued. For Cohort B (patients with any PD-L1 status), a safety lead-in is performed using 6 patients with PD-L1 TPS < 50%. If surgical safety criteria are not met, enrollment of Cohort B is halted. If surgical safety criteria are met, enrollment of Cohort B is continued, and patients having PD-L1 TPS < 50% and PD-L1 TPS 50% are enrolled. After 8 patients with tumors expressing PD-L1 50% have been enrolled into Cohort B, enrollment of patients having PD-L1 TPS
50% into Cohort A is continued.
FIG. 21 is a flow chart of a phase ll trial schema. 1L = first line; CDx =
companion diagnostic;
ECOG PS = Eastern Cooperative Oncology Group performance status; IHC =
immunohistochemistry;
IRC = independent review committee; PD-L1 = programmed death-ligand 1; 03W =
every 3 weeks; R =
randomization; sip = status-post; IV = intravenous.
FIG. 22 is a flow chart of a Phase lb trial schema. TNBC = triple-negative breast cancer; G-CSF
= granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor;
Rand. = randomization, pCR = pathologic complete response, OW = once a week, 02W = every two weeks, 03W = every three weeks.
FIG. 23 is a flow chart of a Phase II trial schema. HPV = Human papillomavirus; IHC =
immunohistochemistry; IV = intravenous; 03W = every 3 weeks; PD-L1 low = TIC

10%-49%; PD-L1 high = TIC 50%; SCCHN = squamous cell carcinoma of head and neck; RECIST = Response Evaluation Criteria in Solid Tumors.
FIG. 24 is a schematic diagram showing the design of the muscle-invasive bladder cancer (MIBC) cohorts of the W039613 Phase 113/11 clinical trial. At the screening stage, patients having MIBC

who are cisplatin ineligible and either PD-L1 positive (+) (top) or PD-L1 negative (-) (bottom) are identified. Following randomization (R), patients are treated with atezolizumab (Atezo; control) or atezolizumab and tiragolumab (Tira).
FIG. 25 is a schematic diagram showing the design of the metastatic urothelial carcinoma (mUC) cohorts of the W039613 Phase lb/II clinical trial. At the screening stage, patients having second-line locally advanced or metastatic UC who have progressed during or following platinum-containing therapy and who are cancer immunotherapy (CIT) naïve are identified. Following randomization (R), patients are treated with atezolizumab (Atezo; control); atezolizumab and enfortumab vedotin (EV); atezolizumab and niraparib (Nira); atezolizumab and Hu5F9-G4; atezolizumab and tiragolumab (Tira); atezolizumab and sacituzumab govitecan (SG); atezolizumab and tocilizumab (TCZ); atezolizumab and R07122290 (FAP-4-1BBL); or R07121661 (PD1/TIM-3) during Stage 1. aDuring Stage 1, patients who experience loss of clinical benefit, as determined by the investigator, or unacceptable toxicity may be eligible to receive a different treatment combination during Stage 2, provided they meet the eligibility criteria. bThe Atezo+Nira arm has 40 patients. Patients who received enfortumab vedotin in Stage 1 do not receive enfortumab vedotin in Stage 2, and patients who received sacituzumab govitecan in Stage 1 do not receive sacituzumab govitecan in Stage 2; other patients who are eligible for more than one treatment arm are assigned a treatment arm by the investigator. Once the Atezo+SG arm opens, enrollment in the Atezo+EV arm is closed. dThe Atezo+R07122290 (FAP-4-1BBL) arm is only opened in ex-U.S.
countries.
FIG. 26 is a diagram showing the objective response rate (ORR) (complete response/partial response (CR/PR); stable disease/progressive disease (SD/PD); or not evaluable (NE)) in patients from the CITYSCAPE trial having low or high PD-L1 TPS as assessed by the pharmDx 22C3 IHC assay (high TPS ?...50 /0; low TPS 1-49%) or low or high PD-L1 tumor content (TC) as assessed by the CE-IVD
VENTANA SP263 IHC assay (high TC 50%; low TC 1-49%).
FIG. 27A is a bar graph showing the response rate (95% confidence interval (Cl)) for patients from the CITYSCAPE trial having a TPS A, as measured using the 22C3 IHC
assay.
FIG. 27B is a bar graph showing the response rate (95% CI) for patients from the CITYSCAPE
trial having a TC '1 /0 as measured using the 5P263 IHC assay (and TPS % as measured using the 22C3 IHC assay).
FIG. 28A is a graph showing progression-free survival (percent) for patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo and had a TPS -1 /0 as measured using the 22C3 IHC assay. The inset table shows median PFS in months (mo) and hazard ratio (HR).
FIG. 28B is a graph showing progression-free survival (percent) for patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo and had a TC 1 /0 as measured using the 5P263 IHC assay (and TPS 1 /c, as measured using the 22C3 IHC assay). The inset table shows median PFS in months and HR.
FIG. 29A is a bar graph showing the response rate (95% confidence interval (Cl)) for patients from the CITYSCAPE trial having a TPS ?..50% as measured using the 22C3 IHC
assay.

FIG. 29B is a bar graph showing the response rate (95% Cl) for patients from the CITYSCAPE
trial having a TC .?.50 /0 as measured using the SP263 IHC assay.
FIG. 30A is a graph showing progression-free survival (percent) for patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo and had a TPS 50 /µ, as measured using the 22C3 IHC assay. The inset table shows median PFS in months and HR.
FIG. 30B is a graph showing progression-free survival (percent) for patients from the CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo and had a TC 50 /0 as measured using the 513263 IHC assay. The inset table shows median PFS in months and HR.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides therapeutic methods and compositions for treatment of cancer (e.g., a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV
NSCLC (e.g., wherein the subject has not been previously treated for Stage IV
NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC
(e.g., an early TNBC
(eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HOC and/or unresectable HCC); a bladder cancer (e.g., MIBC, locally advanced UC, or m UC);
an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC);
a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC (e.g., MSS or MSI-Low CRC)). The invention is based, at least in part, on the discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with a PD-1 axis binding antagonist, a VEGF antagonist, and/or a chemotherapeutic agent can be useful in the treatment of cancer. Compositions, uses, and kits involving 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 commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D.
Flames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984);
Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press;
Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B.
Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P.
Cabs, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); lmmunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P.
Finch, 1997); Antibodies: A
Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanotti and J.
D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).
II. DEFINITIONS
It is to be understood that aspects and embodiments of the invention described herein include "comprising," "consisting," and "consisting essentially of" aspects and embodiments. As used herein, the singular form "a," "an," and "the" includes plural references unless indicated otherwise.
The term "about" as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to "about" a value or parameter herein 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" in general are used interchangeably and generally refer to the amount of a biomarker in a biological sample.
"Expression" generally refers to the process by which information (e.g., gene-encoded and/or epigenetic information) is converted into the structures present and operating in the cell. Therefore, as used herein, "expression" may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis. "Expressed genes" include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs).
An "amount" or "level" (e.g., expression level) of a biomarker can be measured by methods known to one skilled in the art and also disclosed herein. The amount or level of a biomarker associated with an increased clinical benefit to an individual can, for example, be a detectable level in a biological sample. In some aspects, the expression level or amount of a biomarker can be used to identify/characterize a subject having a cancer who may be likely to respond to, or benefit from, a particular therapy (e.g., a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist and an anti-TIGIT

antagonist antibody or a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody).
"Increased expression," "increased expression level," "increased levels,"
"elevated expression,"
"elevated expression levels," or "elevated levels" refers to an increased expression or increased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control (e.g., a housekeeping biomarker).
"Decreased expression," "decreased expression level," "decreased levels,"
"reduced expression,"
"reduced expression levels," or "reduced levels" refers to a decrease expression or decreased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control (e.g., 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 a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, immunohistochemistry ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, flow cytometry, fluorescence activated cell sorting ("FACS"), MassARRAY, proteomics, 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., next-generation sequencing), NANOSTRINGe, polymerase chain reaction (PCR) including quantitative real time PCR (qRT-PCR) and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray analysis, gene expression profiling, and/or serial analysis of gene expression ("SAGE"), as well as any one of the wide variety of assays that can be performed by protein, gene, and/or tissue array analysis.
Typical protocols for evaluating the status of genes and gene products are found, for example in Ausubel et al., eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Multiplexed immunoassays such as those available from Rules Based Medicine or IVleso Scale Discovery ("MSD") may also be used.
By "correlate" or "correlating" is meant comparing, in any way, the performance and/or results of a first analysis or protocol with the performance and/or results of a second analysis or protocol. For example, one may use the results of a first analysis or protocol in carrying out a second protocol and/or one may use the results of a first analysis or protocol to determine whether a second analysis or protocol should be performed. With respect to the aspect of polypeptide analysis or protocol, one may use the results of the polypeptide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed. With respect to the aspect of polynucleotide analysis or protocol, one may use the results of the polynucleotide expression analysis or protocol to determine whether a specific therapeutic regimen should be performed.
The phrase "substantially reduced" or "substantially different," as used herein, denotes a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference/comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values (e.g., KD values). The difference between said two values is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or greater than about 50% as a function of the value for the reference/comparator molecule.
The term "substantially similar" or "substantially the same," as used herein, denotes a sufficiently high degree of similarity between two numeric values (for example, one associated with an antibody of the invention and the other associated with a reference/comparator antibody), such that one of skill in the art would consider the difference between the two values to be of little or no biological and/or statistical significance within the context of the biological characteristic measured by said values (e.g., KD values).
The difference between said two values is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and/or less than about 10% as a function of the reference/comparator value.
The phrase "based on" when used herein means that the information about one or more biomarkers is used to inform a treatment decision, information provided on a package insert, or marketing/promotional guidance, and the like.
The term "TIGIT" or "T-cell immunoreceptor with Ig and ITIM domains" as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses "full-length," unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ
ID NO: 30), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO:
31). The term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1.
The terms "programmed death ligand 1" and "PD-L1" refer herein to native sequence human PD-L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot Accession No.
Q9NZQ7 (SEQ ID NO: 32). For example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1). In another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3). The term also encompasses naturally occurring variants of PD-L1, e.g., splice variants, or allelic variants. PD-L1 is also referred to in the art as "programmed cell death 1 ligand 1," "PDCD1LG1," "CD274," "B7-H," and "PDL1."
The term "PD-1" or "Programmed Cell Death protein 1" refers herein to any native PD-1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. PD-1 is also known in the art as CD279, PDCD1, and programmed cell death 1. The term also encompasses naturally occurring variants of PD-1, e.g., splice variants, or allelic variants. The amino acid sequence of an exemplary human PD-1 may be found under UniProt Accession Number Q15116.

The term "PD-L2" or "Programmed Cell Death 1 Ligand 2" refers herein to any native PD-L2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. PD-L2 is also known in the art as CD273 molecule, B7DC, and PDCD1L2. The term also encompasses naturally occurring variants of PD-L2, e.g., splice variants, or allelic variants. The amino acid sequence of an exemplary human PD-L2 may be found under UniProt Accession Number Q9BQ51.
The term "antagonist" is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments (e.g., antigen-binding fragments), fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying antagonists of a polypeptide may comprise contacting a polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.
The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In one aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.
In another aspect, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In another aspect, the PD-1 axis binding antagonist is a PD-L2 binding antagonist.
The term "PD-1 binding antagonist" refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. 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 instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1. In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680 (AMP 514), PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, BI

754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, OX-188, JTX-4014, 609A, Sym021, LZMO09, F520, S0001, AM0001, ENUM 24408, ENUM 388D4, STI-1110, AK-103, and hAb21.
In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab, previously known as lambrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MEDI-0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. 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 an antigen-binding fragment or variant thereof that is capable of binding PD-1 with sufficient affinity such that it substantially or completely inhibits the biological activity of PD-1. For example, an anti-PD-1 antagonist antibody may decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with either one or more of its binding partners, such as PD-L1 and/or PD-L2.
It will be understood by one of ordinary skill 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 of the methods or uses described herein is an anti-PD-1 antagonist antibody that antagonizes PD-1 activity in response to one of its binding partners (e.g., PD-L1 or PD-L2) without affecting or minimally affecting any of the other PD-1 interactions. In one aspect, the extent of binding of an anti-PD-1 antagonist antibody to an unrelated, non-PD-1 protein is less than about 10% of the binding of the antibody to PD-1 as measured, e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-PD-1 antagonist antibody that binds to PD-1 has a dissociation constant (KD) of 5 1pM, 5 100 nM, 5 10 nM, 5. 1 nM, 5. 0.1 nM, 5. 0.01 nM, or 5 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 1013 M, e.g., from 10-9 M to 10-13 M). In certain aspects, an anti-PD-1 antagonist antibody binds to an epitope of PD-1 that is conserved among PD-1 from different species or an epitope on PD-1 that allows for cross-species reactivity. 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" refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1. In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1. In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional 1-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1.
In some instances, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, 1OB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, 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 specific 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 (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab, marketed as TECENTRIQTm.
Atezolizumab is described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485). In another specific aspect, an anti PD-L1 antibody is MSB0015718C.
The term "anti-PD-L1 antagonist antibody" refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding PD-L1 with sufficient affinity such that it substantially or completely inhibits the biological activity of PD-L1. For example, an anti-PD-L1 antagonist antibody may decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1.
It will be understood by one .. of ordinary skill 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, an anti-PD-L1 antagonist antibody for use in certain of the methods or uses described herein is an anti-PD-L1 antagonist antibody that antagonizes PD-L1 activity in response to one of its binding partners (e.g., PD-1 or B7-1) without affecting or minimally affecting any of the other PD-L1 interactions. In one aspect, the extent of binding of an anti-PD-L1 antagonist antibody to an unrelated, non-PD-L1 protein is less than about 10% of the binding of the antibody to PD-L1 as measured, e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-PD-L1 antagonist antibody that binds to PD-L1 has a dissociation constant (Ka) of 5 1pM, 5 100 nM, 5 10 nM, 5 1 nM, 5 0.1 nM, 5 0.01 nM, or 5. 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9 M to 10-13 M). In certain aspects, an anti-PD-L1 antagonist antibody binds to an epitope of PD-L1 that is conserved among PD-L1 from different species or an epitope on PD-L1 that allows for cross-species reactivity. In one aspect, the anti-PD-L1 antagonist antibody is atezolizumab.
The term "PD-L2 binding antagonist" refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. 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." An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51.
In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a 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 other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin.
Further examples of PD-1 axis binding antagonists include cemiplimab, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, spartalizumab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001, envafolimab, 1QB2450, ZKAB001, LP-002, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, CX-072, IMC-001, KL-A167, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZMO09, F520, SG001, APL-502, cosibelimab, lodapolimab, GS-4224, INCB086550, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004, AM0001, CB201, ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21, AVA-004, PDL-GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL-007, ABSK041, GB7003, JS-003, and HS-636.
For the purposes herein, "atezolizumab" is an Fc-engineered, humanized, 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 comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU
numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485).
As used herein, "pembrolizumab" is a recombinant humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1. Pembrolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 72, Vol. 28, No. 3, published 2014 (see page 407).
As used herein, "tiragolumab" is a fully human IgG1/kappa MAb-derived in Open Monoclonal Technology (OMT) rats that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 33 and the light chain sequence of SEQ ID NO: 34. Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31, No. 2, published July 7, 2017 (see page 343).

As used herein, "bevacizumab" is a recombinant humanized monoclonal antibody that recognizes all isoforms of VEGF, which is described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 83, Vol. 14, No. 2, published 2000 (see page 107).
Bevacizumab comprises the heavy chain variable region sequence of SEQ ID NO: X
and the light chain variable region sequence of SEQ ID NO: X.
The term "anti-TIGIT antagonist antibody" refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody may block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation.
For example, an anti-TIGIT antagonist antibody may block signaling through PVR
without impacting PVR-CD226 interaction. It will be understood by one of ordinary skill 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 of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions. In one aspect, the extent of binding of an anti-TIGIT
antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT as measured, e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-TIGIT
antagonist antibody that binds to TIGIT has a dissociation constant (KD) of 5 1pM, _5 100 nM, _5 10 nM, _5 1 nM, _5 0.1 nM, _5 0.01 nM, or 5 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M
to 10-13 M). In certain aspects, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT
from different species or an epitope on TIGIT that allows for cross-species reactivity. In some aspects, the anti-TIGIT binding antibody has intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, E0S084448, or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc-mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT
binding antibody lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or C0M902). In some aspects, the anti-TIGIT binding antibody is an IgG1 class antibody (e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, E0S084448 (E0S-448), TJ-T6, or AB308). In other aspects, the anti-TIGIT binding antibody is an IgG4 class antibody (e.g., ASP8374 or C0M902). In one aspect, the anti-TIGIT antagonist antibody is tiragolumab.
As used herein, "administering" is meant a method of giving a dosage of a compound (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF
antagonist, or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin)), an antibody-drug conjugate (ADC) (e.g., enfortumab vedotin or sacituzumab govitecan), and/or a colony stimulating factor (CSF) (e.g., pegfilgrastim, filgrastim, or sargramostim)) to a subject. The compounds and/or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).
A "fixed" or "flat" dose of a therapeutic agent (e.g., an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic agent), an ADC (e.g., enfortumab vedotin or sacituzumab govitecan), or a CSF (e.g., pegfilgrastim, filgrastim, or sargramostim)) refers to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose is therefore not provided as a mg/kg dose or a mg/m2 dose, but rather as an absolute amount of the therapeutic agent (e.g., absolute amount of the therapeutic agent in mg).
As used herein, the term "treatment" or "treating" refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals. For example, treating comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic agent), an ADC
(e.g., enfortumab vedotin or sacituzumab govitecan), and/or a CSF (e.g., pegfilgrastim, filgrastim, or sargramostim)) or combination of therapeutic agents. Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. The treatment may be first-line treatment (e.g., the patient may be previously untreated or not have received prior systemic therapy), or second line or later treatment.
As used herein, "in combination with" or "in conjunction with" refers to administration of one treatment modality in addition to another treatment modality, for example, a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., atezolizumab), a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic agent), an ADC (e.g., enfortumab vedotin or sacituzumab govitecan), and/or a CSF
(e.g., pegfilgrastim, filgrastim, or sargramostim) and an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab). As such, "in combination with" refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the patient.
A drug that is administered "concurrently" with one or more other drugs is administered during the same treatment cycle, on the same day of treatment, as the one or more other drugs, and, optionally, at the same time as the one or more other drugs. For instance, for cancer therapies given every 3 weeks, the concurrently administered drugs are each administered on day 1 of a 3-week cycle.
As used herein, the term "perioperative treatment" refers to a treatment that is administered before and after a surgery. A perioperative treatment may include administration of a neoadjuvant therapy prior to a surgery (e.g., a cystectomy) and a therapy (e.g., an adjuvant therapy) following the surgery. For example, a perioperative treatment may include a neoadjuvant therapy (e.g., an anti-TIGIT
antagonist antibody and a PD-1 axis binding antagonist neoadjuvant therapy) that is administered after diagnosis and before (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 weeks or more before) a surgery (e.g., a cystectomy) and a therapy (e.g., an adjuvant therapy (e.g., an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist adjuvant therapy)) following the surgery (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 weeks or more following the surgery).
A "disorder" or "disease" is any condition that would benefit from treatment including, but not limited to, disorders that are associated with some degree of abnormal cell proliferation, e.g., cancer.
The term "dysfunction," in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation.
The term "dysfunctional," as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon) and/or target cell killing.
The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Cancers include solid tumor cancers and non-solid tumor cancers and locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors). Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include, but are not limited to urothelial carcinoma (UC), including locally advanced and metastatic UC (mUC), bladder cancer (e.g., muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC), e.g., BCG-refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney or renal cancer (e.g., renal cell carcinoma (RCC)); cancer of the urinary tract; lung cancer, such as small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung, or squamous cell cancer (e.g., epithelial squamous cell cancer (e.g., squamous carcinoma of the lung); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)); head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN, and head and neck squamous cell cancer (HNSCC); ovarian cancer (OC); esophageal cancer; cancer of the peritoneum;
hepatocellular cancer; gastric cancer (GC) (e.g., gastroesophageal junction (GEJ) cancer) or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer;
glioblastoma; cancer of the urinary tract; hepatoma; breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC (e.g., early TNBC (eTNBC)), which are estrogen receptors (ER-), progesterone receptors (PgR-), and HER2 (HER2-) negative); prostate cancer, such as castration-resistant prostate cancer (CRPC);
cancer of the peritoneum; hepatocellular cancer; gastric or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); 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)),; endometrial or uterine carcinoma; salivary gland carcinoma; prostate cancer; vulval cancer; thyroid cancer; hepatic carcinoma;
anal carcinoma; penile carcinoma; melanoma, including superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, and nodular melanomas; multiple myeloma and B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) NHL;
intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myologenous leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, brain cancer, head and neck cancer, and associated metastases.
The term "persistent cervical cancer" as used herein refers to a cervical cancer that has not been rendered undetectable or benign after previous therapy.
As used herein, "Stage IVB cervical cancer" refers to a cervical cancer that is classified as such using a cervical cancer staging system (e.g., International Federation of Gynecology and Obstetrics (FIGO) staging system). In some aspects, a cervical cancer is classified as Stage IVB if it has metastasized to distant organs (including the parenchyma of the spleen or liver) or to the inguinal and extra-abdominal lymph nodes.
As used herein, the term "recurrent cervical cancer" refers to a cervical cancer that has been detected or has returned following an 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 (e.g., 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 a type of cancer that typically occurs in the urinary system, and includes muscle-invasive bladder cancer (MIBC) and muscle-invasive urinary tract urothelial cancer (UTUC). UC is also referred to in the art as transitional cell carcinoma (TCC).
The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive as referred to herein.
A "tumor cell" as used herein, refers to any tumor cell present in a tumor or a sample thereof.
Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and/or described herein.
"Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.
As used herein, "metastasis" is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass.
Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.
The term "cytotoxic agent" as used herein refers to any agent that is detrimental to cells (e.g., causes cell death or destruction, inhibits proliferation, or otherwise inhibits or prevents a cellular function).
Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, 1131, 1125, yso, Reis, Rem, srn1535 131212, p32, pb212 and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; 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 the various antitumor or anti-cancer agents disclosed below. Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one instance, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one instance, the cytotoxic agent is an antagonist of EGFR, e.g., N-(3-ethynylphenyI)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib).
In one instance the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor. In one instance the RAF inhibitor is vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.
"Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer.
Examples of chemotherapeutic agents include erlotinib (TARCEVA0, Genentech/OSI
Pharm.), bortezomib (VELCADE , Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX , AstraZeneca), sunitinib (SUTENT , Pfizer/Sugen), letrozole (FEMARA
, Novartis), imatinib mesylate (GLEEVECe, Novartis), finasunate (VATALANIBe, Novartis), oxaliplatin (ELOXATINe, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNEe, Wyeth), Lapatinib (TYKERB , GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR , Bayer Labs), gefitinib (IRESSA0, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXANe cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1);
eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;
antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1I and calicheamicin w1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCINe (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;
pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane;
folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine;

bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone;
elfomithine; elliptinium acetate;
an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine;
maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;
nitraerine; pentostatin;
phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSKe .. polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane;
rhizoxin; sizofuran;
spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine;
trichothecenes (especially 1-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine;
mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa;
taxanes (taxoids), e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (e.g., nanoparticle albumin-engineered paclitaxel (nab-paclitaxel)) (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE (docetaxel, doxetaxel; Sanofi-Aventis);
chloranmbucil; GEMZARe (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;
vincristine; NAVELBINE0 (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin;
capecitabine (XELODAe);
ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMF0); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTONe (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE
(megestrol acetate), AROMASIN (exemestane; Pfizer), formestanie, fadrozole, RIVISOR (vorozole), FEMARA (letrozole; Novartis), and ARIMIDEX (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans retionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors (e.g., an anaplastic lymphoma kinase (Alk) inhibitor, such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME0) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN , LEUVECTIN , and VAXIDe; PROLEUKINe, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECANe;
ABARELIXe rmRH;
and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.
Chemotherapeutic agents also include "platinum-based" chemotherapeutic agents, also referred to herein as "platinum agents," which comprise an organic compound which contains platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes called "platins" in the art. Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin. Platinum-based chemotherapeutic agents (e.g., cisplatin or carboplatin) may be administered in combination with one or more additional chemotherapeutic agents, e.g., a nucleoside analog (e.g., gemcitabine), an antimetabolite (e.g., pemetrexed or gemcitabine), or a taxane (e.g., paclitaxel or nab-paclitaxel).
The term "eligible for treatment with a platinum-based chemotherapy" means that the subject is eligible for treatment with a platinum-based chemotherapy, either in the attending clinician's judgment or according to standardized criteria for eligibility for platinum-based chemotherapy that are known in the art.
Chemotherapeutic agents also include "non-platinum-based chemotherapeutic agents," which, as used herein, refer to chemotherapeutic agents that are not "platinum-based."
As used herein, the terms "non-platinum-based chemotherapeutic agents" and "non-platinum agents" are used interchangeably.
Exemplary non-platinum-based chemotherapeutic agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), taxanes (e.g., paclitaxel (e.g., albumin-engineered paclitaxel, also referred to as nanoparticle-albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).
Exemplary non-platinum-based chemotherapeutic agents also include alkylating agents (e.g., cyclophosphamide).
A "nucleoside analog," as used herein, refers to a nucleoside that includes a nucleic acid analog and a sugar. Nucleoside analogs may function as antimetabolites. Exemplary nucleoside analogues include but are not limited to gemcitabine, cytarabine, fludarabine, and cladribine.
A "taxane" as used herein is a diterpene which may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization.
Taxanes included herein include taxoid 10-deacetylbaccatin Ill and/or derivatives thereof. Exemplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL", CAS # 33069-62-4), docetaxel (i.e., TAXOTERE , CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel. In some aspects, the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., ABRAXANE" and/or nab-docetaxel, ABI-008). In some aspects, the taxane is nab-paclitaxel (ABRAXANE"). In some aspects, the taxane is formulated in CREMAPHOR" (e.g., TAXOL") and/or in Tween such as polysorbate 80 (e.g., TAXOTERE"). In some aspects, the taxane is liposome-encapsulated taxane. In some aspects, the taxane is a prodrug form and/or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleylcarbonate-paclitaxel). In some aspects, the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR and/or Tween-such as TOCOSOL"
paclitaxel).
An "antimetabolite" as used herein is a chemotherapeutic agent that interferes with and inhibits (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell).
Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.
Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, paliferm in, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.
Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate;
immune selective anti-inflammatory peptides (1mSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA0); Interleukin 13 (IL-13) blockers such as lebrikizumab;
Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7;
IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/132 blockers such as Anti-lymphotoxin alpha (LTa);
radioactive isotopes (e.g., At211, 1131,1125, Y90, Re186, Re188, 5m153, Bi212, P32, Pb212 and radioactive isotopes of Lu);
miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOLO); beta-lapachone; lapachol; colchicines; betulinic acid;
acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL0); bexarotene (TARGRETINO);
bisphosphonates such as clodronate (for example, BONEFOSO or OSTAC0), etidronate (DIDROCAL0), NE-58095, zoledronic acid/zoledronate (ZOMETA8), alendronate (FOSAMAX0), pamidronate (AREDIA0), tiludronate (SKELIDO), or risedronate (ACTONEL0); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE vaccine; perifosine, COX-2 inhibitor (e.g., celecoxib or etoricoxib), proteosome inhibitor (e.g., PS341); CCI-779; tipifarnib (R11577);
orafenib, ABT510; BcI-2 inhibitor such as oblimersen sodium (GENASENSE0); pixantrone;
farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
Chemotherapeutic agents also include "EGFR inhibitors," which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist." Examples of such agents include small molecules that bind to EGFR. EGFR antagonists include small molecules such as compounds described in US Patent Nos:
5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT
publications: W098/14451, W098/50038, W099/09016, and W099/24037. Particular small molecule EGFR
antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA Genentech/OSI Pharmaceuticals); PD
183805 (Cl 1033, 2-propenamide, Ni4-[(3-chloro-4-fluorophenyl)amino]-743-(4-morpholinyppropoxy]-6-quinazolinyli-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA6) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-pheny1)-N2-(1-methyl-piperidin-4-y1)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Inge!helm); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-y1]-phenol); (R)-6-(4-hydroxypheny1)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N44-[(3-bromophenyl)amino]-6-quinazoliny1]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinoliny1]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERI36, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]pheny1]-6[5[[[2methylsulfonypethyl]aminoimethyl]-2-furany11-4-quinazolinamine).
Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR-targeted drugs noted in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI8), and ceritinib (ZYKADIA8); small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER
inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (G5K572016; available from Glaxo-SmithKline), an oral HER2 and EGFR

tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER
inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS
Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC , available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT , available from Pfizer); VEGF receptor tyrosine kinase inhibitors 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) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]
pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid);
quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396);
ZD6474 (Astra Zeneca);
PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer);
Affinitac (ISIS 3521;
Isis/Lilly); imatinib mesylate (GLEEVEC0); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG);
INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE ); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO

(American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO
1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).
The term "anthracycline" relates to a chemotherapeutic agent, an anticancer agent for inducing apoptosis, preferably by inhibiting the rebinding of DNA in topoisomerase II.
Examples include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pyrarubicin, valrubicin, N-trifluoro-acetyl doxorubicin-14-valerate, aclacinomycin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), 5-iminodaunomycin, mitoxantrone and aclacinomycin A (aclarubicin). In some aspects, the anthracycline is administered in combination with an alkylating agent, e.g., doxorubicin in combination with cyclophosphamide (treatment with AC).
An "alkylating agent" as used herein is a chemotherapeutic agent which causes DNA damage by attaching an alkyl group to DNA. Alkylating agents include cyclophosphamide and N,I\l',N"-triethylenethiophosphoramide.
An "effective amount" of a compound, for example, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody), a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic agent), an ADC (e.g., enfortumab vedotin or sacituzumab govitecan), or a CSF (e.g., pegfilgrastim, filgrastim, or sargramostim), is at least the minimum amount required to achieve the desired therapeutic result, such as a measurable increase in overall survival or progression-free survival of a particular disease or disorder (e.g., a cancer).
An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the subject. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSE), reduction in symptoms per the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or general level of physical emotional, cognitive, or social functioning), reduction in pain as measured by, e.g., the 10-point pain severity (measured at its worst) numerical rating scale (NRS), increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease (e.g., progression-free survival or radiographic progression-free survival (rPFS); delay of unequivocal clinical progression (e.g., cancer-related pain progression, symptomatic skeletal-related event, deterioration in Eastern Cooperative Group Oncology Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily living abilities of the patient), and/or initiation of next systemic anti-cancer therapy), and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, 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. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. In some aspects, beneficial or desired results are reduction in symptoms associated with lung cancer per the health-related quality of life (HROoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspnea and chest pain) and/or delaying time to lung-specific antigen progression).
"Immunogenicity" refers to the ability of a particular substance to provoke an immune response.
Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response. Examples of enhancing tumor immunogenicity include but are not limited to treatment with a TIGIT and/or PD-L1 antagonist (e.g., anti-TIGIT antagonist antibodies and/or anti-PD-L1 antibodies).
"Individual response" or "response" can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., progression of cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a UC, e.g., a bladder cancer (e.g., an MIBC), a urothelial bladder cancer (UBC), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a hepatocellular carcinoma (HCC), a colorectal cancer (CRC; e.g., CRC
with microsatellite-stable (MSS) and microsatellite instability (MSI) low (MSI-Low)), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PgR-), and HER2 (HER2-) negative))), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) increase or extend in the length of survival, including overall survival and progression-free survival; and/or (9) decreased mortality at a given point of time following treatment.
As used herein, "pathological complete response" (pCR) is defined as the proportion of patients with an absence of residual invasive cancer of the complete resected specimen.
In the context of breast cancer, "pathological complete response" or "pCR" refers to eradication of tumor from both breast and lymph nodes (ypTO/is ypN0).
As used herein in the context of urothelial carcinoma (UC), "pathological downstaging rate" is defined as the proportion of patients that reach pT1pN0 at the time of cystectomy.
As used herein, "complete response" or "CR" refers to disappearance of all target lesions.
As used herein, "partial response" or "PR" refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.
As used herein, "objective response rate" (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate.
As used herein, "duration of objective response" (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression, or death from any cause within 30 days of the last dose of a treatment, whichever occurs first.
"Sustained response" refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some aspects, the sustained response has a duration at least the same as the treatment duration, at least 1.5x, 2.0x, 2.5x, or 3.0x length of the treatment duration.
An "effective response" of a subject or a subject's "responsiveness" to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a subject as risk for, or suffering from, a disease or disorder, such as cancer. In one aspect, such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a CR or a PR); or improving signs or symptoms of cancer.
A subject who "does not have an effective response" to treatment refers to a subject who does not have any one of extending survival (including overall survival and progression free survival); resulting .. in an objective response (including a CR or a PR); or improving signs or symptoms of cancer.
As used herein, "survival" refers to the patient remaining alive, and includes overall survival as well as progression-free survival.
As used herein, "overall survival" and "OS" refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer) that the patient is still alive. For example, OS may be defined as the time from randomization to death from any cause.
As used herein, "overall survival rate" refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., six months, 1 year, or 5 years from the time of diagnosis or treatment.
As used herein, "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.
As used herein, "event-free survival" (EFS) is defined as the time from randomization to any of the following events (whichever occurs first): disease progression (e.g., progression that precludes surgery, as assessed by the investigator); local or distant disease recurrence; or death from any cause.
As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a CR or a PR, as well as the amount of time patients have experienced stable disease.
As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify for CR or PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
As used herein, "progressive disease" or "PD" refers to at least a 20%
increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.
As used herein, "major pathological response" (MPR) is defined as 10% residual viable tumor at the time of surgical resection in the primary tumor.
As used herein, "delaying progression" of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease. For example, in a late stage cancer, development of central nervous system (CNS) metastasis, may be delayed.
As used herein, the term "reducing or inhibiting cancer relapse" means to reduce or inhibit tumor or cancer relapse, or tumor or cancer progression.

By "reduce or inhibit" is meant the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to the symptoms of the disorder being treated (e.g., cancer), the presence or size of metastases, or the size of the primary tumor.
By "extending survival" is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent. An objective response refers to a measurable response, including CR or PR.
The terms "detecting" and "detection" are used herein in the broadest sense to include both qualitative and quantitative measurements of a target molecule. Detecting includes identifying the mere presence of the target molecule in a sample as well as determining whether the target molecule is present in the sample at detectable levels. Detecting may be direct or indirect.
As used herein, a "PD-L1-positive tumor cell fraction" is the percentage of viable tumor cells showing partial or complete membrane staining (exclusive of cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample, following staining of the sample in the context of an immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using the antibody SP142, SP263, 22C3, or 28-8. Accordingly, a PD-L1-positive tumor cell fraction may be calculated using the PD-L1 IHC SP263 (Ventana) assay, for example, by 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), wherein PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond with a particular IHC
assay protocol and/or scoring terminology that can be used to derive a PD-L1-positive tumor cell fraction. For example, a PD-L1-positive tumor cell fraction can be derived from a tumor cell sample stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTIVIEWO detection and amplification on Benchmark ULTRA, or EnVision Flex on AutostainerLink 48, respectively. In another example, a PD-L1-positive tumor cell fraction may be calculated using the PD-L1 IHC 22C3 pharmDx assay (Dako) according to the formula above. A skilled artisan will appreciate that the sensitivities can vary between different PD-L1 antibodies used in IHC
assays. For example, only about 64% of samples that meet a 1% TC or 25% TC threshold, as defined respectively by staining with 28-8 or 22C3 and SP263, 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 proportion score" (TPS) are used interchangeably.
As used herein, the "Ventana SP142 IHC assay" is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
As used herein, the "Ventana 5P263 IHC assay" is conducted according to the Ventana PD-L1 (5P263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

As used herein, the "pharmDx 22C3 IHC assay" is conducted according to the PD-pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.
As used herein, the "pharmDx 28-8 IHC assay" is conducted according to the PD-pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.
A "tumor-infiltrating immune cell," as used herein, refers to any immune cell present in a tumor or a sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stroma cells (e.g., fibroblasts), or any combination thereof.
Such tumor-infiltrating immune cells can be, for example, T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.
The term "biomarker," as used herein, refers to an indicator, e.g., predictive, diagnostic, and/or prognostic, which can be detected in a sample, for example, PD-L1, ctDNA, or cytokines (e.g., cytokines associated with T-cell activation and/or lymphocyte subpopulations). The biomarker may 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 aspects, a biomarker is a gene.
Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA (e.g., ctDNA), and/or RNA), polynucleotide copy number alterations (e.g., DNA copy numbers), polypeptide and polynucleotide modifications (e.g., posttranslational modifications), carbohydrates, and/or glycolipid-based molecular markers. In some aspects, the biomarker is PD-L1. In some aspects, the biomarker is ctDNA. In some aspects, the biomarker is one or more cytokines (e.g., one or more cytokines associated with T-cell activation and/or lymphocyte subpopulations). In some aspects, the biomarker is a cell (e.g., an immune cell, e.g., a T cell, e.g., a T cell subset, e.g., an activated T cell). In some aspects, the biomarker is a direct or indirect indicator of human papillomavirus (HPV) status. In some aspects, the biomarker is p16.
In some aspects, the biomarker is an HPV protein or nucleic acid.
The term "housekeeping biomarker" refers to a biomarker or group of biomarkers (e.g., polynucleotides and/or polypeptides) which are typically similarly present in all cell types. In some aspects, the housekeeping biomarker is a "housekeeping gene." A "housekeeping gene" refers herein to a gene or group of genes which encode proteins whose activities are essential for the maintenance of cell function and which are typically similarly present in all cell types.
As used herein, "circulating tumor DNA" and "ctDNA" refer to tumor-derived DNA
in the circulatory system that is not associated with cells. ctDNA is a type of cell-free DNA (cfDNA) that may originate from tumor cells or from circulating tumor cells (CTCs). ctDNA may be found, e.g., in the bloodstream of a patient, or in a biological sample (e.g., blood, serum, plasma, or urine) obtained from a patient. In some aspects, ctDNA may include aberrant mutations (e.g., patient-specific variants) and/or methylation patterns.
The term "antibody" includes monoclonal antibodies (including full-length antibodies which have an immunoglobulin Fc region), polyclonal antibodies, antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies, and single-chain molecules, as well as antibody fragments, including antigen-binding fragments, such as Fab, F(ab')2, and Fv, so long as they exhibit the desired biological activity. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. In one instance, the antibody is a full-length monoclonal antibody.
The term IgG "isotype" or "subclass" as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.
Depending on the amino acid sequences of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, e, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mot.
Immunology, 401 ed. (W.B.
Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.
The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages in combination with the J chain. In the case of IgGs, the 4-chain unit is generally about 150,000 Da!tons. 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 the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and y chains and four CH domains for p. and c isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain at its other end. The VL is aligned with the VH
and the CL is aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G.
Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain 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, having heavy chains designated a, 6, c, y, and po, respectively. The y and a classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1 and IgA2.

The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example "complementarity determining regions" ("CDRs").
Generally, antibodies comprise six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:
(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. MoL Biol. 196:901-917 (1987));
(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. MoL Biol. 262: 732-745 (1996)).
Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra. One of skill in the art will understand that the CDR designations can also 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 complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR
domains: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.
The term "variable-domain residue-numbering as in Kabat" or "amino-acid-position numbering as in Kabat," and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat etal., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (e.g., residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard"
Kabat numbered sequence.
The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., 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 generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., 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 across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see Kabat eta!,, Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
The "variable region" or "variable domain" of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as "VH" and "VL", respectively. These domains are generally the most variable parts of the 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 FR of a variable domain generally consists of four FR domains:
FR1, FR2, FR3, and FR4.
Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): 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 an antibody fragment. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, the intact antibody may have one or more effector functions.
A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.
An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and/or the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(a1.3)2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produced two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1).
Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(a1:02 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region.
Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(a1.3')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 comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.
"Functional fragments" of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability. Examples of antibody fragments include linear antibody, 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. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute 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 comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
"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 enables the sFv to form the desired structure for antigen binding. For a review of the sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).
The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a 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. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447).
Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (31y446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without the C-terminal lysine (Lys447) if not indicated otherwise. In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine residue (G446). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal lysine residue (K447). In one aspect, the Fc region contains a single amino acid substitution N297A of the heavy chain.
Unless otherwise specified herein, numbering of amino acid residues in the Fe region or constant region is according to the EU
numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
"Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG
antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition 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 etal., Immunomethods 4: 25-34 (1994);
and de Haas et al., J.
.. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein.
The term "diabodies" refers to small antibody fragments prepared by constructing sFy fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" sFy fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described in greater detail in, for example, EP 404,097; WO 93/11161;
Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).
The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is (are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest.
As used herein, "humanized antibody" is used a subset of "chimeric antibodies."
The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG2, IgG3, !gat, IgAi, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 6, e, y, and 11, respectively.
"Affinity" refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen, e.g., TIGIT, PD-L1, or VEGF). Unless indicated otherwise, as used herein, "binding affinity"
refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KO.
Affinity can be measured by common methods known in the art, including those described herein.
Specific illustrative and exemplary aspects for measuring binding affinity are described in the following.
A "human antibody" is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et aL, J. MoL Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole eta!,, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985); Boerner etal., J. ImmunoL, 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. PharmacoL, 5:368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSETm technology). See also, for example, Li etal., Proc. Natl. Acad. ScL USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.
"Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one aspect, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR
(hereinafter defined) of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and/or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR
regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR are typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin. For further details, see, e.g., Jones etal., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunot 1:105-115(1998); Harris, Biochem. Soc.
Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat.
Nos. 6,982,321 and 7,087,409.

The term an "isolated antibody" when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). In preferred aspects, the antibody will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes antibodies in situ within recombinant cells, because at least one component of the polypeptide 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 population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.
As used herein, the term "binds," "specifically binds to," or is "specific for" refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets. In one aspect, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by a radioimmunoassay (RIA). In certain aspects, an antibody that specifically binds to a target has a dissociation constant (KD) of 5. 1pM, .5. 100 nM, 5 10 nM, 5. 1 nM, or 5. 0.1 nM. In certain aspects, an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species. In another aspect, specific binding can include, but does not require exclusive binding. The term as used herein can be exhibited, for example, by a molecule having a KD
for the target of 10-4M or lower, alternatively 10-5M or lower, alternatively 10-6 M or lower, alternatively 10-7 M or lower, alternatively 10-8 M or lower, alternatively 10-0 M or lower, alternatively 10-10 M or lower, alternatively 10-1' M or lower, alternatively 10-12 M or lower or a KD in the range of 10-4 M to 10-6 M or 10-6 M to 10-10 M or 10-7 M to 10-0 M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In one aspect, the term "specific binding" refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
"Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full 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 was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D.
All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain A, amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:
100 times the fraction X/Y
where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B
will not equal the %
amino acid sequence identity of B to A. Unless specifically stated otherwise, all ./0 amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.
As used herein, "subject" or "individual" is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
In some aspects, the subject is a human. Patients are also subjects herein.
The term "patient" refers to a human patient. For example, the patient may be an adult.

The term "diagnosis" is used herein to refer to the identification or classification of a molecular or pathological state, disease or condition (e.g., cancer). For example, "diagnosis" may refer to identification of a particular type of cancer. "Diagnosis" may also refer to the classification of a particular subtype of cancer, for instance, by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)).
The term "sample," as used herein, refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example, based on physical, biochemical, chemical, and/or physiological characteristics. For example, the phrase "tumor sample", "disease sample" and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.
Samples include, but are not limited to, tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, stool, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof.
By "tissue sample" or "cell sample" is meant a collection of similar cells obtained from a tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ.
For instance, a "tumor sample" is a tissue sample obtained from a tumor or other cancerous tissue. The tissue sample may contain a mixed population of cell types (e.g., tumor cells and non-tumor cells, cancerous cells and non-cancerous cells). The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, wax, nutrients, antibiotics, or the like. In some aspects, the sample is a tumor tissue sample. In some aspects, the tumor tissue sample is a UC tumor tissue sample (e.g., a bladder cancer tumor tissue sample (e.g., an MIBC tumor tissue sample)). In some aspects, the sample is a transurethral resection of bladder tumor (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., an early stage lung cancer tissue sample (e.g., an NSCLC tumor tissue sample (e.g., a stage II, IIIA, or IIIB
NSCLC tumor tissue sample), e.g., squamous or non-squamous NSCLC tumor tissue sample, e.g., a resectable NSCLC tumor tissue sample)). In some aspects, the sample is a locally advanced unresectable NSCLC tumor tissue sample (e.g., Stage IIIB NSCLC tumor tissue sample), or recurrent or metastatic NSCLC tumor tissue sample (e.g., Stage IV NSCLC tumor tissue sample)), a pancreatic cancer tumor tissue sample (e.g., a PDAC tumor tissue sample), e.g., a metastatic PDAC tumor tissue sample)), or a breast cancer tumor tissue sample (e.g., a H ER2+ breast cancer tumor tissue sample or a TNBC tumor tissue sample).

For the purposes herein a "section" of a tissue sample is meant a single part or piece of a tissue sample, for example, a thin slice of tissue or cells cut from a tissue sample (e.g., a tumor sample). It is to be understood that multiple sections of tissue samples may be taken and subjected to analysis, provided that it is understood that the same section of tissue sample may be analyzed at both morphological and molecular levels, or analyzed with respect to polypeptides (e.g., by immunohistochemistry) and/or polynucleotides (e.g., by in situ hybridization).
A "reference sample," "reference cell," "reference tissue," "control sample,"
"control cell," or "control tissue," as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes. In one aspect, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject or individual. For example, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue may be healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another aspect, a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject or individual. In yet another aspect, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of an individual who is not the subject or individual. In even another aspect, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject or individual.
The term "protein," as used herein, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length," unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.
"Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction. Thus, for instance, polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA
including single- and double-stranded regions, single- and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-stranded or, more typically, double-stranded or include single- and double-stranded regions. In addition, the term "polynucleotide" as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules.
The regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically includes mRNA and cDNAs.
A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The 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, for example, "caps," substitution of one or more of the naturally-occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, and the like) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the like), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, and the like), those with intercalators (e.g., acridine, psoralen, and the like), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, and the like), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-0-methyl-, 2'-0-ally1-, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, aspects wherein phosphate is replaced by P(0)S ("thioate"), P(S)S ("dithioate"), "(0)NR2 ("amidate"), P(0)R, P(0)OR', CO or CH2 ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA
and DNA.
"Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. 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) polypeptide;
proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine;
monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins;
chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol;
salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTm, polyethylene glycol (PEG), and PLURONICSTM.
The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products or medicaments that contain information about the indications, usage, dosage, administration, combination therapy, other medicaments to be combined with the packaged product, and/or contraindications and/or warnings concerning the use of such therapeutic products or medicaments.
As used herein, the term "induction phase" refers to a series of one or more dosing cycles (e.g., about 4-6 cycles) of one or more therapeutic agents (e.g., an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, and/or a chemotherapeutic agent) administered to a subject, wherein the one or more dosing cycles are optionally followed by a maintenance phase.
The term "maintenance phase" as used herein refers to a series of one or more dosing cycles of .. one or more therapeutic agents (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and/or a chemotherapeutic agent) that are administered to a subject subsequent to an induction phase. In some instances, the maintenance phase is initiated only if the subject did not experience disease progression or unacceptable toxicity during the induction phase. The induction phase and maintenance phase may or may not comprise use of the same therapeutic agents.
For example, in some instances, the induction phase includes use of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, and the maintenance phase includes use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.
In the context of bladder cancer, the term "ineligible for treatment with a platinum-based chemotherapy" or "unfit for treatment with a platinum-based chemotherapy"
means that the subject is ineligible or unfit for treatment with a platinum-based chemotherapy, either in the attending clinician's judgment or according to standardized criteria for eligibility for platinum-based chemotherapy that are known in the art. For example, the criteria set forth in Galsky et al. Lancet Oncol. 12(3):211-4, 2011, which is incorporated herein by reference in its entirety, may be used to determine whether a subject is eligible for cisplatin-based chemotherapy. Galsky et al. describe a consensus definition of patients with metastatic UC (m UC) in which patients meeting at least one of the following are considered unfit for cisplatin-based chemotherapy: (i) a World Health Association (WHO) or Eastern Cooperative Oncology Group (ECOG) performance status of 2, or Karnofsky performance status of 60-70%; (ii) creatinine clearance (calculated or measured) less than 1 mils; (iii) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 audiometric 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 unfit for cisplatin-based chemotherapy if they have one or more of the following: impaired renal function (e.g., glomerular filtration rate (GFR) >30 but <60 mUmin); GFR
may be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if .. not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)); hearing loss (e.g., NCI CTCAE v4.0 Grade 2 2 audiometric hearing loss of 25 decibels at two contiguous frequencies);
peripheral neuropathy (e.g., NCI CTCAE v4.0 Grade 2 peripheral neuropathy (i.e., sensory alteration or paresthesia, including tingling)); and/or ECOG performance status assessment (see Oken et al. Am. J.
Clin. Oncol. 5:649-655, 1982, which is incorporated herein by reference in its entirety) (e.g., an ECOG
performance status of 2). In some aspects, a subject having one of the following may be eligible for carboplatin-based chemotherapy: impaired renal function (e.g., GFR >30 but <60 mUmin); GFR may be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)); hearing loss (e.g., CTCAE v4.0 Grade 2 audiometric hearing loss of 25 decibels at two contiguous frequencies); peripheral neuropathy (e.g., NCI CTCAE v4.0 Grade 2 peripheral neuropathy (i.e., sensory alteration or paresthesia, including tingling)); and/or ECOG performance status assessment (e.g., an ECOG
performance status of 2). For example, cisplatin ineligibility may be defined by any one of the following criteria: (i) impaired renal function (GFR <60 mL/min); GFR may be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft Gault formula); (ii) a hearing loss (measured by audiometry) of 25 dB
at two contiguous frequencies; (iii) Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling); and (iv) ECOG Performance Status of 2.
III. THERAPEUTIC AND DIAGNOSTIC METHODS AND USES
A. Therapeutic methods and uses relating to cancers Therapeutic methods and uses Provided herein are methods and uses for treating cancer (e.g., a solid tumor and/or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a small cell lung cancer (SCLC) (e.g., an extensive stage (ES)-SCLC), a non-small cell lung cancer (NSCLC) (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a triple-negative breast cancer (TNBC) (e.g., an estrogen receptor negative (ER-), progesterone receptor negative (PR-), and HER2 negative (HER2-) breast cancer, e.g., an early TNBC (eTNBC)) or a HER2-positive breast cancer);
a head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally advanced or metastatic HCC
and/or unresectable HCC); a bladder cancer (e.g., muscle-invasive bladder cancer (MIBC) or locally advanced or metastatic urothelial carcinoma (mUC)); an esophageal cancer; a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC); a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a colorectal cancer (CRC; e.g., CRC with microsatellite-stable (MSS) or microsatellite instability (MSI) low (MSI-Low)) in a subject comprising administering to the subject one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody, e.g., tiragolumab), or a combination of 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 such as pembrolizumab).
The present invention includes methods and uses involving administration of 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 antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in a complete response (CR) or a partial response (PR). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in progression-free survival (PFS) or duration of objective response (DOR). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in overall survival (OS). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in PFS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
The present invention includes methods and uses involving administration of 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 four weeks (e.g., on Day 1 of each 28-day dosing cycle).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered every four weeks (e.g., on Day 1 of each 28-day dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) is administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIC IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in PFS
of the subject compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in DOR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends OS of the subject.
The present invention includes methods and uses involving administration of 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) is administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). The present invention includes methods and uses involving administration of 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 antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in PFS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
The present invention includes methods and uses involving administration of 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., on Day 1 of each 21-day dosing cycle).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) is administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In certain instances, the present invention includes methods and uses involving administration of 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., on Day 1 of each 21-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in PFS of the subject compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends OS of the subject. In some instances, the present invention includes a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. In some instances, the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of 500 mg to 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of 900 mg to 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.
In certain instances, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered without a chemotherapeutic agent (e.g., without any chemotherapeutic agent, e.g., the entire dosing regimen is devoid of administration of a chemotherapeutic agent to the subject).
In some embodiments, the subject has not been previously treated with a therapy (e.g., a cancer immunotherapy and/or a chemotherapeutic agent) for the cancer. In some embodiments, the subject has received prior treatment with a therapy (e.g., a cancer immunotherapy and/or a chemotherapeutic agent) for the cancer. In some instances, the subject has not received prior systemic therapy (e.g., e.g., prior systemic therapy with curative intent, e.g., chemotherapy) within at least the month prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody (e.g., within the two months prior, three months prior, four months prior, six months prior, one year prior, two years prior, three years prior, four years prior, five years prior, or ten years prior to the administration with the PD-1 axis binding antagonist and the anti-TIC IT antagonist antibody). In some instances, the subject is chemotherapy naïve.
In some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered in conjunction with a chemotherapy. For example, a once-every-two-weeks (02W), once-every-three-weeks (03W), or once-every-four-weeks (04W) dosing regimen of the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody can be administered in conjunction with one or more chemotherapeutic agents. The one or more chemotherapeutic agents can be administered at the same frequency as the frequency of administration of the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody (02W, 03W, or 04W) or at a different frequency (e.g., 3-weeks on/1-week off schedule (e.g., 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 two weeks and the one or more chemotherapeutic agents is administered every week, 3-weeks on/1-week off, every two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every three weeks and the one or more chemotherapeutic agents is administered every week, two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered every four weeks and the one or more chemotherapeutic agents is administered every week, 3-weeks on/1-week off, every two weeks, every three weeks, or every four weeks. In certain instances, a chemotherapeutic agent is administered multiple times per week (e.g., 2, 3, 4, 5, 6 or 7 times per week (e.g., at Days 1, 2, and 3 of a dosing cycle).
In some embodiments, the dose of a chemotherapeutic agent is reduced after one or more initial doses (e.g., after one, two, three, four, or more initial doses). For example, a subsequent dose of the chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) can be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose. For example, an initial dose of nab-paclitaxel of 125 mg/m2 can be reduced for a subsequent dose, e.g., to 100 mg/m2 or 75 mg/m2;
an initial dose of nab-paclitaxel of 100 mg/m2 can be reduced for a subsequent dose, e.g., to 75 mg/m2;
an initial dose of paclitaxel of about 175 mg/m2 can be reduced for a subsequent dose, e.g., to 150 mg/m2, 125 mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of paclitaxel of about 200 mg/m2 can be reduced for a subsequent dose, e.g., to 175 mg/m2, 150 mg/m2, 125 mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of gemcitabine of about 1000 mg/m2 can be reduced for a subsequent dose, e.g., to 900 mg/m2, 800 mg/m2, 750 mg/m2, 700 mg/m2, 600 mg/m2, or 500 mg/m2; an initial dose of cisplatin of about 75 mg/m2 can be reduced for a subsequent dose, e.g., to 70 mg/m2, 65 mg/m2, 60 mg/m2, 55 mg/m2, 50 mg/m2, or 45 mg/m2; an initial dose of pemetrexed of about 500 mg/m2 can be reduced for a subsequent dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300 mg/m2, 250 mg/m2, or 200 mg/m2; and/or an initial dose of carboplatin of a dose sufficient to achieve AUC = 6 mg/ml/min can be reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUG = 5.5. mg/ml/mm, 5.0 mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min. In some examples, an initial dose of nab-paclitaxel of 125 mg/m2 can be reduced for a subsequent dose, e.g., to 100 mg/m2 or 75 mg/m2; an initial dose of nab-paclitaxel of 100 mg/m2 can be reduced for a subsequent dose, e.g., to 75 mg/m2; an initial dose of paclitaxel of 175 mg/m2 can be reduced for a subsequent dose, e.g., to 150 mg/m2, 125 mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of paclitaxel of 200 mg/m2 can be reduced for a subsequent dose, e.g., to 175 mg/m2, 150 mg/m2, 125 mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of gemcitabine of 1000 mg/m2 can be reduced for a subsequent dose, e.g., to 900 mg/m2, 800 mg/m2, 750 mg/m2, 700 mg/m2, 600 mg/m2, or 500 mg/m2; an initial dose of cisplatin of 75 mg/m2 can be reduced for a subsequent dose, e.g., to 70 mg/m2, 65 mg/m2, 60 mg/m2, 55 mg/m2, 50 mg/m2, or 45 mg/m2; an initial dose of pemetrexed of 500 mg/m2 can be reduced for a subsequent dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300 mg/m2, 250 mg/m2, or 200 mg/m2; and/or an initial dose of carboplatin of a dose sufficient to achieve AUC = 6 mg/ml/min can be reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUC =
5.5. mg/ml/min, 5.0 mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min.
The present invention includes methods and uses involving administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy combination to a subject in need thereof. In some embodiments, the anti-TIGIT
antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered every four weeks (e.g., on Day 1 of each 28-day dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) is administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the chemotherapy combination includes 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 instances, the first non-platinum-based chemotherapeutic agent is an antimetabolite and the second non-platinum-based chemotherapeutic agent is a taxane. In some embodiments, the chemotherapy combination (e.g., the antimetabolite (e.g., gemcitabine, pemetrexed, or capecitabine) and the taxane (e.g., nab-paclitaxel and paclitaxel)) is administered weekly, biweekly, or three times every four weeks (e.g., on Days 1, 8, and 15 of each 28-day dosing cycle).
In particular embodiments, the method involves administration of 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, e.g., atezolizumab), gemcitabine, and paclitaxel to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle) and the chemotherapy combination (e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)) is administered more frequently (e.g., three times every four weeks (e.g., on Days 1, 8, and 15 of each 28-day dosing cycle).
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) results in an increase in PFS of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) extends OS of the subject.
The present invention includes methods and uses involving administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent. In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the platinum-based .. chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is an antimetabolite (e.g., pemetrexed). In some embodiments, the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent and the antimetabolite (e.g., pemetrexed)) are 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 particular embodiments, the method involves administration of 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, 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, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and the antimetabolite (e.g., pemetrexed) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21-day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum-based chemotherapeutic agent.

In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in an increase in PFS of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) extends OS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC
(e.g., an ES-SCLC), a NSCLC
(e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC
(e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC
(eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low CRC).
The present invention also includes methods and uses involving administration of an effective amount of an anti-TIC IT 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 antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) to a subject in need thereof. In some instances, the anti-TIGIT
antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every four weeks (e.g., 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 (e.g., on Days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments, the chemotherapy is administered weekly.
In some instances, administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in a CR or a PR. In some instances, administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in an increase in PFS of the subject compared to a reference. In some instances, administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in an increase in DOR. In some instances, administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) extends OS of the subject.
The present invention also includes methods and uses involving administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is a taxane (e.g., paclitaxel or nab-paclitaxel). In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some embodiments, the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent and the taxane (e.g., paclitaxel or nab-paclitaxel)) are 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 particular embodiments, the method involves administration of 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, 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, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and the taxane (e.g., paclitaxel or nab-paclitaxel) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21-day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum-based chemotherapeutic agent.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) results in an increase in PFS of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) extends OS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC (eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low CRC).
Also provided herein are methods and uses involving administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II
inhibitor (e.g., etoposide). In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some embodiments, the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor (e.g., etoposide)) are 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 some embodiments, the topoisomerase II
inhibitor (e.g., etoposide) is administered more frequently than the platinum-based chemotherapeutic agent (e.g., three times per week, e.g., on Days 1, 2, and 3 of each dosing cycle).
In particular embodiments, the method involves administration of 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, 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, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and the topoisomerase II inhibitor (e.g., etoposide) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21-day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum-based chemotherapeutic agent or the topoisomerase II inhibitor (e.g., etoposide).
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) results in (a) a CR or a PR.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) results in an increase in PFS
of the subject. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) extends OS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC (eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low CRC).
Also provided herein are methods and uses involving administration of 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 an anti-PD-1 antagonist antibody such as pembrolizumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) to a subject in need thereof. In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In particular embodiments, the method involves administration of 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, e.g., atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF
antibody (e.g., bevacizumab)) results in an increase in OS of the subject. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in PFS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF
antibody (e.g., bevacizumab)) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or .. persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
The present invention includes a method of treating cancer in a cancer patient comprising administering to the patient a combination of atezolizumab, bevacizumab, and tiragolumab in an amount effective to treat the cancer.
Also provided herein are methods and uses involving administration of 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)) to a subject in need thereof, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some instances, the anti-TIGIT antagonist antibody (e.g., 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)) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist antibody is pembrolizumab.
In particular embodiments, the method involves administration of 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)) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in OS
of the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in PFS of the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is being treated for a solid tumor or a locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is pembrolizumab.
Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
Also provided herein are methods and uses involving administration of an effective amount of tiragolumab and pembrolizumab to a subject in need thereof. In some instances, tiragolumab is administered every three weeks (e.g., on Day 1 and Day 22 of each 42-day dosing cycle) and pembrolizumab is administered every six weeks (e.g., on Day 1 of each 42-day dosing cycle).
In particular embodiments, the method involves administration of an effective amount of tiragolumab and pembrolizumab to a subject in need thereof, wherein tiragolumab is administered every three weeks (e.g., on Day 1 and Day 22 of each 42-day dosing cycle) and pembrolizumab is administered every six weeks (e.g., on Day 1 of each 42-day dosing cycle). In some instances, the effective amount of tiragolumab and pembrolizumab results in an increase in OS of the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some instances, the effective amount of tiragolumab and pembrolizumab results in an increase in PFS of the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab.
In some instances, the subject receiving tiragolumab and pembrolizumab is being treated for a solid tumor or a locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is pembrolizumab. Additionally or alternatively, the cancer may be a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC
(e.g., a squamous NSCLC
or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB
NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
Also provided herein are methods of treating a subject having a cancer, the methods comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. In some instances, the method comprises an induction phase and a maintenance phase.
In some instances, the induction phase and maintenance phase each comprise one or more dosing cycles. In some instances, the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent. In some instances, the maintenance phase does not comprise administration of the non-platinum-based chemotherapeutic agent. In some instances, the maintenance phase comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.
Also provided herein are methods of treating a subject having a cancer, the methods comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 mg every three weeks, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

Also provided herein are an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having a cancer, wherein the method is according to a method provided herein.
Also provided herein is use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or population of subjects having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to a method provided herein. In some aspects, the PD-1 axis binding antagonist are provided in separate formulations. 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.
Dosing of agents Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, VEGF antagonists, and chemotherapeutic agents is described in Section III(K).
Cancer characterization and selection In any of the methods, uses, or compositions for use described herein, the cancer may be solid tumor or a locally advanced or metastatic cancer. In some instances, the cancer is a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB
NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC
(e.g., wherein the subject has not been previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC
(eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive .. SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low CRC). In some instances in which the subject has a breast cancer, the subject has not received prior systemic therapy for metastatic breast cancer.
In some instances, in any of the methods, uses, or compositions for use described herein, the subject has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a sensitizing EGFR gene mutation or ALK gene rearrangement. In some instances, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
Methods for detecting the mutational status EGFR and ALK are well known in the art, and include, but are not limited to, sequencing DNA from clinical samples (e.g., tumor biopsies or blood samples (e.g., circulating tumor DNA in blood)) using a next-generation sequencing method, such as the .. targeted gene pulldown and sequencing method described in Frampton et al.
(Nature Biotechnology.

31(11): 1023-1033, 2013), which is incorporated by reference herein in its entirety. Such a next-generation sequencing method can be used with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small-core needle biopsies, fine-needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods for the detection of the mutational status of EGFR and ALK include fluorescence in situ hybridization (FISH) and immunohistochemical (INC) methods. Exemplary methods for the detection of the mutational status of ALK are disclosed in U.S. Patent No: 9,651,555, which is herein incorporated by reference in its entirety. In some instances, the VENTANA anti-ALK(D5F3) IHC
assay is used to determine the mutational status of the ALKgene.
In some instances of any of the methods described herein, the mutation is a sensitizing EGFR
mutation. Sensitizing EGFR mutations are well known in the art and include those described in U.S.
Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in Medical Oncology. 9(3):
201-216, 2017), which are incorporated by reference herein in their entireties. In some instances, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some instances, the sensitizing EGFR mutation is a deletion of exon 19 (dell 9). In other instances, sensitizing EGFR mutation is a L858R point mutation in exon 21. In some instances, the sensitizing EGFR mutation is a G719X point mutation in exon 18, wherein "X" is most commonly C, A, or S. In some instances, the sensitizing EGFR mutation is a G719S point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a S720F point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a L8610 point mutation in exon 21. In some instances, the sensitizing EGFR mutation is a L861R point mutation in exon 21. In other instances, the sensitizing EGFR mutation is a T790M point mutation. In some instances, the sensitizing EGFR mutation is an E709X point mutation, where "X" is most commonly K, A, or H. In some instances, the sensitizing EGFR mutation is a S768I point mutation.
In some instances of any of the methods described herein, the mutation is an ALKgene rearrangement. ALKgene rearrangements are well known in the art and include those described in U.S.
Patent No: 9,651,555 and in Du et al. (Thoracic Cancer. 9: 423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, the ALKgene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways resulting in increased cell proliferation and survival. In some instances, the ALKgene rearrangement is an ALK rearrangement with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SOSTM1, NPM1, BCL11A, BIRC6, RANBP2, AT/C, CLTC, TMP4, and MSN resulting in the formation of .. a fusion oncogene. In some instances, the ALKgene rearrangement is an EML4 rearrangement with ALK resulting in the formation of the fusion oncogene EML4-ALK.
In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. Methods for detecting the subtype of NSCLC are well known in the art, and include, but are not limited to, methods of determination by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)). In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample.
In some instances, 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 a known or suspected chronic active EBV infection. Indicators of active or chronic active EBV infections for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles detected in a sample from the subject (e.g., a blood or serum sample).
Methods for detecting the presence of one or more indicators of active or chronic active EBV infection, including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles in a sample from a subject are well known in the art, and include, but are not limited to, methods involving serological diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis of a blood sample for the detection of EBV viral particles) or EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV
.. IgM, or EBV IgG using heterophilic antibodies). In some instances, the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample. In some instances, the subject is negative for EBV IgM and/or negative by EBV PCR. In some instances, the subject is negative for EBV IgM and/or negative by EBV PCR and is positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA). In other instances, the subject is negative for EBV
IgG and/or negative for EBNA.
In some instances, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., a tumor PD-L1 expression with a minimum PD-L1-positive tumor cell fraction or TPS ?..= 30% (e.g., 50%) as determined by an IHC with the SP263 or 22C3 antibody or a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) is greater than or equal to 1% in the tumor sample as determined by an IHC with the SP142 antibody). In some instances, the PD-L1 selected tumor is a tumor that has been determined to have a PD-L1-positive tumor cell fraction or PD-L1 TPS of greater than, or equal to, 30% (e.g., greater than, or equal to, 50%) by an immunohistochemical (IHC) assay. In some instances, the PD-L1 selected tumor is a tumor that has been determined to have a proportion of tumor area occupied by PD-L1-expressing immune cells (ICs) greater than or equal to 1% by an immunohistochemical (IHC) assay. In some instances, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the tumor sample has been determined to have a TPS of greater than, or equal to, 50%. In some instances, the PD-L1-positive .. tumor cell fraction is greater than, or equal to, 50% (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1-positive tumor cell fraction is greater than, or equal to, 30%, as determined by positive staining with the anti-PD-L1 antibody SP142. In some instances, the ICs has been determined to be greater than, or equal to, 1%
(e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 5% (e.g., as determined using the Ventana (5P142) PD-L1 IHC
assay). In some instances, the ICs has been determined to be greater than, or equal to, 10% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 1% and less than 50% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 1 ./0 and less than 30% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some instances, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1 ./c, of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1%
of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1`)/0 and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5%
and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.
In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some instances, the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH, or a combination thereof. In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample. In some instances, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
Responses to Treatment In some embodiments of any of the methods described herein, a subject's response to the therapy can be characterized by one or more measures. In some embodiments, the treatment results in a CR or a PR. In some embodiments, the treatment results in an increase in PFS
or DOR.

In some instances, the treatment results in an increase in PFS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
For example, in embodiments in which no chemotherapeutic agent is administered (e.g., only an anti-TIGIT antagonist antibody (e.g., tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., atezolizumab) is administered), the treatment may result in an increase in PFS
of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))), the treatment may result in an increase in PFS of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without the PD-1 axis binding antagonist; and/or (iii) as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody without the one or more chemotherapeutic agents.
In some instances, the treatment extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. For example, in embodiments in which no chemotherapeutic agent is administered (e.g., only an anti-TIGIT antagonist antibody (e.g., tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., atezolizumab) is .. administered), the treatment may result in an increase in OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In embodiments in which an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed, gemcitabine, or capecitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))), the treatment may result in an increase in OS of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without the PD-1 axis binding antagonist; and/or (iii) as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody without the one or more chemotherapeutic agents.
Progression-free survival of the subject can be measured 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 period of time from the start of treatment to the first occurrence of disease progression as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from the start of treatment to the time of death.
In some embodiments, a treatment described herein extends the PFS of the subject by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,

11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some embodiments, the treatment extends the PFS of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the PFS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by 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, a treatment described herein extends the DOR of the subject by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 .. months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some embodiments, the treatment extends the DOR of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the DOR of the subject by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by 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 period of time from the start of treatment to death.
In some instances, the treatment extends the OS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances, the treatment extends the OS of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances, the treatment extends the OS of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 .. months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
B. Therapeutic methods and uses relating to lung cancer Lung cancer remains the leading cause of cancer deaths worldwide. In the United States, it is the most common cancer in both men and women and accounts for 12%-14% of all new cancer cases.
In 2020, there will be an estimated 228,820 new cases of lung cancer, resulting in 135,720 deaths in the .. United States (Siegel et al. CA Cancer J Clin. 70:7-30 (2020)).
Non-small cell lung cancer Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, accounting for approximately 85% of all cases.
Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, accounting for approximately 80%-85% of all cases (Osmani et al. Semin Cancer Biol. 52 (Pt 1):103-9 (2018)). NSCLC
can be divided into two major histologic types: adenocarcinoma and squamous cell carcinoma (Travis et al. 2011). Adenocarcinoma histology accounts for approximately 40%-50% of all NSCLC, while squamous cell histology accounts for approximately 20%-30% of NSCLC (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 are of poorly differentiated histology.
In its 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 intervention for early-stage NSCLC.

For advanced disease, the overall five-year survival rate is 2%-4%. Poor prognostic factors for survival in patients with NSCLC include advanced stage of disease at the time of initial diagnosis, poor performance status, and a history of unintentional weight loss. More than half of the patients with NSCLC
are diagnosed with distant disease, which directly contributes to poor survival prospects.
Despite improvements in the first-line treatment of patients with advanced NSCLC that have resulted in longer survival times and reduced disease-related symptoms, nearly all patients experience disease progression. Cancer immunotherapies, in particular, offer the possibility of long-term disease control. In the metastatic NSCLC setting, PD-L1/PD-1 blocking antibodies (e.g., atezolizumab, nivolumab, and pembrolizumab) provided clinically meaningful benefit in either unselected or PD-L1-selected advanced NSCLC patients; however, a substantial proportion of patients still remained unresponsive or progressed on anti-PD-L1/PD-1 treatment, and the escape mechanisms to such treatment are poorly understood.
Thus, there is an unmet need in the field for the development of efficacious immunotherapies and methods of dosing the same for the treatment (e.g., first-line treatment) of lung cancer (e.g., NSCLC (e.g., .. non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) that achieve a more favorable benefit-risk profile.
Small cell lung cancer Small cell lung cancer (SCLC) accounts for approximately 15% of all cases of lung cancer. The majority (approximately 70%) of patients with SCLC are diagnosed with extensive-stage disease (ES-SCLC), which has poor survival prospects (median OS approximately 10-12 months). While chemotherapy alone can palliate symptoms and prolong survival for patients with ES-SCLC, long-term survival is rare. The five-year relative survival rate for people with stage I
SCLC is approximately 31%.
At stage IV, the five-year relative survival rate declines to approximately 2%.
Thus, there is a need in the field for improved treatments for lung cancer (e.g., SCLC, e.g., ES-SCLC).
i. Methods and uses for treating lung cancer Provided herein are methods of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase ll inhibitor, wherein the treatment results in a median PFS of the population of subjects of at least about 6 months (e.g., at least about 6 months (e.g., between 6 months and 24 months (e.g., between about 6 months to about 15 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, or 15 months), e.g., between about 6 months to about 13 months (e.g., 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months,

12 months, 12.5 months, 13 months)),e.g., between about 8 months to about 10 months (e.g., 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, 8.6 months, 8.7 months, 8.8 months, 8.9 months, 9.0 months, 9.1 months, 9.2 months, 9.3 months, 9.4 months, 9.5 months, 9.6 months, 9.7 months, 9.8 months, 9.9 months, 10.0 months)). In some instances, treatment results in a median PFS of the population of subjects of about 8.2 months to about 9.2 months (e.g., about 8.2, 8.4, 8.6, 8.8, 9.0, or 9.2 months, e.g., 8.2-8.4, 8.4-8.6, 8.6-8.8, 8.8-9.0, or 9.0-9.2 months).
Also provided herein are methods of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment results in a median OS of the population of subjects of at least about 12 months (e.g., between about 12 months to about 40 months (e.g., between about 12 to about 30 months (e.g., 12 months, 13 months, 14 months, 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 to about 20 months (e.g., 12 months, 13 months, 14 months, 15 months, 16 months, 17 10 months, 18 months, 19 months, or 20 months))). In some instances, the treatment results in a median OS of the population of subjects of about 15.3 months to about 17.6 months (e.g., about 15.5, 16, 16.5, 17, 17.5, or 17.6 months, e.g., 15.3-16 months, 16-17 months, or 17-17.6 months).
Methods and uses for treating small cell lung cancer 15 Provided herein are methods and uses for treating lung cancer (e.g., small cell lung cancer (SCLC), e.g., extensive stage SCLC (ES-SCLC)) in a subject or population of subjects comprising administering to the subject or population of subjects one or more dosing cycles of 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), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide).
Dosing Regimens, Administration, and Response to Treatment The therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having a lung cancer (e.g., SCLC, e.g., ES-SCLC) an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), a platinum-based chemotherapeutic agent, and a topoisomerase II
inhibitor, wherein the treatment extends progression-free survival (PFS) of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody, thereby treating the subject or population of subjects. In some instances, the treatment extends OS of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT
antagonist antibody.
In some embodiments, the PFS of the individual is measured 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 period of time from the start of treatment to the first occurrence of disease progression as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from the start of treatment to the time of death.
In some embodiments, the treatment extends the PFS of the subject or population of subjects by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In some embodiments, the treatment extends the PFS of the subject or population of subjects by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 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) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In some embodiments, the treatment extends the PFS of the subject or population of subjects by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In some aspects, the treatment extends the PFS of the subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody.
In some instances, the methods and uses of treating a subject or population of subjects having a lung cancer (e.g., SCLC, e.g., ES-SCLC) include administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide), wherein the treatment extends OS of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase ll inhibitor without the anti-TIGIT
antagonist antibody.
In some embodiments, OS is measured as the period of time from the start of treatment to death.
In some instances, the treatment extends the OS of the subject or population of subjects by at least about 2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In some instances, the treatment extends the OS of the subject or population of subjects by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT
antagonist antibody. In some instances, the treatment extends the OS of the subject or population of subjects by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g. a fixed dose) of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg (e.g., between about 50 mg to about 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of about 600 mg every three weeks.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g. a fixed dose) of between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between 30 mg to 600 mg (e.g., between 50 mg to 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg to 600 mg, e.g., between 200 mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg to 500 mg, e.g., between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of 600 mg every three weeks.
In some instances, effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) dose of 600 mg every three weeks. In some instances, the dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab)), topoisomerase II inhibitor (e.g., etoposide), and/or a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between 80 mg to 2000 mg (e.g., between 100 mg to 1600 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1600 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of 840 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of about 1400 mg to 2000 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-.. PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of 1400 mg to 2000 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of about 1680 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of 1680 mg every four weeks. In .. some instances, the dose (e.g., fixed dose) of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab), a topoisomerase II inhibitor (e.g., etoposide), and/or a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) may be reduced as compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2 mg/kg, about 15 1 mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 15 mg/kg of 15 the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg, e.g., between about 0.5 mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g., between about 2.5 mg/kg to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15 1 mg/kg, e.g., about 20 15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 15 mg/kg administered every three weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 50 mg/kg of the subject's body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 2 mg/kg, 15 1 mg/kg, 15 0.5 mg/kg, 15 0.2 mg/kg, or 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 15 mg/kg of the subject's body weight (e.g., between 0.1 mg/kg to 15 mg/kg, e.g., between 0.5 mg/kg to 15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15 mg/kg, e.g., between 5 mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg to 15 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15 1 mg/kg, e.g., 15 0.5 mg/kg, e.g., 15 0.2 mg/kg, e.g., 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 15 mg/kg administered every three weeks.
In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), a topoisomerase II inhibitor (e.g., etoposide), and/or a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) may be reduced as compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.
In some instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve an AUC from 1-50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, e.g., 2 mg/ml/min, 3 mg/1111/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/mVmin, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/mVmin, 50 mg/ml/min). In some instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve AUC = 5 mg/ml/mm.
AUC can be calculated using the Calvert formula (Calvert et al., J. Clin.
Orval. 1989, 7:1748-56):
Total dose (mg) = (target AUC) x (glomerular filtration rate [GFR] + 25) In some instances, for example, 1200 mg of atezolizumab is equivalent to an average body weight-based dose of 15 m/kg.
In some instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100 mg, or 500 mg-1000 mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg). In some instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or .. cisplatin) is about 500 mg-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 instances, the effective amount of the topoisomerase ll inhibitor (e.g., etoposide) is from 10-1000 mg/m2 (e.g., from 20-800 mg/m2, from 30-700 mg/m2, from 40-500 mg/m2, from 50-300 mg/m2, from 75-200 mg/m2, or from 80-150 mg/m2, e.g., 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/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/m2, or about 1000 mg/m2). In some instances, the effective amount of the topoisomerase II
inhibitor (e.g., etoposide) is about 100 mg/m2.
In some instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100 mg, or 500 mg-1000 mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, e.g., 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 instances, the effective amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 500 mg-1000 mg (e.g., 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg).
In some instances, the effective amount of the topoisomerase II inhibitor (e.g., etoposide) is from 10-1000 mg/m2 (e.g., from 20-800 mg/m2, from 30-700 mg/m2, from 40-500 mg/m2, from 50-300 mg/m2, from 75-200 mg/m2, or from 80-150 mg/m2, e.g., 20 mg/m2, 30 mg/m2, 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, 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/m2, 900 mg/m2, or 1000 mg/m2). In some instances, the effective amount of the topoisomerase II inhibitor (e.g., etoposide) is 100 mg/m2.
In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide)) 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 instances, dosing cycles of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) (with or without the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or the topoisomerase II inhibitor (e.g., etoposide)) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some instances, the length of each dosing cycle is about 18 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 instances, the length of each dosing cycle is about 21 days.
In other instances, the .. length of each dosing cycle is about 14 days. In other instances, the length of each dosing cycle is about 28 days.
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 of each dosing cycle, e.g., each 21-day cycle (i.e., at a dose of about 600 mg every three weeks). In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each dosing cycle, e.g., each 21-day cycle (i.e., at a dose of 600 mg every three weeks). Similarly, in some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle.
For example, in some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously 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 three weeks). In other instances, e.g., the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously 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 three weeks). In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose of 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks). In some instances, both the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. In some instances, the platinum-based chemotherapeutic agent is administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. In some instances, the topoisomerase II inhibitor is on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, in some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) 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 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously 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 three weeks), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each of the four initial dosing cycles, and the topoisomerase II
inhibitor (e.g., etoposide) is administered at a dose of 100 mg/m2on each of Days 1,2, and 3 of each of the four initial dosing cycles. In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose of1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each of the four initial dosing cycles, and the topoisomerase ll inhibitor (e.g., etoposide) is administered at a dose of 100 mg/m20n each of Days 1, 2, and 3 of each of the four initial dosing cycles.
In some instances, the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered in each of four initial dosing cycles. In some instances, the anti-TIGIT antagonist antibody is administered at a dose from about 30 mg to about 1200 mg on Day 1 of each of the four initial dosing cycles. In some instances, the anti-TIGIT antagonist antibody is administered at a dose from about 30 mg to about 600 mg on Day 1 of each of the four initial dosing cycles. In some instances, the anti-TIGIT
antagonist antibody is administered at a dose of about 600 mg on Day 1 of each of the four initial dosing cycles. In some instances, the PD-1 axis binding antagonist is administered at a dose from about 80 mg to about 1600 mg on Day 1 of each of the four initial dosing cycles (e.g., at a dose of about 1200 mg on Day 1 of each of the four initial dosing cycles). In some instances, the anti-TIGIT antagonist antibody is administered at a dose from 30 mg to 1200 mg on Day 1 of each of the four initial dosing cycles.
In some instances, the anti-TIGIT antagonist antibody is administered at a dose from 30 mg to 600 mg on Day 1 of each of the four initial dosing cycles. In some instances, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg on Day 1 of each of the four initial dosing cycles. In some instances, the PD-1 axis binding antagonist is administered at a dose from 80 mg to 1600 mg on Day 1 of each of the four initial dosing cycles (e.g., at a dose of 1200 mg on Day 1 of each of the four initial dosing cycles). In some instances, the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each of the four initial dosing cycle, and/or the topoisomerase II inhibitor is administered at a dose of 100 mg/m2on each of Days 1, 2, and 3 of each of the four initial dosing cycles.
In some instances, 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. In some instances, the anti-TIGIT antagonist antibody is administered at a dose from about 30 mg to about 1200 mg on Day 1 of each of the one or more additional dosing cycles (e.g., at a dose from about 30 mg to about 600 mg on Day 1 of each of the one or more additional dosing cycles). In some instances, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, the PD-1 axis binding antagonist is administered at a dose from about 80 mg to about 2000 mg on Day 1 of each of the one or more additional dosing cycles (e.g., at a dose of about 840 mg, 1200 mg, or 1680 mg on Day 1 of each of the one or more additional dosing cycles). In some instances, the additional dosing cycles include administration of the PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of about 840 mg every two weeks, about 1200 mg every three weeks, or about 1680 mg every four weeks. For example, in some instances, each of the one or more dosing cycles is about 14 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of about 840 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, each of the one or more dosing cycles is about 21 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of about 1200 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, each of the one or more dosing cycles is about 28 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of about 1 680 mg on Day 1 of each of the one or more additional dosing cycles.
In some instances, the anti-TIGIT antagonist antibody is administered at a dose from 30 mg to 1200 mg on Day 1 of each of the one or more additional dosing cycles (e.g., at a dose from 30 mg to 600 mg on Day 1 of each of the one or more additional dosing cycles). In some instances, the anti-TIGIT
antagonist antibody is administered at a dose of 600 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, the PD-1 axis binding antagonist is administered at a dose from 80 mg to 2000 mg on Day 1 of each of the one or more additional dosing cycles (e.g., at a dose of 840 mg, 1200 mg, or 1680 mg on Day 1 of each of the one or more additional dosing cycles).
In some instances, the additional dosing cycles include administration of the PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every four weeks. For example, in some instances, each of the one or more dosing cycles is 14 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of 840 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, each of the one or more dosing cycles is 21 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of 1200 mg on Day 1 of each of the one or more additional dosing cycles. In some instances, each of the one or more dosing cycles is 28 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of 1680 mg on Day 1 of each of the one or more additional dosing cycles.

In some instances, a subject or population of subjects having lung cancer (e.g., SCLC, e.g., ES-SCLC) is treated by administering to the subject or population of subjects one or more dosing cycles (e.g., 21-day dosing cycles) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose from about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) on Day 1 of each dosing cycle, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose from about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) on Day 1 of each dosing cycle (e.g., at a dose from about 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) on Day 1 of each dosing cycle, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose from 80 mg to 2000 mg (e.g., between 100 mg to 1600 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1600 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) on Day 1 of each dosing cycle), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) at a dose sufficient to achieve AUC from 1-50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or mg/ml/min, e.g., 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/mm, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min, e.g., 5 mg/ml/min) on Day 1 of each dosing cycle, and a topoisomerase II inhibitor (e.g., etoposide) at a dose of 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle, wherein the treatment extends PFS and/or OS of the subject or population of subjects as compared to treatment with PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)), platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and topoisomerase II
inhibitor (e.g., etoposide) without the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab).
In some instances, a subject or population of subjects having lung cancer (e.g., SCLC, e.g., ES-SCLC) is treated by administering to the subject or population of subjects one or more dosing cycles (e.g., 21-day dosing cycles) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose from 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) on Day 1 of each dosing cycle, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) at a dose from 80 mg to 2000 mg (e.g., between 100 mg to 1600 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1600 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) on Day 1 of each dosing cycle, a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) at a dose sufficient to achieve AUC from 1-50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, e.g., 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min, e.g., mg/ml/min) on Day 1 of each dosing cycle, and a topoisomerase II inhibitor (e.g., etoposide) at a dose of 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle, wherein the treatment extends PFS
and/or OS of the subject or population of subjects as compared to treatment with PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)), platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g., etoposide) without the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab).
In some instances, the treatment extends the OS of the subject or population of subjects by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by 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 5 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) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase It inhibitor without the anti-TIG IT antagonist antibody. In some instances, the treatment extends the OS of the subject or population of subjects by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody.
In some embodiments, the treatment extends the PFS of the subject or population of subjects by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In some embodiments, the treatment extends the PFS of the subject or population of subjects by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 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) as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist antibody.
In some embodiments, the subject or population of subjects receives one or more additional dosing cycles (e.g., 21-day dosing cycles) of the anti-TIGIT antagonist antibody at a dose from about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab at a dose from about 80 mg to about 2000 mg on Day 1 of each additional dosing cycle, wherein carboplatin and etoposide are omitted from each of the one or more additional dosing cycles.

In some instances, the 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 by intravenous infusion over about 60 15 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject or population of subjects by intravenous infusion over about 60 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).
In some instances, the 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 before the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)). In some instances, for example, following administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis binding antagonist, the method includes an intervening first observation period. In some instances, the method further includes a second observation period following administration of the PD-1 axis binding antagonist. In some instances, the method includes both a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration of PD-1 axis binding antagonist. In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration of the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration of the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist during the first and second observation periods, respectively.
In other instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject or population of subjects before the anti-TIGIT antagonist .. antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab). In some instances, for example, following administration of the PD-1 axis binding antagonist and before administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some instances, the method includes a second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the method includes both a first observation period following administration of the PD-1 axis binding antagonist and second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody during the first and second observation periods, respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 (atezolizumab) antagonist antibody) are administered to the subject or population of subjects simultaneously. In some instances, for example, following administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) the method includes an observation period. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In instances in which the observation period is about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and anti-TIGIT antagonist antibody during the observation period. In instances in which the observation period is about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and anti-TIGIT antagonist antibody during the observation period.
In any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody (e.g., atezolizumab)), platin urn-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g., etoposide)), or a medicament thereof, may be administered in conjunction with (either separately or together), one or more additional anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOYO)), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiation therapy, and/or an anti-hormonal agent, such as those recited herein above).

In some instances, the lung cancer is a small cell lung cancer (SCLC), such as extensive stage SCLC (ES-SCLC). In some instances, the subject or population of subjects is treatment-naïve for ES-SCLC (e.g., chemotherapy-naïve for ES-SCLC).
In some instances, the lung cancer is unselected for PD-L1 expression. In other instances, the lung cancer is selected for PD-L1 expression. In some instances, the lung cancer is selected for PD-L1 expression by an immunohistochemical (INC) assay comprising staining with an anti-PD-L1 antibody, such as SP263, 2203, SP142, or 28-8. In some instances, the anti-PD-L1 antibody is SP263 and the IHC assay is the Ventana SP263 IHC assay; the anti-PD-L1 antibody is 2203 and the IHC assay is the pharmDx 2203 IHC assay; the anti-PD-L1 antibody is SP142 and the IHC assay is the Ventana SP142 IHC assay, or the anti-PD-L1 antibody is 28-8 and the IHC assay is the pharmDx 28-8 IHC assay.
In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some instances, the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH, or a combination thereof. In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample. In some instances, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, .. the SCLC is extensive-stage small cell lung cancer (ES-SCLC), also referred to as stage 4 (IV) SCLC. In some embodiments, the SCLC is histologically or cytologically confirmed ES-SCLC, according to or as defined by the Veterans Administration Lung Study Group (VALG) staging system (see, e.g., Micke et at.
Lung Cancer 2002, 37:271-6). In some embodiments, SOLO is classified as ES-SOLO if the individual is inoperable and cannot be classified as having limited or limited stage SOLO (L-SCLC or LS-SCLC). In .. some embodiments, the ES-SOLO is detectable and/or has spread outside the originally affected lung. In some embodiments, the ESSCLC is detectable and/or has spread further into other (e.g., distant) organs, such as (but not limited to) the liver, adrenal glands, lymph nodes and/or brain. In some embodiments, the ESSCLC is difficult to treat.
In some embodiments, the subject or population of subjects has a poor prognosis. In some embodiments, the subject or population of subjects is a treatment-naïve subject or population of subjects (e.g., a chemotherapy-naïve subject or population of subjects). In some embodiments, a treatment-naïve subject is a subject who has not received prior treatment, e.g., for cancer, for SOLO, or for ES-SCLC. In some embodiments, the treatment naïve subject is a subject who has not received prior treatment for ES-SOLO. In some embodiments, the treatment-naïve subject is chemotherapy naïve, e.g., a subject who has not received prior chemotherapy for the treatment of, e.g., cancer, SCLC, and/or ES-SOLO. In some embodiments, the subject or population of subjects has not received treatment for ES-SCLC. In some embodiments, the subject or population of subjects has not received prior systemic treatment for ES-SOLO. In some embodiments, the subject or population of subjects has received prior chemoradiotherapy for limited stage SOLO (LS-SCLC) with curative intent, and has experienced a treatment-free cycle of at least six months since the last chemotherapy, radiotherapy, or chemoradiotherapy cycle from the diagnosis of ES-SCLC. In some embodiments, the subject or population of subjects has asymptomatic supratentorial or cerebellar central nervous system (CNS) metastases. In some embodiments, the subject or population of subjects does not have metastases to the midbrain, pans, medulla, or spinal cord. In some embodiments, the subject or population of subjects has CNS disease and does not require corticosteroid treatment for CNS disease.
In some embodiments, the subject or population of subjects has new asymptomatic metastases and has received radiation therapy and/or surgery for CNS metastases. In some embodiments, the subject or population of subjects has measurable disease, according to/as defined by RECIST v1.1 criteria (see, e.g., Eisenhauer et al., Eur. J. Cancer 2009, 45: 228-247). In some embodiments, the subject or population of subjects has not .. received prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.
In some instances, the treatment results in a CR or a PR. In some instances, the PFS of the subject or population of subjects is increased as compared to a reference PFS
time. In some instances, wherein the reference PFS time is the median PFS time of a population of subjects who have received a treatment with (e.g., anti-PD-L1 antibody (e.g., atezolizumab)), platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g., etoposide) without the anti-TIGIT
antagonist antibody (e.g., tiragolumab).
In some instances, the methods further comprise an additional therapy. The additional therapy may be radiation therapy, surgery (e.g., lumpectomy and a mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is the administration of small molecule enzymatic inhibitor or anti-metastatic agent.
In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti-nausea agents, etc.). In some .. embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiation therapy and surgery.
In some embodiments, the additional therapy is gamma irradiation.
Additional therapeutic antibodies contemplated for use herein include, without limitation, alemtuzumab (Campath), bevacizumab (AVASTIN , Genentech); cetuximab (ERBITUX , Imclone);
panitumumab (VECTIBIX , Amgen), rituximab (RITUXANO, Genentech/Biogen Idec), pertuzumab (OMNITARGO, 2C4, Genentech), trastuzumab (HERCEPTIN , Genentech), tositumomab (Bexxar, Corixia), the antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG , Wyeth), apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, pal ivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, .. tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories).
In some embodiments, the additional therapy is therapy targeting PI3K/AKT/mTOR
pathway, HSP90 inhibitor, tubulin inhibitor, apoptosis inhibitor, and/or chemopreventative agent. In some embodiments, the additional therapy is CTLA-4 (also known as CD152), e.g., a blocking antibody, ipilimumab (also known as MDX-010, MDX-101, or Yervoy0), tremelimumab (also known as ticilimumab or CP-675,206), an antagonist directed against B7-H3 (also known as CD276), e.g., a blocking antibody, MGA271, an antagonist directed against TGF beta, e.g., metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299, a treatment comprising adoptive transfer of a T
cell (e.g., a cytotoxic T cell or CTL) expressing a chimeric antigen receptor (CAR), a treatment comprising adoptive transfer of a T cell comprising a dominant-negative TGF beta receptor, e.g., a dominant-negative TGF beta type ll receptor, a treatment comprising a HERCREEK/I
protocol (see, e.g., ClinicalTrials.gov Identifier NC100889954), an agonist directed against CD137 (also known as TNFRSF9, 4-1BB, or ILA), e.g., an activating antibody, urelumab (also known as BMS-663513), an agonist directed against CD40, e.g., an activating antibody, CP-870893, an agonist directed against 0X40 (also known as CD134), e.g., an activating antibody, administered in conjunction with a different anti-0X40 antibody (e.g., Agon0X)., an agonist directed against CD27, e.g., an activating antibody, CDX-1127, indoleamine-2,3-dioxygenase (IDO), 1-methyl- D-tryptophan (also known as 1-D-MT), an antibody-drug conjugate (in some embodiments, comprising mertansine or monomethyl auristatin E (MIVIAE)), an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599), trastuzumab emtansine (also known as TDM1, ado-trastuzumab emtansine, or KADCYLA , Genentech), DMUC5754A, an antibody-drug conjugate targeting the endothelin B receptor (EDNBR), e.g., an antibody directed against EDNBR
conjugated with MMAE, an angiogenesis inhibitor, an antibody directed against a VEGF, e.g., VEGF-A, bevacizumab (also known as AVASTIN , Genentech), an antibody directed against angiopoietin 2 (also known as Ang2), MEDI3617, an antineoplastic agent, an agent targeting CSF-1R
(also known as M-CSFR or CD115), anti-CSF-1R (also known as IMCCS4), an interferon, for example interferon alpha or interferon gamma, Roferon-A, GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GMCSF, sargramostim, or Leukine0), IL-2 (also known as aldesleukin or Proleukine), IL-12, an antibody targeting CD20 (in some embodiments, the antibody targeting CD20 is obinutuzumab (also known as GA101 or Gazyva0) or rituximab), an antibody targeting GITR (in some embodiments, the antibody targeting GITR is TRX518), in conjunction with a cancer vaccine (in some embodiments, the cancer vaccine is a peptide cancer vaccine, which in some embodiments is a personalized peptide vaccine; in some embodiments the peptide cancer vaccine is a multivalent long peptide, a multi-peptide, a peptide cocktail, a hybrid peptide, or a peptidepulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci, 104:14-21, 2013)), in conjunction with an adjuvant, a TLR agonist, e.g., Poly-ICLC (also known as Hiltonole), LPS, MPL, or CpG ODN, tumor necrosis factor (TNF) alpha, IL-1, HMGB1, an IL-10 antagonist, an IL-4 antagonist, an IL-13 antagonist, an HVEM antagonist, an ICOS
agonist, e.g., by administration of ICOS-L, or an agonistic antibody directed against ICOS, a treatment targeting CX3CL1, a treatment targeting CXCL10, a treatment targeting CCL5, an LFA-1 or ICAM1 agonist, a Selectin agonist, a targeted therapy, an inhibitor of B-Rat, vemurafenib (also known as Zelboraf , dabrafenib (also known as Tafinlar8), erlotinib (also known as Tarceva0), an inhibitor of a MEK, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2).
cobimetinib (also known as GDC-0973 or XL-518), trametinib (also known as Mekiniste), an inhibitor of K-Ras, an inhibitor of c-Met, onartuzumab (also known as MetMAb), an inhibitor of Alk, AF802 (also known as CH5424802 or alectinib), an inhibitor of a phosphatidylinositol 3-kinase (PI3K), BKM120, idelalisib (also known as GS-1101 or CAL 101), perifosine (also known as KRX-0401), an Akt, MK2206, GSK690693, GDC-0941, an inhibitor of mTOR, sirolimus (also known as rapamycin), temsirolimus (also known as CCI-779 or Torisele), everolimus (also known as RAD001), ridaforolimus (also known as AP-23573, MK-8669, or deforolimus), OSI-027, AZD8055, INK128, a dual PI3K/mTOR inhibitor, XL765, GDC-0980, BEZ235 (also known as NVP-BEZ235), BGT226, GSK2126458, PF- 04691502, PF-05212384 (also known as PKI-587).
The additional therapy may be one or more of the chemotherapeutic agents described herein.
iii. Methods and uses for treating locally advanced unresectable or metastatic lung cancer Provided herein are methods and uses for treating lung cancer (e.g., non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage 1118 NSCLC), or recurrent or metastatic NSCLC
(e.g., Stage IV
NSCLC), small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC), and adenocarcinoma of the lung) in a subject or population of subjects comprising administering to the subject or population of subjects one or more dosing cycles of 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), and a first and second chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent).
The present invention includes methods and uses involving administration of 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), and a chemotherapy combination to a subject or population of subjects in need thereof. In some embodiments, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle). In some aspects, the invention includes methods and uses involving administration of 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 antibody, such as atezolizumab) based on body weight (BW) or body surface area (BSA) of a subject or population of subjects every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In some aspects, the invention includes methods and uses involving administration of 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), and a chemotherapy combination to a subject or population of subjects in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent. In some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle). In some instances, the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is an antimetabolite (e.g., pemetrexed).
In particular embodiments, the method involves administration of 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, 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, wherein the anti-TIGIT
antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and the chemotherapy combination (e.g., the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and the antimetabolite (e.g., pemetrexed) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21-day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum-based chemotherapeutic agent.
In some instances, the present invention includes methods and uses involving administration of 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 antibody, such as atezolizumab) to a subject or population of subjects in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in PFS
or DOR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in OS.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in progression-free survival of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) extends OS of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, administration of the 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), and a chemotherapy combination to a subject or population of subjects in need thereof (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) results in an increase in a median PFS of the subject or population of subjects as compared to treatment with pembrolizumab and the chemotherapy combination (e.g., the antimetabolite (e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)).
In some instances, the treatment extends the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months (e.g., at least about 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, or 4.7 months, e.g., at least about 3.5-3.7 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, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median PFS
of greater than 8.8 months (e.g., at least 8.9 months, at least 9.0 months, at least 9.2 months, at least 9.5 months, at least 10 months, at least 11 months, at least 12 months, at least

13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or more, e.g., about 8.9 months, about 9.0 months, about 9.2 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more). In some instances, the treatment results in a median PFS of the population of subjects of at least about 8 months (e.g., between 8 months and 36 months, e.g., between 8 months and 24 months (e.g., 8 months, 9 months, 10 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months).
In some instances, the treatment results in a median PFS of the population of subjects of about 12.5 months to about 14.7 months (e.g., 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7,13.9, 14.1, 14.3, 14.5, or 14.7 months, e.g., about 12.5-13 months, 13-13.5 months, 13.5-14 months, or 14-14.7 months. In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median PFS of at least 10 months. In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median PFS of at least 12 months.
In some instances, administration of the 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), and a chemotherapy combination to a subject or population of subjects having a lung cancer (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) results in an increase in a median OS (OS) of the subject or population of subjects as compared to treatment with pembrolizumab and the chemotherapy combination (e.g., the antimetabolite (e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)). In some instances, the treatment extends the OS of the subject or population of subjects by at least about 4 months (e.g., between 4 and 12 months (e.g., 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months)). In some instances, the treatment extends the OS of the subject or population of subjects by at least about 5.5 months to about 8.0 months (e.g., 5.5., 6.0, 6.5, 7.0, 7.5, or 8.0 months, e.g., 5.5-6.5, 6.5-7.5, or 7.5-8.0 months).
In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median OS
of greater than 22 months (e.g., at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 42, at least 48, at least 54, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, or at least 200 months, e.g., about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about, 33, about 34, about 35, about 36, about 40, about 42, about 48, about 54, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200 months). In some embodiments, the treatment results in a median OS of the population of subjects of at least about 24 months (e.g., between 24 months and 42 months (e.g., between 24 months and 36 months (e.g., 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months))). In some embodiments, the treatment results in a median OS of the population of subjects of about 27.5 months to about 32.0 months (e.g., 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, or 32.0 months (e.g., 27.5-28.5, 28.5-29.5, 29.5-30.5, 30.5-31.5, or 31.5-32 months).
In some embodiments, the administration of the 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), and a chemotherapy combination to a subject or population of subjects in need thereof (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median OS of at least 24 months. In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in a median OS of at least 36 months.
In some instances, administration of the 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), and a chemotherapy combination to a subject or population of subjects in need thereof (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) results in an increase in an overall response rate (ORR) of the subject or population of subjects as compared to treatment with pembrolizumab and the chemotherapy combination (e.g., the antimetabolite (e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)), e.g., an increase in ORR of at least 10%, (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%) as compared to treatment with pembrolizumab and the chemotherapy combination (e.g., the antimetabolite (e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)).
In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a .. lung cancer (e.g., an NSCLC) according to any of the methods described herein results in an ORR of greater than 47.5% (e.g., at least 48%, at least 49%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%, e.g., about 48%, about 49%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the administration of .. the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in an ORR of at least 50%. In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in an ORR of at least 60%. In some embodiments, the administration of the 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), and a chemotherapy combination (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects having a lung cancer (e.g., an NSCLC) according to any of the methods described herein results in an ORR of at least 70%.
The present invention includes methods and uses involving administration of 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 population of subjects in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in progression-free survival of the subject or population of subjects compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in DOR. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends OS of the subject or population of subjects.
The present invention includes methods and uses involving administration of 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 antibody, such as atezolizumab) to a subject or population of subjects in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in progression-free survival of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIC IT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) extends OS of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT
antagonist antibody without the PD-1 axis binding antagonist.
In certain instances, the present invention includes methods and uses involving administration of 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 population of subjects in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in progression-free survival of the subject or population of subjects compared to a reference. In some instances, administration of the effective amount of the anti-TIC IT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends OS of the subject or population of subjects.
In some instances, the subject or population of subjects has not received prior systemic therapy (e.g., e.g., prior systemic therapy with curative intent, e.g., chemotherapy) within the month prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody (e.g., within the two months prior, three months prior, four months prior, six months prior, one year prior, two years prior, three years prior, four years prior, five years prior, or ten years prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody). In some instances, the subject or population of subjects is chemotherapy naïve.
In some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered in conjunction with a chemotherapy. For example, a once-every-two-weeks (Q2W), once-every-three-weeks (Q3W), or once-every-four-weeks (04W) dosing regimen of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can be administered in conjunction with one or more chemotherapeutic agents. The one or more chemotherapeutic agents can be administered at the same frequency as the frequency of administration of the PD-1 axis binding antagonist and the anti-TIC IT
antagonist antibody (Q2W, Q3W, or Q4W) or at a different frequency (e.g., 3-weeks on/1-week off schedule). For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered every two weeks and the one or more chemotherapeutic agents is administered every week, 3-weeks on/1-week off, every two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are administered every three weeks and the one or more chemotherapeutic agents is administered every week, two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every four weeks and the one or more chemotherapeutic agents is administered every week, 3-weeks on/1-week off, every two weeks, every three weeks, or every four weeks. In certain instances, a chemotherapeutic agent is administered multiple times per week (e.g., 2, 3, 4, 5, 6 or 7 times per week (e.g., at Days 1, 2, and 3 of a dosing cycle)).
In some embodiments, the dose of a chemotherapeutic agent is reduced after one or more initial doses (e.g., after one, two, three, four, or more initial doses). For example, a subsequent dose of the chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) can be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose.
For example, an initial dose of cisplatin of about 75 mg/m2 can be reduced for a subsequent dose, e.g., to 70 mg/m2, 65 mg/m2, 60 mg/m2, 55 mg/m2, 50 mg/m2, or 45 mg/m2; an initial dose of pemetrexed of about 500 mg/m2 can be reduced for a subsequent dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300 mg/m2, 250 mg/m2, or 200 mg/m2; and/or an initial dose of carboplatin of a dose sufficient to achieve AUC = 5 mg/ml/min can be reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUC = 4.5 mg/ml/min, 4.0 mg/ml/min, 3.5 mg/ml/min, or 3.0 mg/ml/min.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in a CR or a PR. In some instances, administration of the effective amount of the anti-TIC IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in an increase in progression-free survival of the subject or population of subjects. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., .. carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) extends OS of the subject or population of subjects.
In some instances, the subject or population of subjects receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) is being treated for a lung cancer, e.g., an NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC))).
Dosing of agents Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents is described in Section III(K).
Cancer characterization In any of the methods, uses, or compositions for use described herein, the lung cancer may be an NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC))). In some instances, the subject or population of subjects has not received prior systemic therapy for the lung cancer.
In some instances, in any of the methods, uses, or compositions for use described herein, the subject has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have an EGFR gene mutation (e.g., a sensitizing EGFR gene mutation) or ALKgene rearrangement. In some instances, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
Methods for detecting the mutational status EGFR and ALK are well known in the art, and include, but are not limited to, sequencing DNA from clinical samples (e.g., tumor biopsies or blood samples (e.g., circulating tumor DNA in blood)) using a next-generation sequencing method, such as the targeted gene pulldown and sequencing method described in Frampton et al.
(Nature Biotechnology.
31(11): 1023-1033, 2013), which is incorporated by reference herein in its entirety. Such a next-generation sequencing method can be used with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small-core needle biopsies, fine-needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods for the detection of the mutational status of EGFR and ALK include fluorescence in situ hybridization (FISH) and immunohistochemical (INC) methods. Exemplary methods for the detection of the mutational status of ALK are disclosed in U.S. Patent No: 9,651,555, which is herein incorporated by reference in its entirety. In some instances, the VENTANA anti-ALK(D5F3) IHC
assay is used to determine the mutational status of the ALK gene.
In some instances of any of the methods described herein, the mutation is a sensitizing EGFR
mutation. Sensitizing EGFR mutations are well known in the art and include those described in U.S.
Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in Medical Oncology. 9(3):
201-216, 2017), which are incorporated by reference herein in their entireties. In some instances, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some instances, the sensitizing EGFR mutation is a deletion of exon 19 (deli 9). In other instances, sensitizing EGFR mutation is a L858R point mutation in exon 21. In some instances, the sensitizing EGFR mutation is a G719X point mutation in exon 18, wherein "X" is most commonly C, A, or S. In some instances, the sensitizing EGFR mutation is a G719S point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a S720F point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a L861Q point mutation in exon 21. In some instances, the sensitizing EGFR mutation is a L861R point mutation in exon 21. In other instances, the sensitizing EGFR mutation is a T790M point mutation. In some instances, the sensitizing EGFR mutation is an E709X point mutation, where "X" is most commonly K, A, or H. In some instances, the sensitizing EGFR mutation is a S768I point mutation.
In some instances of any of the methods described herein, the mutation is an ALKgene rearrangement. ALKgene rearrangements are well known in the art and include those described in U.S.
Patent No: 9,651,555 and in Du et al. (Thoracic Cancer. 9: 423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, the ALKgene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways resulting in increased cell proliferation and survival. In some instances, the ALKgene rearrangement is an ALK rearrangement with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SOSTM1, NPM1, BCL11A, BIRC6, RANBP2, AT/C, CLTC, TMP4, and MSN resulting in the formation of a fusion oncogene. 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 instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. Methods for detecting the subtype of NSCLC are well known in the art, and include, but are not limited to, methods of determination by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)). In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample.
In some instances, 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 a known or suspected chronic active EBV
infection. Indicators of active or chronic active EBV infections for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles detected in a sample from the subject (e.g., a blood or serum sample). Methods for detecting the presence of one or more indicators of active or chronic active EBV infection, including EBV
IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles in a sample from a subject are well known in the art, and include, but are not limited to, methods involving serological diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis of a blood sample for the detection of EBV viral particles) or EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV IgM, or EBV
IgG using heterophilic antibodies). In some instances, the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample. In some instances, the subject is negative for EBV IgM and/or negative by EBV PCR. In some instances, the subject is negative for EBV
IgM and/or negative by EBV PCR and is positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA). In other instances, 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., a tumor PD-L1 expression with a minimum PD-L1-positive tumor cell fraction or TPS 30% (e.g., 50%) as determined by an IHC with the 5P263 or 22C3 antibody or a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) is greater than or equal to 1% in the tumor sample as determined by an IHC
with the SP142 antibody). In some instances, the PD-L1 selected tumor is a tumor that has been determined to have a PD-L1-positive tumor cell fraction or PD-L1 TPS of greater than, or equal to, 30%
(e.g., greater than, or equal to, 50%) by an immunohistochemical (IHC) assay.
In some instances, the PD-L1 selected tumor is a tumor that has been determined to have a proportion of tumor area occupied by PD-L1 expressing immune cells (lCs) greater than or equal to 1% by an immunohistochemical (IHC) assay. In some instances, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the INC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the tumor sample has been determined to have a TPS of greater than, or equal to, 50%. In some instances, the PD-L1-positive tumor cell fraction is greater than, or equal to, 50% (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1-positive tumor cell fraction is greater than, or equal to, 30%, as determined by positive staining with the anti-PD-L1 antibody SP142. In some instances, the ICs has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 5% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 10%
(e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 1 ./0 and less than 50% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be greater than, or equal to, 1 ./0 and less than 30% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some instances, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1 A, of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1%
of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1 ./0 and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5%

and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.
In some instances, the subject has a lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) that has not been evaluated from PD-L1 expression. For example, in some instances, the subject having a lung cancer has not been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 50% (e.g., the subject has not been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 45%, 40%, 35%, or 30%). For example, in some instances, the subject has not been determined to have a TPS of greater than, or equal to, 50% PD-L1-positive (e.g., the subject has not been determined to have a TPS of greater than, or equal to, 45% PD-L1-positive, 40% PD-L1-positive, 35% PD-L1-positive, or 30% PD-L1-positive), e.g., as assessed using any of the IHC methods described herein or known in the art.
In some instances, the subject having a lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) has been determined to have a PD-L1-positive tumor cell fraction of less than 50% (e.g., from 1% to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20% to 30%, e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25%
to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%, e.g., less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0%). For example, in certain instances, the subject having a lung cancer has been determined to have a PD-L1-positive tumor cell fraction from 1-49% (e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%). In other instances, the subject having a lung cancer has been determined to have a PD-L1-positive tumor cell fraction of less than 1% (e.g., about 0%, or an undetectable PD-L1 expression).
For example, in some instances, the subject having a lung cancer (e.g., NSCLC
(e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) has been determined to have a TPS of less than 50%
PD-L1-positive (e.g., from 1% to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20% to 30% PD-L1-positive, e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49% PD-L1-positive, e.g., less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0% PD-L1-positive). For example, in certain instances, the subject having a lung cancer has been determined to have a TPS from 1-49% PD-L1-positive (e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49% PD-L1-positive). In other instances, the subject having a lung cancer has been determined to have a TPS of less than 1% PD-L1-positive (e.g., about 0%, or an undetectable PD-L1 expression).
In particular embodiments, the subject has an NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC))) that has not been evaluated from PD-L1 expression. For example, in some instances, the subject having an NSCLC has not been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 50% (e.g., the subject has not been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 45%, 40%, 35%, or 30%). For example, in some instances, the subject has not been determined to have a TPS of greater than, or equal to, 50% PD-L1-positive (e.g., the subject has not been determined to have a TPS of greater than, or equal to, 45% PD-L1-positive, 40% PD-L1-positive, 35% PD-L1-positive, or 30% PD-L1-positive), e.g., as assessed using any of the IHC methods described herein or known in the art.
In some instances, the subject having an NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC))) has been determined to have a PD-L1-positive tumor cell fraction of less than 50% (e.g., from 1% to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20%
to 30%, e.g., from 1 /0 to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%, e.g., less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0%). For example, in certain instances, the subject having an NSCLC has been determined to have a PD-L1-positive tumor cell fraction from 1-49% (e.g., from 1%
to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%). In other instances, the subject having an NSCLC has been determined to have a PD-L1-positive tumor cell fraction of less than 1% (e.g., about 0%, or an undetectable PD-L1 expression).
For example, in some instances, the subject having an NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC))) has been determined to have a TPS of less than 50% PD-L1-positive (e.g., from 1 /0 to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20%
to 30% PD-L1-positive, e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49% PD-L1-positive, e.g., less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than .. 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0% PD-L1-positive).
For example, in certain instances, the subject having an NSCLC has been determined to have a TPS
from 1-49% PD-L1-positive (e.g., from 1% to 5%, from 5% to 10 /e, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40%
to 45%, or from 45%
to 49% PD-L1-positive). In other instances, the subject having an NSCLC has been determined to have a TPS of less than 1% PD-L1-positive (e.g., about 0%, or an undetectable PD-L1 expression).

In some instances, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some instances, the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof. In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample. In some instances, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
In some instances, a tumor sample obtained from a subject having a lung cancer (e.g., NSCLC
(e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC
(e.g., Stage IV non-squamous NSCLC)))) has a low or undetectable nucleic acid expression level of PD-L1. In some instances, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH, or a combination thereof. In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample. In some instances, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
In some instances of any of the methods described herein, the subject having a lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) has received no prior systemic treatment for the lung cancer (e.g., no prior systemic treatment with curative intent). In particular embodiments, the subject has a locally advanced lung cancer and has received no prior systemic treatment for the locally advanced lung cancer. In some instances, the subject has an NSCLC (e.g., a non-squamous NSCLC, e.g., a locally advanced unresectable or metastatic non-squamous NSCLC) and has received no prior systemic treatment for the NSCLC (e.g., a non-squamous NSCLC, e.g., a locally advanced unresectable or metastatic non-squamous NSCLC). Prior systemic treatments include prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, and chemoradiotherapy with curative intent for non-metastatic disease.
In other instances, the subject having a lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)))) has received prior systemic treatment for the lung cancer and has experienced a treatment-free interval of at least 12 months before treatment according to any of the methods of the present invention.
iv. Methods and uses for treating resectable lung cancer Provided herein are methods and uses for treating lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) in a subject comprising administering to the subject one or more dosing cycles of 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 antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab). In some instances, at least one dosing cycle is administered as a neoadjuvant treatment. In some instances, the treatment is a neoadjuvant treatment.

In some instances, at least one dosing cycle is administered as an adjuvant treatment. In some instances, the treatment is an adjuvant treatment. In some instances, the treatment comprises a neoadjuvant treatment and an adjuvant treatment. In some instances, the lung cancer is a resectable lung cancer. In some instances, the lung cancer is an early stage lung cancer (e.g., stage II, IIIA, or IIIB
lung cancer). In some instances, the lung cancer is an NSCLC (e.g., a squamous or non-squamous NSCLC). In some instances, the lung cancer is PD-L1 positive (e.g., PD-L1 high). In some instances, the lung cancer has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some embodiments, the subject has not been previously treated for lung cancer (e.g., a prior surgery, a prior immunotherapy, a prior chemotherapy, or a prior radiotherapy). In some instances, the subject is eligible to receive a platinum-based chemotherapy regimen. In some instances, the subject is eligible for an RO resection with curative intent.
The subject is preferably a human.
The present invention includes methods and uses for treating a subject having a resectable lung cancer (e.g., a resectable NSCLC (e.g., a resectable squamous or non-squamous NSCLC)), the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks (e.g., on Day 1 of each 21-day dosing cycle). In some aspects, the method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks (e.g., on Day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
The present invention includes methods and uses involving administration of 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 antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) to a subject in need thereof every three weeks (e.g., on Day 1 of each 21-day dosing cycle). In some instances, at least one of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks (e.g., a dose of 600 mg every three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1 600 mg every three weeks (e.g., a dose of about 1200 mg every three weeks) as a neoadjuvant treatment. In some instances, at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks (e.g., a dose of 600 mg every three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks (e.g., a dose of about 1200 mg every three weeks) as an adjuvant treatment. In some instances, at least one of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks (e.g., a dose of 600 mg every three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks (e.g., a dose of 1200 mg every three weeks) as a neoadjuvant treatment. In some instances, at least one of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks (e.g., a dose of 600 mg every three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks (e.g., a dose of 1200 mg every three weeks) as an adjuvant treatment.
In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab) is being treated for a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a squamous or non-squamous .. NSCLC)))).
The PD-1 axis binding antagonist anti-TIGIT antagonist antibody may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and anti-TIGIT
antagonist antibody may be administered sequentially (on different days) or concurrently (on the same day or during the same treatment cycle). In some instances, the anti-TIGIT
antagonist antibody and/or the PD-1 axis binding antagonist are administered on about Day 1 (e.g., Day -3, Day -2, Day -1, Day 1, Day 2, or Day 3) of a dosing cycle. In some instances, the PD-1 axis binding antagonist and anti-TIGIT
antagonist antibody may be administered on the same day. In some instances, the PD-1 axis binding antagonist is administered before the anti-TIGIT antagonist antibody. In some instances, the PD-1 axis binding antagonist is administered after the anti-TIGIT antagonist antibody.
In some instances, the PD-1 axis binding antagonist is administered simultaneously with the anti-TIGIT
antagonist antibody. In some instances, the PD-1 axis binding antagonist may be administered prior to an anti-TIGIT antagonist antibody that is administered on the same day. In some instances, the PD-1 axis binding antagonist may be administered after to an anti-TIGIT antagonist antibody that is administered on the same day. In yet other instances, the PD-1 axis binding antagonist is administered at the same time as the anti-TIGIT
antagonist antibody. In some instances, the PD-1 axis binding antagonist is in a separate composition as the anti-TIGIT antagonist antibody. In some instances, 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 through a separate intravenous line from any other therapeutic agent administered to the patient on the same day. The PD-1 axis binding antagonist and anti-TIGIT
antagonist antibody may be administered by the same route of administration or by different routes of administration. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the PD-1 axis binding antagonist is administered intravenously. In some instances, the anti-TIGIT
antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, there is a first observation period following administration of the PD-1 axis binding antagonist. In some instances, there is a second observation period following administration of the PD-1 axis binding antagonist. In some instances, there is a first observation period following administration of the anti-TIGIT antagonist antibody. In some instances, there is a second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In some instances, the anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist are administered intravenously or subcutaneously. In some instances, 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; if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. In some examples, the PD-1 axis binding antagonist is not administered as an intravenous push or bolus. In one example, tiragolumab may be administered intravenously over 60 minutes; if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. In some examples, the anti-TIGIT antagonist antibody is not administered as an intravenous push or bolus.
In any of the preceding examples, each dosing cycle may have any suitable length, e.g., about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21, 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or longer. In some instances, each dosing cycle is about 21 days.
In some instances, a PD-L1 expression level of a sample (e.g., a tumor sample, a blood sample (e.g., a plasma sample), or a lymph sample) obtained from the subject has been determined. In some instances, the sample has been determined to have a detectable expression level of PD-L1 (e.g., a detectable protein and/or nucleic acid expression level of PD-L1). In some instances, the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.
In some instances, the detectable expression level of PD-L1 is a PD-L1-positive tumor cell fraction (e.g., a PD-L1-positive tumor cell fraction of greater than or equal to 50%). In some instances, the detectable protein expression level of PD-L1 has been determined by an immunohistochemical (INC) assay comprising staining with an anti-PD-L1 antibody suitable for staining (e.g., anti-PD-L1 antibody SP263). In some instances, the IHC
assay is a Ventana SP263 IHC assay. In some instances, the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1. In some instances, the mutational status of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) is determined. In some instances, the method further comprises obtaining a sample from the subject. In some instances, the method further comprises determining the expression level of PD-L1.
In some instances, the first dosing cycle is initiated prior to a surgery (e.g., a segmentectomy, a lobectomy, a bilobectomy, or a pneumonectomy). In some instances, one or more dosing cycles are completed prior to a surgery. In some instances, at least 1, 2, 3, or 4 dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) are completed prior to a surgery. In some instances, 4 dosing cycles are completed prior to a surgery. In some instances, 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 a surgery. In some instances, 16 dosing cycles are completed after a surgery. In some instances, the treatment includes a surgery. In some instances, the surgery is a segmentectomy, a lobectomy, a bilobectomy, or a pneumonectomy. In some instances, the treatment includes a radiotherapy (e.g., a post-operative radiotherapy).
In some instances, the treating results in an increase in major pathological response (MPR) rate as compared to a reference MPR rate. In some instances, the treating results in a pathological complete response (pCR) and/or an increase in pCR rate as compared to a reference pCR
rate. In some instances, the treating results in an increase in event-free survival (EFS) as compared to a reference EFS
time. In some instances, the treating results in an increase in OS as compared to a reference OS time.
In some instances, the reference MPR rate, reference pCR rate, and/or reference EFS time are an MPR
rate, a pCR rate, and/or an EFS time of a population of subjects who have received a treatment comprising: (a) a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody; and/or (b) cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in MPR rate. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in a pCR. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in EFS. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase in OS.
In some instances, the treatment further comprises one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some instances, the neoadjuvant and/or adjuvant treatment further comprises one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some instances, the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. In some instances, the platinum-based chemotherapeutic agent is carboplatin or cisplatin. In some instances, the non-platinum-based chemotherapeutic agents are an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel). In some instances, 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 (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some instances, at least one or more chemotherapeutic agents are: (a) carboplatin and pemetrexed;
(b) carboplatin and paclitaxel; (c) cisplatin and pemetrexed; (d) carboplatin and gemcitabine; or (e) cisplatin and gemcitabine.
In some instances, the one or more chemotherapeutic agents used in a treatment for non-squamous NSCLC are (a) carboplatin and pemetrexed, (b) carboplatin and paclitaxel, or (c) cisplatin and pemetrexed. In some instances, the one or more chemotherapeutic agents used in a treatment for squamous NSCLC are (a) carboplatin and gemcitabine, (b) carboplatin and paclitaxel, or (c) cisplatin and gemcitabine. In some instances, the treatment further comprises administering one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some instances, the one or more chemotherapeutic agents are administered every three weeks. In some instances, the one or more chemotherapeutic agents are administered on about Day 1 (e.g., Day -3, Day -2, Day -1, Day 1, Day 2, or Day 3) of one or more dosing cycles. In some instances, the one or more chemotherapeutic agents are administered on about Day 1 (e.g., Day -3, Day -2, Day -1, Day 1, Day 2, or Day 3) and on about Day 8 (e.g., Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, or Day 11) of one or more dosing cycles. In some instances, the dosing cycles are, e.g., about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21, 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or longer. In some instances, each dosing cycle is about 21 days. In some instances, the one or more chemotherapeutic agents are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist (e.g., atezolizumab) and/or anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab). In some instances, the non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)) is administered before the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin).
The present invention includes methods and uses for treating a subject having a resectable lung cancer (e.g., an early stage resectable lung cancer (e.g., a resectable NSCLC
(e.g., a resectable squamous or non-squamous NSCLC))), the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg every three weeks, 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) at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks, 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 a taxane (e.g., paclitaxel or nab-paclitaxel)). In some aspects, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between 30 mg to 600 mg every three weeks, 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) at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks, 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 a taxane .. (e.g., paclitaxel or nab-paclitaxel)).
The present invention includes methods and uses for treating a subject having a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC)))), the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), 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), 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 a taxane (e.g., paclitaxel or nab-paclitaxel)), wherein at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg every three weeks, the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks, 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 a taxane (e.g., paclitaxel or nab-paclitaxel)) as a neoadjuvant treatment.
In some aspects, at least one of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 600 mg every three weeks, the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks, 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 a taxane (e.g., paclitaxel or nab-paclitaxel)) as a neoadjuvant treatment.
The present invention includes methods and uses for treating a subject having a resectable lung cancer (e.g., an early stage resectable lung cancer (e.g., a resectable NSCLC
(e.g., a resectable squamous or non-squamous NSCLC))), the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg every three weeks, 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) at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks, and: (a) (i) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose of about 75 mg/m2 every three weeks; and (b) (i) an antimetabolite 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) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks. In some aspects, the method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between 30 mg to 600 mg every three weeks, 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) at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks, and: (a) (i) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose of 75 mg/m2 every three weeks; and (b) (i) an antimetabolite at a dose of 500 mg/m2 every three weeks or 1000 mg/m2 or 1250 mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) a taxane at a dose of 100 mg/m2, 175 mg/m2, or 200 mg/m2 every three weeks.
The present invention includes methods and uses for treating a subject having a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC)))), the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), 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), 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 a taxane (e.g., paclitaxel or nab-paclitaxel)), wherein at least one of the dosing cycles comprises administering to the subject: (a) the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg every three weeks; (b) the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks; (c) the platinum-based chemotherapeutic agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) at a dose of about 75 mg/m2 every three weeks; and (d) the non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) an antimetabolite 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) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks; wherein the treatment is a neoadjuvant treatment. In some aspects, at least one of the dosing cycles comprises administering to the subject: (a) the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 600 mg every three weeks; (b) the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks; (c) the platinum-based chemotherapeutic agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) at a dose of 75 mg/m2 every three weeks;
and (d) the non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) an antimetabolite at a dose of 500 mg/m2 every three weeks or 1000 mg/m2 or 1250 mg/m2 on Days 1 and 8 .. of each dosing cycle; or (ii) a taxane at a dose of 100 mg/m2, 175 mg/m2, or 200 mg/m2 every three weeks; wherein the treatment is a neoadjuvant treatment.
The present invention includes methods and uses for treating a subject having a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC)))), 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: (a) at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks as a neoadjuvant treatment; and (b) at least one of the dosing cycles comprises administering to the subject .. the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks as an adjuvant treatment. 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 .. administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks as a neoadjuvant treatment; and (b) at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks as an adjuvant treatment.
The present invention includes methods and uses for treating a subject having a lung cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC)))), 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: (I) at least one of the dosing cycles is a neoadjuvant treatment and comprises administering to the subject: (a) the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks; (b) the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600 mg every three weeks as a neoadjuvant treatment; (c) a platinum-based chemotherapeutic agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) at a dose of about 75 mg/m2 every three weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) an antimetabolite 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) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks; and (II) at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1 600 mg every three weeks as an adjuvant treatment. In some aspects, the method comprises administering to the subject: (a) the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks;
(b) the PD-1 axis binding .. antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks as a neoadjuvant treatment; (c) a platinum-based chemotherapeutic agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/milmin every three weeks; or (ii) at a dose of 75 mg/m2 every three weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) an antimetabolite at a dose of 500 mg/m2 every three weeks or 1000 .. mg/m2 or 1250 mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) a taxane at a dose of 100 mg/m2, 175 mg/m2, or 200 mg/m2 every three weeks; and (II) at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks as an adjuvant treatment.
In some instances, the treatment may further comprise an additional therapy.
Any suitable additional therapy known in the art or described herein may be used. The additional therapy may be radiation therapy (e.g., a post-operative radiotherapy), surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or a combination of the foregoing.
In some instances, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti-nausea agents, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose of 1-2 mg/kg/day), hormone replacement medicine(s), and the like).
Also provided herein are methods for treating lung cancer in a subject comprising administering to the subject a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., atezolizumab) and/or anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) in combination with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel))) and/or cancer therapy (e.g., a surgery and/or a radiotherapy). For example, a PD-1 axis binding antagonist may be administered in combination with an additional chemotherapy or chemotherapeutic agent (see definition above); a targeted therapy or targeted therapeutic agent; an immunotherapy or immunotherapeutic agent, for example, a monoclonal antibody;
one or more cytotoxic agents (see definition above); or combinations thereof.
Dosing of agents Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents is described in Section III(K).
Cancer characterization and selection In some instances, in any of the methods, uses, or compositions for use described herein, the lung cancer (e.g., early-stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) is resectable (e.g., eligible for RO resection with curative intent). In some instances, the lung cancer is an NSCLC. In some instances, the NSCLC is a squamous or non-squamous NSCLC. In some instances, the lung cancer is PD-L1 positive. In some instances, the lung cancer is PD-L1 high. In some instances, the lung cancer has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some instances, the lung cancer is a stage II, IIIA, or IIIB lung cancer.
In some instances, in any of the methods, uses, or compositions for use described herein, the subject is eligible for platinum-based chemotherapy. In some instances, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. In some instances, the subject has not received a prior therapy (e.g., an immunotherapy, a chemotherapy, or a radiotherapy) for lung cancer.
In some instances, in any of the methods, uses, or compositions for use described herein, the presence or level of circulating tumor DNA (ctDNA) may be assessed. In some instances, ctDNA is assessed in a sample (e.g., a blood sample (e.g., a plasma sample)) from the subject. In some instances, ctDNA is assessed in a sample from the subject prior to day 1 of the first dosing cycle (e.g., the first dosing cycle of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist). In some instances, ctDNA is assessed in a sample from the subject prior to surgery. In some instances, ctDNA is assessed in a sample from the subject after surgery.
In some instances, in any of the methods, uses, or compositions for use described herein, the presence or level of immune cells (e.g., T cells) may be assessed. In some instances, the presence or level of immune cells is assessed in a sample (e.g., a blood sample, a tumor tissue sample, or a lymph node sample) from the subject. In some instances, the presence or level of immune cells is assessed in a sample from the subject prior to surgery. In some instances, the presence or level of immune cells is assessed in a sample from the subject after surgery.
Assessment of PD-L1 Expression The expression of PD-L1 may be assessed as described in Section 1I1(L).
Assessment of EGFR and ALK aberrations Methods for detecting the mutational status EGFR and ALK are described in Section III(N) herein.
Responses to Treatment In some embodiments of any of the methods described herein, a subject's response to the therapy can be characterized by one or more measures. In some embodiments, the treatment results in an increase in major pathological response (MPR) rate. In some embodiments, the treatment results in a pCR. In some embodiments, the treatment results in an increase in event-free survival (EFS). In some embodiments, the treatment results in an improvement in patient-reported outcomes. In some embodiments, the treatment results in an improvement in patient-reported physical functioning, role functioning, or GHS/QoL, as measured by the EORTC-QLQ-C30. In some embodiments, the treatment results in an improvement in patient-reported lung cancer symptoms for cough, dyspnea, and chest pain, as measured through the use of the EORTC-QLQ-LC13.
In some instances, the treatment results in an increase in MPR rate of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some instances, the treatment results in an increase in MPR
rate of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody without chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some instances, the treatment results in an increase in pCR of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, the treatment results in an increase in pCR of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some instances, the treatment extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some instances, the treatment extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some instances, the treatment extends EFS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some instances, the treatment extends EFS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some embodiments, a treatment described increases the MPR rate by at least 1% (e.g., by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).
In some embodiments, a treatment described herein extends the pCR of the subject by at least about 2 months (e.g., by 2-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 .. months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the pCR of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 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, a treatment described herein extends the EFS of the subject by at least about 2 months (e.g., by 2-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the .. treatment extends the EFS of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some embodiments, OS is measured as the period of time from the start of treatment to death.
In some instances, the treatment extends the OS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances, .. the treatment extends the OS of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances, the treatment extends the OS of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months,

14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
C. Therapeutic and diagnostic methods and uses relating to cervical cancer Cervical cancer Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related death. More than 500,000 women are diagnosed with cervical cancer annually worldwide, resulting in more than 300,000 deaths. Almost 90% of cervical cancer deaths occur in developing countries. In the United States, there are 13,000 new cases of invasive cervical cancer and approximately 4000 cancer-related deaths each year.
Treatment for early and locally advanced cervical cancer consists of surgery and definitive chemoradiotherapy, respectively, and can be quite effective in eliciting a remission. However, if cancer recurs or fails to resolve with primary treatment, prognosis is quite poor with 5-year survival rates of approximately 15%, which is comparable to that of patients with de novo metastatic disease. With few exceptions, the standard of care for recurrent, persistent, or de novo metastatic disease is chemotherapy plus bevacizumab based on the Gynecology Oncology Group 240 trial, which showed that bevacizumab added to chemotherapy improved median OS compared with chemotherapy alone (17 vs. 13.3 months, respectively).
Currently, no globally-accepted standard of care exists after recurrence or progression on chemotherapy plus bevacizumab. As such, treatment options for these patients largely comprise various cytotoxic chemotherapy agents, administered as either a single agent or in combination. However, given the historically low response rates of approximately 10%-15%, increasing focus has been given to whether cytotoxic chemotherapies represent an acceptable standard of care over best supportive care given the impact and burden such agents can impart on patient quality of life.
Historically low efficacy rates of existing therapies, coupled with the engagement of the immune response owing to HPV infection of the cervical epithelial cells, makes cervical cancer a particularly attractive opportunity for novel immunotherapy-based approaches.

Thus, there is an unmet need in the field for the development of efficacious immunotherapies and methods of dosing the same for the treatment of cancers (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma).
Methods and uses for treating cervical cancer Provided herein are methods and uses for treating cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma) in a subject or population of subjects comprising administering to the subject or population of subjects one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))).
Dosing Regimens and Administration The therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma) one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, 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 MK-3475 (pembrolizumab, previously known as lambrolizumab))), thereby treating the subject or population of subjects.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between about mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., 30 between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of about 600 mg every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between 30 mg to 600 mg (e.g., between 50 mg to between 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg to 600 mg, e.g., between 200 mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg to 500 mg, e.g., between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of 600 mg every three weeks. In some instances, effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of 600 mg every three weeks. In some instances, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment 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, previously known as lambrolizumab))) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between about 80 mg to about 2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg to about 1900 mg, e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to about 1700 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg, e.g., between about 600 mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g., between about 740 mg to about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about 815 mg to about 865 mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 1900 mg, e.g., between about 300 mg to about 1700 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg, e.g., between about 400 mg to about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g., between about 600 mg to about 1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between about 800 mg to about 1800 mg, e.g., between about 900 mg to about 1800 mg, e.g., between about 1000 mg to about 1800 mg, e.g., between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to about 1800 mg, e.g., between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about 1800 mg, e.g., between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about 1780 mg, e.g., between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about 1705 mg, e.g., between about 1670 mg to about 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between 80 mg to 2000 mg (e.g., between 80 mg to 1950 mg, e.g., between 80 mg to 1900 mg, e.g., between 80 mg to 1800 mg, e.g., between 100 mg to 1700 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1400 mg, e.g., between 400 mg to 1300 mg, e.g., between 500 mg to 1200 mg, e.g., between 600 mg to 1100 mg, e.g., between 700 mg to 1000 mg, e.g., between 740 mg to 940 mg, e.g., between 790 mg to 890 mg, e.g., between 815 mg to 865 mg, e.g., between 830 mg to 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 1900 mg, e.g., between 300 mg to 1700 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 2000 mg, e.g., between 300 mg to 2000 mg, e.g., between 400 mg to 2000 mg, e.g., between 500 mg to 2000 mg, e.g., between 600 mg to 1900 mg, e.g., between 700 mg to 1800 mg, e.g., between 800 mg to 1800 mg, e.g., between 900 mg to 1800 mg, e.g., between 1000 mg to 1800 mg, e.g., between 1100 mg to 1800 mg, e.g., between 1200 mg to 1800 mg, e.g., between 1300 mg to 1800 mg, e.g., between 1400 mg to 1800 mg, e.g., between 1500 mg to 1800 mg, e.g., between 1580 mg to 1780 mg, e.g., between 1630 mg to 1730 mg, e.g., between 1655 mg to 1705 mg, e.g., between 1670 mg to 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1680 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1680 mg every four weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2 mg/kg, about 15 1 mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 15 mg/kg of the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg, e.g., between about 0.5 mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g., between about 2.5 mg/kg to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15 1 mg/kg, e.g., about

15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three .. weeks. In some instances, the effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 15 mg/kg administered every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 50 mg/kg of the subject's body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 2 mg/kg, 15 1 mg/kg, 15 0.5 mg/kg, 15 0.2 mg/kg, or 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 15 mg/kg of the subject's body weight (e.g., between 0.1 mg/kg to 15 mg/kg, e.g., between 0.5 mg/kg to 15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15 mg/kg, e.g., between 5 mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg to 15 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15 1 mg/kg, e.g., 15 0.5 mg/kg, e.g., 15 0.2 mg/kg, e.g., 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of 15 mg/kg administered every three weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg to about 220 mg, e.g., between about 190 mg to about 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200 1.0 mg, e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg to 220 mg, e.g., between 190 mg to 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200 1.0 mg, e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of 200 mg every three weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 mg, e.g., between about 200 mg to about 280 mg, e.g., between about 220 mg to about 260 mg, e.g., between about 230 mg to about 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of between about 100 mg to about 1000 mg (e.g., between about 200 mg to about 900 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 700 mg, e.g., between about 400 mg to about 600 mg, e.g., between about 400 mg to about 550 mg, e.g., between about 420 mg to about 540 mg, e.g., between about 440 mg to about 520 mg, e.g., between about 460 mg to about 500 mg, e.g., between about 470 mg to about 490 mg, e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 200 mg to 280 mg, e.g., between 220 mg to 260 mg, e.g., between 230 mg to 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of between 100 mg to 1000 mg (e.g., between 200 mg to 900 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 700 mg, e.g., between 400 mg to 600 mg, e.g., between 400 mg to 550 mg, e.g., between 420 mg to 540 mg, e.g., between 440 mg to 520 mg, e.g., between 460 mg to 500 mg, e.g., between 470 mg to 490 mg, e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 480 mg every four weeks.
In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the 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, previously known as lambrolizumab))) 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 instances, the dosing cycles of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some instances, the length of each dosing cycle is about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some instances, the length of each dosing cycle is about 21 days. In some instances, the length of each dosing cycle is about 14 days. In some instances, the length of each dosing cycle is about 28 days. In some instances, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks). In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of .. 600 mg every three weeks). Similarly, in some instances, 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously 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 three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is administered intravenously 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 three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks). In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously 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 three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is administered intravenously 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 three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks).
In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the 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, previously known as lambrolizumab))) are administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose (e.g., a fixed dose) of about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every three weeks). For example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) 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 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., pembrolizumab)) is administered intravenously 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 three weeks). In some examples, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a dose (e.g., a fixed dose) of 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks). For example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., pembrolizumab)) is administered intravenously at a dose of 200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 200 mg every three weeks).
In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the 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, previously known as lambrolizumab))) are administered on about Day 1 (e.g., Day 1 3 days) of the first dosing cycle. For example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose (e.g., a fixed dose) of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) 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 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks). In some examples, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose (e.g., a fixed dose) of 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of 240 mg every two weeks). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three .. weeks), and the PD-1 axis binding antagonist (e.g., 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., at a dose of 480 mg every four weeks).
In some instances, the 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 by intravenous infusion over about 60 15 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some instances, the 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, previously known as lambrolizumab))) is administered to the subject or population of subjects by intravenous infusion over about 60 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).
In some instances, the 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 by intravenous infusion over about 30 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes). In some instances, the 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, previously known as lambrolizumab))) is administered to the subject or population of subjects by intravenous infusion over about 30 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).
In some instances, the 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 before the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some instances, for example, following administration of the anti-TIGIT antagonist antibody and before administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))), the method includes an intervening first observation period. In some instances, the method further includes a second observation period following administration 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., MDX-1106 (nivolumab) or (pembrolizumab, previously known as lambrolizumab))). In some instances, the method includes both a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration of the 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, previously known as lambrolizumab))) during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration of the 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, previously known as lambrolizumab))) during the first and second observation periods, respectively.
In other instances, the 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 (pembrolizumab, previously known as lambrolizumab))) is administered to the subject or population of subjects before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab). In some instances, for example, following administration 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 (pembrolizumab, previously known as lambrolizumab))) and before administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some instances, the method includes a second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the method includes both a first observation period following administration 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., MDX-1106 .. (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, .. respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration 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., 1V1DX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in .. length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the first and second observation periods, respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the 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, previously known as lambrolizumab))) are administered to the subject or population of subjects simultaneously. In some instances, for example, following administration of the anti-TIGIT
antagonist antibody and the 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 (pembrolizumab, previously known as lambrolizumab))) the method includes an observation period. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In .. instances in which the observation period is about 60 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and .. anti-TIGIT antagonist antibody during the observation period. In instances in which the observation period is about 30 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the observation period.
In another aspect, the invention provides a method of treating a subject or population of subjects having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of 600 mg every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg 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, as described in further detail below. In some instances, 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 instances, 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 population of subjects having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg every three weeks.
In another aspect, the invention provides a method of treating a subject or population of subjects having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and pembrolizumab at a dose (e.g., a fixed dose) of 200 mg every three weeks.
In another aspect, the invention provides a method of treating a subject or population of subjects having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 240 mg every two weeks.
In another aspect, the invention provides a method of treating a subject or population of subjects having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 480 mg every four weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and an 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, previously known as lambrolizumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of 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 (pembrolizumab, previously known as lambrolizumab))).

In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 .. mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of between about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to .. 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of between 30 mg to 600 mg (e.g., between 50 mg to between 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg to 600 mg, e.g., between 200 .. mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg to 500 mg, e.g., between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of about 600 mg every three weeks. In some instances, effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of 600 mg every three weeks. In some instances, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered in a combination therapy (e.g., a combination treatment 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, previously known as lambrolizumab))) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody is to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between about 80 mg to about 2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg to about 1900 mg, e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to about 1700 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg, e.g., between about 600 mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g., between about 740 mg to about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about 815 mg to about 865 mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 1900 mg, e.g., between about 300 mg to about 1700 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg, e.g., between about 400 mg to about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g., between about 600 mg to about 1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between about 800 mg to about 1800 mg, e.g., between about 900 mg to about 1800 mg, e.g., between about 1000 mg to about 1800 mg, e.g., between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to about 1800 mg, e.g., between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about 1800 mg, e.g., between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about 1780 mg, e.g., between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about 1705 mg, e.g., between about 1670 mg to about 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between 80 mg to 2000 mg (e.g., between 80 mg to 1950 mg, e.g., between 80 mg to 1900 mg, e.g., between 80 mg to 1800 mg, e.g., between 100 mg to 1700 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1400 mg, e.g., between 400 mg to 1300 mg, e.g., between 500 mg to 1200 mg, e.g., between 600 mg to 1100 mg, e.g., between 700 mg to 1000 mg, e.g., between 740 mg to 940 mg, e.g., between 790 mg to 890 mg, e.g., between 815 mg to 865 mg, e.g., between 830 mg to 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 1900 mg, e.g., between 300 mg to 1700 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200 mg mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist 5 antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 2000 mg, e.g., between 300 mg to 2000 mg, e.g., between 400 mg to 2000 mg, e.g., between 500 mg to 2000 mg, e.g., between 600 mg to 1900 mg, e.g., between 700 mg to 1800 mg, e.g., between 800 mg to 1800 mg, e.g., between 900 mg to 1800 mg, e.g., between 1000 mg to 1800 mg, e.g., between 1100 mg to 1800 mg, e.g., between 1200 mg to 1800 mg, e.g., between 1300 mg to 1800 mg, e.g., between 1400 mg to 1800 mg, e.g., between 1500 mg to 1800 mg, e.g., between 1580 mg to 1780 mg, e.g., between 1630 mg to 1730 mg, e.g., between 1655 mg to 1705 mg, e.g., between 1670 mg to 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 840 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1680 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1680 mg every four weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) to be administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg to about 220 mg, e.g., between about 190 mg to about 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200 1.0 mg, e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg to 220 mg, e.g., between 190 mg to 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200 1.0 mg, e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose of about 200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose of 200 mg every three weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 mg, e.g., between about 200 mg to about 280 mg, e.g., between about 220 mg to about 260 mg, e.g., between about 230 mg to about 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the effective amount of the PD-1 .. axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of about 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of between about 100 mg to about 1000 mg (e.g., between about 200 mg to about 900 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 700 mg, e.g., between about 400 mg to about 600 mg, e.g., between about 400 mg to about 550 mg, e.g., between about 420 mg to about 540 mg, e.g., between about 440 mg to about 520 mg, e.g., between about 460 mg to about 500 mg, e.g., between about 470 mg to about 490 mg, e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 200 mg to 280 mg, e.g., between 220 mg to 260 mg, e.g., between 230 mg to 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of between 100 mg to 1000 mg (e.g., between 200 mg to 900 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 700 mg, e.g., between 400 mg to 600 mg, e.g., between 400 mg to 550 mg, e.g., between 420 mg to 540 mg, e.g., between 440 mg to 520 mg, e.g., between 460 mg to 500 mg, e.g., between 470 mg to 490 mg, e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of about 480 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 480 mg every four weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2 mg/kg, about 15 1 20 mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 15 mg/kg of the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg, e.g., between about 0.5 mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g., between about 2.5 mg/kg to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15 1 mg/kg, e.g., about 15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 15 mg/kg to be administered every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 50 mg/kg of the subject's body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 2 mg/kg, 15 1 mg/kg, 15 0.5 mg/kg, 15 0.2 mg/kg, or 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 15 mg/kg of the subject's body weight (e.g., between 0.1 mg/kg to 15 mg/kg, e.g., between 0.5 mg/kg to 15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15 mg/kg, e.g., between 5 mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg to 15 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15 1 mg/kg, e.g., 15 0.5 mg/kg, e.g., 15 0.2 mg/kg, e.g., 15 0.1 mg/kg, e.g., 15 mg/kg) every three weeks. In some instances, effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of 15 mg/kg to be administered every three weeks. In some instances, the dose 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) administered as a monotherapy.
The anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) 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 instances, the dosing cycles of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some instances, the length of each dosing cycle is about 14 to 28 days (e.g., 14 days,15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some instances, the length of each dosing cycle is about 21 days. In some instances, the length of each dosing cycle is about 14 days. In some instances, the length of each dosing cycle is about 28 days. In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks). Similarly, in some instances, 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is to be administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is to be administered intravenously at a dose (e.g., a fixed dose) of about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is to be administered intravenously 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 three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks).
For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks). In some instances, both the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) are to be administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) are to be administered on about Day 1 (e.g., Day 1 3 days) of the first dosing cycle. For example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered intravenously 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 three weeks), and thePD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered intravenously 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 three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks). In some examples, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is to be administered intravenously at a dose (e.g., a fixed dose) of 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is to be administered intravenously at a dose of 200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 200 mg every three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of 240 mg every two weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of 480 mg every four weeks). In some instances, both the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) are to be administered on Day 1 (e.g., Day 1 3 days) of each dosing cycle. In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) are to be administered on Day 1 (e.g., Day 1 3 days) of the first dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and thePD-1 axis binding antagonist (e.g., 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., at a dose of 240 mg every two weeks). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., 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., at a dose of 480 mg every four weeks).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered to the subject or population of subjects by intravenous infusion over about 60 15 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some instances, 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is to be administered to the subject or population of subjects by intravenous infusion over about 60 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered to the subject or population of subjects by intravenous infusion over about 30 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes). In some instances, 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is to be administered to the subject or population of subjects by intravenous infusion over about 30 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered to the subject or population of subjects before 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some instances, for example, following administration of the anti-TIGIT
antagonist antibody and before administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))), the method includes an intervening first observation period. In some instances, the method further includes a second observation period following administration 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., MDX-1106 (nivolumab) or (pembrolizumab, previously known as lambrolizumab))). In some instances, the method includes both a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration of the 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, previously known as lambrolizumab))) during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration of the 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, previously known as lambrolizumab))) during the first and second observation periods, respectively.
In other instances, 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is to be administered to the subject or population of subjects before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab). In some instances, for example, following administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and before administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some instances, the method includes a second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the method includes both a first observation period following administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and second observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In instances in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration 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., 1V1DX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In instances in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject or population of subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the first and second observation periods, respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the 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, previously known as lambrolizumab))) is to be administered to the subject or population of subjects simultaneously. In some instances, for example, following administration of the anti-TIGIT
antagonist antibody and the 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 (pembrolizumab, previously known as lambrolizumab))) the method includes an observation period. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In instances in which the observation period is about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT
antagonist antibody during the observation period. In instances in which the observation period is about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 10 minutes after administration 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist antibody during the observation period.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of 600 mg every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg 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 a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as described in further detail below. In some instances, 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 instances, the anti-TIGIT antagonist antibody has a VH
domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID
NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of 600 mg every three weeks and pembrolizumab at a dose (e.g., a fixed dose) of 200 mg 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 a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as described in further detail below. In some instances, 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 instances, the anti-TIGIT antagonist antibody has a VH
domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID
NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 240 mg 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 a VL domain comprising the amino acid sequence of SEQ ID NO:
19, as described in further detail below. In some instances, 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 instances, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 480 mg every four weeks, 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, as described in .. further detail below. In some instances, 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 instances, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg every three weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., MK-3475 (pembrolizumab, previously known as lambrolizumab)) for use in a .. method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and pembrolizumab at a dose (e.g., a fixed dose) of 200 mg every three weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., IVIDX-1106 (nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage .. IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 240 mg every two weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., 1VIDX-1106 (nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600 mg every three weeks and nivolumab at a dose (e.g., a fixed dose) of 480 mg every four weeks.
In another aspect, the invention provides uses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) 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, previously known as lambrolizumab))) in the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, and wherein the medicament is formulated for administration of an effective amount of the anti-TIGIT antagonist antibody and an 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., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))).
In another aspect, the invention provides uses of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))), and wherein the medicament is formulated for administration of an effective amount of the anti-TIGIT antagonist antibody and an 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))).
In another aspect, the invention provides uses 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 (pembrolizumab, previously known as lambrolizumab))) in the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administration an 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) and an effective amount of the anti-TIGIT
antagonist antibody is to be administered.
In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In some instances, an effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of between about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) (e.g., between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks.
In some instances, an effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of between 30 mg to 600 mg (e.g., .. between 50 mg to between 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg to 600 mg, e.g., between 200 mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg to 500 mg, e.g., between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg)) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of about 600 mg every three weeks. In some instances, effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of 600 mg every three weeks.
In some instances, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be administered in a combination therapy (e.g., a combination treatment 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, previously known as lambrolizumab)))) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody is to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between about 80 mg to about 2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg to about 1900 mg, e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to about 1700 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg, e.g., between about 600 mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g., between about 740 mg to about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about 815 mg to about 865 mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) (e.g., between 80 mg to 2000 mg (e.g., between 80 mg to 1950 mg, e.g., between 80 mg to 1900 mg, e.g., between 80 mg to 1800 mg, e.g., between 100 mg to 1700 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1400 mg, e.g., between 400 mg to 1300 mg, e.g., between 500 mg to 1200 mg, e.g., between 600 mg to 1100 mg, e.g., between 700 mg to 1000 mg, e.g., between 740 mg to 940 mg, e.g., between 790 mg to 890 mg, e.g., between 815 mg to 865 mg, e.g., between 830 mg to 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg)) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 1900 mg, e.g., between about 300 mg to about 1700 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 1900 mg, e.g., between 300 mg to 1700 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg), e.g., between about 1190 mg to about 1210 mg (e.g., between 1190 mg to 1210 mg), e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g., between about 200 mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg, e.g., between about 400 mg to about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g., between about 600 mg to about 1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between about 800 mg to about 1800 mg, e.g., between about 900 mg to about 1800 mg, e.g., between about 1000 mg to about 1800 mg, e.g., between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to about 1800 mg, e.g., between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about 1800 mg, e.g., between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about 1780 mg, e.g., between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about 1705 mg, e.g., between about 1670 mg to about 1690 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to 2000 mg, e.g., between 300 mg to 2000 mg, e.g., between 400 mg to 2000 mg, e.g., between 500 mg to 2000 mg, e.g., between 600 mg to 1900 mg, e.g., between 700 mg to 1800 mg, e.g., between 800 mg to 1800 mg, e.g., between 900 mg to 1800 mg, e.g., between 1000 mg to 1800 mg, e.g., between 1100 mg to 1800 mg, e.g., between 1200 mg to 1800 mg, e.g., between 1300 mg to 1800 mg, e.g., between 1400 mg to 1800 mg, e.g., between 1500 mg to 1800 mg, e.g., between 1580 mg to 1780 mg, e.g., between 1630 mg to 1730 mg, e.g., between 1655 mg to 1705 mg, e.g., between 1670 mg to 1690 mg), e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1 680 mg every four weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1680 mg every four weeks. In some instances, the dose 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) to be administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 .. antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 .. mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg to about 220 mg, e.g., between about 190 mg to about 210 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg to 220 mg, e.g., between 190 mg to 210 mg), e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200 1.0 mg, e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose of about 200 mg every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a dose of 200 mg every three weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of between about 20 mg to about 1000 mg (e.g., 20 mg to 1000 mg) (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g., between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about 180 mg to about 300 mg, e.g., between about 200 mg to about 280 mg, e.g., between about 220 mg to about 260 mg, e.g., between about 230 mg to about 250 mg (e.g., between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 200 mg to 280 mg, e.g., between 220 mg to 260 mg, e.g., between 230 mg to 250 mg), e.g., 240 mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of about 240 mg every two weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of between about 100 mg to about 1000 mg (e.g., between 100 mg to 1000 mg) (e.g., between about 200 mg to about 900 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 700 mg, e.g., between about 400 mg to about 600 mg, e.g., between about 400 mg to about 550 mg, e.g., between about 420 mg to about 540 mg, e.g., between about 440 mg to about 520 mg, e.g., between about 460 mg to about 500 mg, e.g., between about 470 mg to about 490 mg (e.g., between 200 mg to 900 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 700 mg, e.g., between 400 mg to 600 mg, e.g., between 400 mg to 550 mg, e.g., between 420 mg to 540 mg, e.g., between 440 mg to 520 mg, e.g., between 460 mg to 500 mg, e.g., between 470 mg to 490 mg), e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of about 480 mg every four weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 480 mg every four weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT

antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2 mg/kg, about 15 1 mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg/kg to about 15 mg/kg of the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg, e.g., between about 0.5 mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g., between about 2.5 mg/kg to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15 1 mg/kg, e.g., about 15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g., about 15 mg/kg) every three weeks. In some instances, the effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 15 mg/kg to be administered every three weeks. In some instances, the dose 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In any of the uses of the invention, the medicament comprising the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) 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 instances, the dosing cycles of the medicament comprising anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and 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., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some instances, the length of each dosing cycle is about 14 to 28 days (e.g., 14 days,15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some instances, the length of each dosing cycle is about 21 days. In some instances, the DEMANDE OU BREVET VOLUMINEUX
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Claims (503)

WHAT IS CLAIMED IS:

1. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 rng every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1 500 mg every three weeks, 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 having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.

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

4. The method of claim 2 or 3, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

5. The method of any one of claims 1-4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The method of any one of claims 1-5, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID
NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of 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 ot WASTRES (SEQ ID
NO: 5); and (f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID
NO: 6).

7. The method of any one of claims 1-6, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FRs):
(a) an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC
(SEQ ID NO:
7);

(b) an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEO ID NO:
8);
(c) an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC
(SEQ ID NO: 9); and (d) an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEO ID NO: 10), and the following heavy chain variable region FRs:
(a) an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS
(SEQ ID NO: 11), wherein Xi is E or Q;
(b) an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO:
12);
(c) an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR
(SEQ ID NO: 13); and (d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO:
14).

8. The method of any one of claims 1-7, wherein the anti-TIGIT antagonist antibody comprises:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method of any one of claims 1-8, wherein the anti-TIGIT antagonist antibody is tiragolumab.

10. The method of any one of clairns 1-9, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. The method of any one of claims 1-10, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method of any one of claim 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of clairn 12, wherein the anti-PD-L1 antagonist antibody atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, or HS-636.

14. The method of any one of clairn 1-13, wherein the PD-1 axis binding antagonist is atezolizumab.

15. The method of any one of claim 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of claim 15, wherein the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZMO09, F520, SG001, AM0001, ENUM
244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.

17. The method of any one of claims 2-16, wherein the method comprises administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. The method of claim 1 or 17, wherein the non-platinum-based 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, an ellipticine, aurintricarboxylic acid, or HU-331, in particular etoposide.

20. The method of claim 18 or 19, wherein the topoisomerase II inhibitor is administered at a dose of 100 rng/m2.

21. The method of any one of claims 17-20, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular 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.

24. The method of claim 23, wherein the induction phase comprises four initial dosing cycles and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent are administered in each of four initial dosing cycles.

25. The method of claim 23 or 24, wherein the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent and/or non-platinum based chemotherapeutic agent.

26. The method of any one of claims 1-25, wherein the treatment extends progression-free survival (PFS) of the subject as compared to treatment without the anti-TIGIT
antagonist antibody.

27. The method of any one of claims 1-26, wherein the treatment extends overall survival of the subject as compared to treatment without the anti-TIGIT antagonist antibody.

28. The method of any one of claims 1-27, wherein the cancer is lung cancer.

29. The method of claim 28, wherein the lung cancer is a small cell lung cancer (SCLC), in particular extensive stage SCLC (ES-SCLC).

30. The method of claim 28, wherein the lung cancer is a non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (Stage IIIB NSCLC).

31. The method of claim 28, wherein the lung cancer is locally advanced unresectable or metastatic non-squamous NSCLC.

32. The method of claim 28, wherein the lung cancer is resectable lung cancer.

33. The method of any one of claims 1-27, wherein the cancer is cervical cancer.

34. The method of any one of claims 1-27, wherein the cancer is an early triple-negative breast cancer (eTNBC).

35. The method of any one of claims 1-27, wherein the cancer is a head and neck cancer.

36. The method of any one of claims 1-27, wherein the cancer is a liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method of any one of claims 1-27, wherein the cancer is a bladder cancer.

38. The method of claim 37, wherein the cancer is a urothelial carcinoma (UC), in particular a metastatic urothelial carcinoma (mUC).

39. The method of any one of claims 1-27, wherein the cancer is a pancreatic cancer, in particular a pancreatic ductal adenocarcinoma (PDAC).

40. The method of any one of claims 1-27, wherein the cancer is an esophageal cancer, in particular an advanced or metastatic esophageal cancer.

41. A kit cornprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to the method of any one of claims 1-40.

42. The kit of claim 41, wherein the kit further comprises one or more chemotherapeutic agents.

43. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having a cancer, wherein the rnethod is according to any one of claims 1-40.

44. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of claims 1-40.

45. The use of claim 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The use of clairn 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

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

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

49. The method of claim 47 or 48, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

50. The method of claim 49, wherein the method comprises administering to the subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

51. A rnethod of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1 500 mg every three weeks, 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 the 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 the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent.

55. The method of any one of claims 52-54, wherein the maintenance phase does not comprise administration of the non-platinum-based chemotherapeutic agent.

56. The method of claim 55, wherein the maintenance phase comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 rng every four weeks.

57. A rnethod of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 rng every three weeks, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

58. A rnethod of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of between about 300 mg to about 500 mg every six weeks.

59. A rnethod for treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, and an antimetabolite at a dose of between about 10 mg/m2 to about 10000 mg/m2 twice a day orally every three weeks for 2-weeks on/1-week off.

60. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 rng every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1 500 mg every three weeks, gemcitabine, and nab-paclitaxel.

61. The method of claim 49, wherein the one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel.

62. A rnethod tor treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks, and a VEGF
antagonist at a dose of between about 1 rng/kg to about 35 rng/kg every three weeks.

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

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

65. The method of any one of claims 53-56, 63, and 64, wherein the induction phase comprises four to six dosing cycles.

66. The method of any one of claims 50-56 and 63-65, 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.

67. The method of any one of claims 47-66, wherein the cancer is a solid tumor.

68. The method of any one of claims 47-67, wherein the cancer is locally advanced or metastatic.

69. The method of any one of claims 47-68, wherein the cancer is a lung cancer, a pancreatic cancer, a cervical cancer, a breast cancer, a head and neck cancer, a liver cancer, a bladder cancer, an esophageal cancer, a gastric cancer, a colorectal cancer, a kidney cancer, a renal cancer, a melanoma, or an ovarian cancer.

70. The method of claim 69, wherein the cancer is a lung cancer.

71. The method of claim 70, wherein the lung cancer is an NSCLC, in particular a locally advanced unresectable NSCLC.

72. The method of claim 71, wherein the NSCLC is a Stage IIIB NSCLC.

73. The method of any one of claims 70-72, wherein the lung cancer is a recurrent or metastatic NSCLC.

74. The method of claim 73, wherein the NSCLC is a Stage IV NSCLC.

75. The method of claim 74, wherein the subject has not been previously treated for Stage IV
NSCLC.

76. The method of claim 70, wherein the lung cancer is a small cell lung cancer (SCLC).

77. A rnethod of treating a subject or population of subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II
inhibitor, wherein the treatment extends progression-free survival (PFS) of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

78. A method of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment results in a median PFS
of the population of subjects of about 8.2 months to about 9.2 months.

79. The method of claim 77 or 78, wherein the treatment extends overall survival (OS) of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

80. The method of any one of claims 77-79, wherein the treatment extends the PFS of the subject or population of subjects by at least about 2.4 months as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

81. The method of claim 80, wherein the treatment extends the PFS of the subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

82. A rnethod of treating a subject or population of subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II
inhibitor, wherein the treatment extends OS of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT
antagonist antibody.

83. A method of treating a population of subjects having a lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment results in a median OS
of the population of subjects of about 15.3 months to about 17.6 months.

84. The method of any one of claims 79-83, wherein the treatment extends the OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

85. The method of any one of claims 79-83, wherein the treatment extends the OS of the subject or population of subjects by at least about 3 months to about 5.3 months as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II
inhibitor without the anti-TIGIT antagonist antibody.

86. The method ot any one ot claims 77-85, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered in each of four initial dosing cycles.

87. The method of any one of claims 77-86, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are further administered in one or more additional cycles following the fourth initial dosing cycle.

88. The method of claim 87, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted from each of the one or more additional dosing cycles.

89. The method of any one of claims 77-88, wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

90. The method of any one of claims 77-89, wherein the lung cancer is a small cell lung cancer (SCLC).

91. The method of claim 90, wherein the SCLC is extensive stage SCLC (ES-SCLC).

92. The method of claim 91, wherein the subject or subjects are treatment-naïve for ES-SCLC.

93. The method of any one of claims 77-92, wherein the subject or subjects do not have a presence or history of brain metastases.

94. The method of any one of claims 77-93, wherein the lung cancer is unselected for PD-L1 expression.

95. The method ot any one ot claims 77-93, wherein the lung cancer is selected tor PD-L1 expression.

96. The method of claim 95, wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1.

97. The method of any one of claims 77-96, wherein the lung cancer is metastatic.

98. The method of claim 97, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal gland.

99. The method of claim 97 or 98, wherein the lung cancer has not metastasized to the brain.

100. The rnethod ot any one ot claims 77-99, wherein the treatment results in a complete response (CR) or a partial response (PR).

101. A rnethod for treating a subject or population of subjects having SCLC, the method comprising administering to the subject or population of subjects one or more 21-day dosing cycles of 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 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 a dose of 100 mg/m2on each of Days 1, 2, and 3 of each dosing cycle, wherein the treatment extends PFS
and/or OS of the subject or population of subjects as compared to treatment with atezolizumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

102. A method for treating a subject or population of subjects having ES-SCLC, the method comprising administering to the subject or population of subjects four initial dosing cycles followed by one or more additional dosing cycles, wherein:
(a) the four initial dosing cycles comprise administering 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, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle, and etoposide at a dose of 100 rng/m20n each of Days 1, 2, and 3 of each initial dosing cycle; and (b) the one or more additional dosing cycles comprise administering tiragolumab at a dose of about 600 mg 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, wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment extends PFS and/or OS of the subject or population of subjects as compared to treatment with atezolizumab, carboplatin, and etoposide without the tiragolumab.

103. A method of treating a subject or population ot subjects having a lung cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent which is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent which is a non-platinum-based chemotherapeutic agent.

104. The rnethod of claim 103, wherein the lung cancer has not been evaluated for PD-L1 expression.

105. The rnethod of claim 103 or 104, wherein the subject or subjects have not been determined to have a PD-L1-positive turnor cell fraction of greater than, or equal to, 50%.

106. The rnethod ot claim 105, wherein the subject or subjects have been determined to have a PD-L1-positive tumor cell fraction of less than 50%.

107. The rnethod of claim 105 or 106, wherein the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 2203.

108. The rnethod of any one of claims 103-107, wherein the subject or subjects do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.

109. The rnethod of any one of claims 103-108, wherein the subject or subjects have received no prior systemic therapy for the lung cancer.

110. The rnethod of any one of claims 103-109, wherein the lung cancer is a locally advanced lung cancer.

111. The rnethod of any one of claims 103-110, wherein the lung cancer is an NSCLC, in particular a locally advanced unresectable or metastatic non-squamous NSCLC.

112. The rnethod of claim 111, wherein the non-squamous NSCLC is a Stage IV
non-squamous NSCLC.

113. The rnethod of any one of claims 103-112, wherein the dosing regimen comprises an induction phase comprising four dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chernotherapeutic agent, and the non-platinum-based chemotherapeutic agent are administered on Day 1 of each dosing cycle of the induction phase.

114. The rnethod ot claim 113, wherein the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum-based chemotherapeutic agent are administered on Day 1 of each dosing cycle of the maintenance phase.

115. The rnethod of claim 114, wherein the one or more dosing cycles of the maintenance phase do not comprise administration of the platinum-based chemotherapeutic agent.

116. The rnethod of any one of claims 103-115, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.

117. A method of treating a subject or population of subjects having an advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the tiragolumab is administered at a dose of about 600 mg every three weeks, the atezolizumab is administered at a dose of about 1200 mg every three weeks, the carboplatin is administered at a dose sufficient to achieve an AUC = 5 mg/ml/min every three weeks or the cisplatin is administered at a dose of 75 mg/m2 every three weeks, and the pemetrexed is administered at a dose of about 500 mg/m2 every three weeks on Day 1 of each of the four 21-day dosing cycles.

118. A method of treating a subject or population of subjects having an advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects:
(i) four induction phase dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve an AUC = 5 mg/ml/min every three weeks, and pemetrexed at a dose of about 500 mg/m2 every three weeks; and (11) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and pemetrexed at a dose of about 500 mg/m2 every three weeks, wherein the one or more 21-day dosing cycles of the maintenance phase do not comprise administration of the carboplatin, wherein the subject or population of subjects have received no prior systemic therapy for the advanced non-squamous NSCLC.

119. The rnethod of any one of claims 103-118, wherein the treatment extends the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months.

120. The rnethod of any one of claims 103-118, wherein the treatment results in a median PFS of the population of subjects of about 12.5 months to about 14.7 months.

121. The rnethod of any one of claims 103-118, wherein the treatment extends the OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

122. The rnethod of any one of claims 103-118, wherein the treatment results in a median OS of the population of subjects of about 27.5 months to about 32.0 months.

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

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

125. The rnethod of claim 124, wherein at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 every three weeks as an adjuvant treatment.

126. The rnethod of claim 124 or 125, wherein the lung cancer is a resectable lung cancer.

127. The rnethod of any one of claims 123-126, wherein the lung cancer is an early stage lung cancer.

128. The rnethod of any one of claims 123-127, wherein the lung cancer is a stage II, IIIA, or IIIB lung cancer.

129. The rnethod of any one of claims 123-128, wherein the subject is eligible for an RO resection with curative intent.

130. The rnethod of any one of claims 123-129, wherein the subject has not received a prior therapy for lung cancer.

131. The rnethod of claim 130, wherein the prior therapy is an immunotherapy, a chemotherapy, or a radiotherapy.

132. The rnethod of any one of claims 123-131, wherein the subject is eligible to receive a platinum-based chemotherapy regimen.

133. The rnethod of any one of claims 123-132, wherein the first dosing cycle is initiated prior to a surgery.

134. The rnethod of claim 133, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to the surgery.

135. The rnethod of claim 133 or 134, wherein 4 dosing cycles are completed prior to the surgery.

136. The method of any one of claims 123-135, wherein at least one dosing cycle is initiated after a surgery.

137. The method of claim 136, wherein 16 dosing cycles are completed after the surgery.

138. The method of any one of claims 133-137, wherein the surgery is a segmentectomy, a lobectomy, a bilobectomy, or a pneumonectomy.

139. The rnethod of any one of claims 123-138, wherein the method further comprises a radiotherapy.

140. The rnethod of claim 139, wherein the radiotherapy is a post-operative radiotherapy.

141. The rnethod of any one of claims 123-140, wherein the method further comprises administering one or more chemotherapeutic agents.

142. The rnethod of claim 141, wherein the one or more chemotherapeutic agents are administered after a surgery.

143. The rnethod of claim 142, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after the surgery.

144. The rnethod of any one of claims 141-143, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

145. The rnethod of claim 144, 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.

146. The rnethod of any one of claims 123-145, wherein the treating results in an increase in major pathological response (MPR) rate as compared to a reference MPR rate.

147. The method of claim 146, wherein the reference MPR rate is an MPR rate of population of subjects who have received a treatment comprising:
(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
and/or (b) cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

148. The rnethod of any one of claims 123-147, wherein the treating results in a pathological complete response (pCR) and/or an increase in pCR rate as compared to a reference pCR rate.

149. The rnethod of claim 148, wherein the reference pCR rate is a pCR rate of population of subjects who have received a treatment comprising:
(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
and/or (b) cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

150. The rnethod of any one of claims 123-149, wherein the treating results in an increase in event-free survival (EFS) as compared to a reference EFS time.

151. The rnethod of claim 150, wherein the reference EFS time is an EFS time of a population of subjects who have received a treatment comprising:
(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;
and/or (b) cisplatin and docetaxel or cisplatin, docetaxel, and bevacizurnab.

152. A method for treating a subject having a resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and:
(a) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC
of 6 mg/mL/min every three weeks; or (ii) cisplatin at a dose of about 75 mg/m2 every three weeks; and (b) (i) pemetrexed at a dose of about 500 mg/m2 every three 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 three weeks.

153. A method for treating a subject having a lung cancer, the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein:
(I) at least one of the dosing cycles is a neoadjuvant treatment and comprises administering to the subject:

(a) tiragolumab at a dose of about 1200 mg every three weeks;
(b) atezolizumab at a dose of about 1200 mg every three weeks as a neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/m in every three 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 three 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; and (II) at least one of the dosing cycles comprises administering to the subject tiragolumab at a dose of between about 500 rng to about 700 mg every three weeks and atezolizumab at a dose of between about 900 mg to about 1500 mg every three weeks as an adjuvant treatment.

154. The rnethod of any one of claims 123-153, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 has been determined.

155. The rnethod of claim 154, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction greater than, or equal to, 50%.

156. The rnethod of any one of claims 70, 103-110, and 123-155, wherein the lung cancer is an NSCLC.

157. The rnethod of claim 156, wherein the NSCLC is a squamous NSCLC.

158. The rnethod of claim 156, wherein the NSCLC is a non-squamous NSCLC.

159. The rnethod of claim 69, wherein the cancer is a cervical cancer.

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

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

162. The rnethod of claim 160 or 161, wherein the cervical cancer is a squamous cell carcinoma, adenosquamous carcinorna, or adenocarcinoma.

163. The rnethod of any one of claims 160-162, wherein the cervical cancer is Stage IVB, metastatic, recurrent, or persistent.

164. The rnethod of any one of claims 160-163, wherein the cervical cancer is a metastatic and/or recurrent PD-L1-positive cervical carcinoma.

165. The rnethod of any one of claims 160-164, wherein the subject or subjects have received at least one line of prior therapy.

166. The rnethod of any one of claims 160-165, wherein the subject or subjects have received two lines of prior therapy.

167. The rnethod of any one of claims 160-166, wherein the subject or subjects have not received more than two lines of prior therapy.

168. The rnethod of any one of claims 160-164, wherein the subject or subjects have not received prior therapy.

169. The rnethod of any one of claims 165-168, wherein the prior therapy is chemotherapy, surgery, and/or radiotherapy.

170. The rnethod of any one of claims 160 and 162-169, wherein the treating results in a clinical response.

171. The rnethod of claim 170, wherein the clinical response is an increase in an objective response rate (ORR) of the population of subjects as compared to a reference ORR.

172. The rnethod of claim 171, wherein the reference ORR is the median ORR of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody.

173. The rnethod of claim 170, wherein the reference ORR is at least about 14.6% to about 26%.

174. The rnethod of claim 170, wherein the clinical response is a CR or a PR.

175. The rnethod of any one of claims 170-174, wherein the clinical response is an increase in the progression-free survival (PFS) of the subject as compared to a reference PFS
time, an increase in the duration of response (DOR) of the subject as compared to a reference DOR time, or an increase in the overall survival (OS) of the subject as compared to a reference OS time.

176. The rnethod of claim 175, wherein:
(a) the reference PFS time is the median PFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody;
(b) the reference DOR time is the median DOR time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody; or (c) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody.

177. A method for treating a subject having a cervical cancer with a detectable expression level of PD-L1, the method comprising administering to the subject 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.

178. The rnethod of any one of claims 160-177, wherein the subject is identified as one who is likely to benefit from the treatment based on PD-L1 expression on tumor cells having been detected.

179. The rnethod of any one of claims 160-178, wherein PD-L1 expression level is detected using anti-PD-L1 antibody SP263.

180. The rnethod of any one of claims 160-179, wherein the detectable expression level of PD-L1 is a tumor-associated immune-cell (TIC) of greater than or equal to 5% in a sample from the subject.

181. The rnethod of any one of claims 160-178, wherein PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.

182. The rnethod of any one of claims 160-179, wherein the detectable expression level of PD-L1 is a combined positive score (CPS) of greater than or equal to 1 in a sample from the subject.

183. The method of claim 69, wherein the cancer is a breast cancer.

184. A method of treating a subject or population of subjects having a breast cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of tiragolumab at a dose of about 840 mg every four weeks, atezolizumab at a dose of about 1680 mg every tour weeks, and nab-paclitaxel at a dose ot about 100 mg/m2 tor 3-weeks on/1-week off.

185. The method of claim 183 or 184, wherein the breast cancer is a triple-negative breast cancer (TNBC).

186. The method of claim 185, wherein the TNBC is an unresectable locally advanced or metastatic TNBC.

187. The method of any one of claims 183-186, wherein the subject or subjects have not received prior systemic therapy for metastatic breast cancer.

188. The method of any one of claims 183-187, wherein the treatment results in an ORR of the population of subjects of at least about 53% to at least about 67.5%.

189. The mthod of any one of claims 183-188, wherein the treatment results in a median OS of the population of subjects of about 25.0 months.

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

191. The method of claim 190, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

192. The method of claim 191, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

193. The mthod of claim 190, wherein the method further comprises administering (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).

194. The rnethod of claim 192 or 193, wherein the alkylating agent is cyclophosphamide.

195. The rnethod of claim 194, wherein the 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 the method comprises further administering to the subject a G-CSF, or GM-CSF.

197. The rnethod of claim 193 or 196, wherein the G-CSF is pegfilgrastim or filgrastim.

198. The rnethod of claim 197, wherein the G-CSF is pegfilgrastim.

199. The rnethod of claim 198, wherein the pegfilgrastim is administered at a dose of about 6 mg.

200. The rnethod of any one of claims 191, 192, and 194-199, wherein the method comprises further administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

201. The rnethod of any one of claims 191, 192, and 194-200, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once per week, once every two weeks, or once every three weeks.

202. The rnethod of any one of claims 192-201, wherein the platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered every week, the topoisomerase 11 inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF or GM-CSF is administered every two weeks.

203. The rnethod of any one of claims 192-202, wherein the taxane or the taxane and the platinum-based chemotherapeutic agent are administered for the first 12 weeks of the dosing regimen.

204. The rnethod ot any one ot claims 192-203, wherein the topoisomerase 11 inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered during weeks 13-19 of the dosing regimen.

205. The rnethod of any one of claims 190-204, wherein the total length of the dosing regimen is 19 weeks.

206. The rnethod of any one of claims 190-205, wherein the method is a neoadjuvant treatment.

207. The rnethod of any one of claims 190-206, wherein the dosing regimen is followed by surgery.

208. The rnethod of claim 207, wherein the surgery is performed between two and six weeks after the last dose of the dosing regimen.

209. The method of claim 207 or 208, wherein the surgery comprises a mastectomy.

210. The rnethod of any one of claims 207-209, wherein the surgery comprises an axillary lymph node surgery.

211. The rnethod of any one of claims 192-210, wherein the topoisomerase II
inhibitor is doxorubicin.

212. The rnethod 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 rnethod of claim 211 or 212, wherein doxorubicin is administered at a dose of about 60 mg/m2.

214. A method of treating a subject having an eTNBC, the method comprising administering to the subject a dosing regimen 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 every week and carboplatin at a dose targeted to achieve an AUC of 5 mg/mUmin every three weeks for the first 12 weeks of the dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/m2 every two weeks, cyclophosphamide at a dose of about 600 mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of the dosing regimen; or (b) (i) nab-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/m2 every two weeks, cyclophosphamide at a dose of about 600 mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of the dosing regimen;
wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

215. The rnethod of any one of claims 184-214, wherein a detectable protein expression level of PD-L1 in a tumor sample from the subject is determined by an IHC assay comprising staining with anti-PD-L1 antibody SP142 has been determined.

216. The rnethod of claim 215, wherein a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating irnrnune cells (lCs) in the tumor sample is greater than or equal to 1%.

217. The rnethod of any one of claims 190-216, wherein the eTNBC is a T2-4d TNBC at presentation.

218. The rnethod of any one of claims 190-217, wherein the eTNBC is a cT2-cT4, cN0-cN3, and cM0 TNBC at presentation.

219. The rnethod of any one of claims 190-218, wherein the subject has not been previously treated for eTNBC.

220. The rnethod of any one of claims 190-219, wherein the treatment results in a pathological complete response (pCR).

221. The rnethod of any one of claims 190-220, wherein the treatment results in an increase in overall survival (OS) or event-free survival (EFS).

222. The rnethod of claim 69, wherein the cancer is a head and neck cancer.

223. The rnethod of claim 222, wherein the head and neck cancer is a squamous cell carcinoma of the head and neck (SCCHN).

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

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

226. A method for treating a subject having an SCCHN with a detectable expression level of PD-L1, the method comprising administering to the subject 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.

227. The rnethod of any one of claims 224-226, wherein a tumor sample obtained from the subject or subjects have been determined to have a detectable expression level of PD-L1.

228. The rnethod of any one of claims 223-227, wherein the SSCHN is human papillomavirus (HPV)-positive.

229. The rnethod of any one of claims 223-228, wherein the SSCHN is HPV-negative.

230. The rnethod of claim 228 or 229, wherein HPV status is determined by p16 IHC, in situ hybridization, or by PCR.

231. The rnethod of any one of claims 223-230, wherein the SCCHN is a recurrent and/or metastatic SCCHN.

232. The rnethod of any one of claims 222-231, wherein the subject or subjects have not received prior therapy.

233. The rnethod of claim 232, wherein the prior therapy is a prior systemic therapy for recurrent and/or metastatic disease.

234. The rnethod of any one of claims 222-224 and 226-233, wherein the treating results in a CR or PR.

235. The rnethod of any one of claims 222-224 and 226-233, wherein the treating results in an increase in the objective response rate (ORR) of the population of subjects as compared to a reference ORR.

236. The rnethod of claim 235, wherein the reference ORR is the median ORR of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody.

237. The rnethod of claim 235 or 236, wherein the reference ORR is at least about 19% to about 36%.

238. The rnethod of any one of claims 222-224 and 226-237, wherein the treating results in an increase in the progression-free survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in the duration of response (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in the overall survival (OS) of the subject or population of subjects as compared to a reference OS time.

239. The method of claim 238, wherein:
(a) the reference PFS time is the median PFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody;
(b) the reference DOR time is the median DOR time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody; or (c) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody.

240. The method of claim 238, wherein the reference DOR time is at least about 6.7 months to about 23.4 months.

241. The method of claim 238, wherein the reference OS time is at least about 11.6 months to about 14.9 months.

242. The method of any one of claims 224-241, wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by an irnrnunohistochemical (IHC) assay comprising staining with anti-PD-L1 antibody SP263.

243. The method of claim 242, wherein the detectable protein expression level of PD-L1 is a tumor-associated immune-cell (TIC) of:
(a) greater than or equal to 5%;
(b) greater than or equal to 5% and less than 20%; or (c) greater than or equal to 20% in the tumor sample.

244. The rnethod of any one of claims 224-243, wherein the subject or population of subjects are identified as one who is likely to benefit from the treatment based on PD-L1 expression on tumor cells having been detected.

245. The method of claim 69, wherein the cancer is a liver cancer.

246. The method of claim 245, wherein the liver cancer is a hepatocellular carcinoma (HCC).

247. A method of treating a subject or population of subjects having a hepatocellular carcinoma (HCC), the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects have received no prior systemic treatment for HCC.

248. The rnethod of claim 247, wherein the method further comprises administering to the subject or population ot subjects a VEGF antagonist.

249. A method of treating a subject or population of subjects having an HCC, the method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT
antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

250. The method of claim 248 and 249, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

251. The rnethod of any one of claims 247-250, wherein the anti-TIGIT
antagonist antibody is administered at a dose of about 500 mg to about 700 mg every three weeks.

252. The rnethod of any one of claims 247-251, wherein the PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every three weeks.

253. The rnethod of claim 248 or 249, wherein the VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

254. The rnethod of claim 253, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

255. The rnethod of claim 254, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 rng/kg, or about 10 mg/kg every two weeks.

256. The rnethod of any one of claims 247-249 and 253-255, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 800 mg every two weeks.

257. The rnethod of any one of claims 247-249 and 253-256, wherein the PD-1 axis binding antagonist is administered at a dose of about 200 mg to about 1200 mg every two weeks.

258. The rnethod of claim 247-249, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 700 mg to about 1000 mg every four weeks.

259. The method of any one of claims 247-249 and 258, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every four weeks.

260. The method of any one of claims 247-259, wherein the HCC is a locally advanced or metastatic HCC.

261. The method ot any one ot claims 247-260, wherein the HCC is an unresectable HCC.

262. The method of any one of claims 247-261, wherein the subject or subjects have been determined to have adequate liver function.

263. The method of claim 262, wherein the adequate liver function is characterized as Child-Pugh class A.

264. The method of any one of claims 247-263, wherein an HCC tumor sample obtained from the subject or subjects has been determined to have a detectable expression level of PD-L1.

265. The method of any one of claims 247-264, wherein the method comprises administering to the subject or population of subjects at least four dosing cycles.

266. The method of claim 261, wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.

267. A method of treating a subject or population of subjects having an HCC, the method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200 mg every three weeks, and bevacizumab at a dose of about 15 mg/kg every three weeks.

268. The method of any one of claims 249-267, wherein the subject or subjects have received no prior systemic treatment for HCC.

269. The method of any one of claims 247-268, wherein the treatment results in a median PFS of the population of subjects of at least about 5.6 months to at least about 6.83 months.

270. The method of claim 69, wherein the cancer is a bladder cancer.

271. The method of claim 270, wherein the bladder cancer is a muscle-invasive bladder cancer (MIBC).

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

273. A method tor treating a subject or population ot subjects having an MIBC, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 rng to about 1500 mg every three weeks, wherein the treatment is a perioperative treatment.

274. The method of claim 272 or 273, wherein the subject or subjects have a creatinine clearance of <60 mUmin.

275. The method of any one of claims 272-274, wherein the subject or subjects have a greater than or equal to grade 2 hearing loss.

276. The method of any one of claims 272-275, wherein the subject or subjects have a greater than or equal to grade 2 neuropathy.

277. The method of any one of claims 272-276, wherein the subject or subjects have refused treatment with a platinum-based chemotherapeutic agent.

278. The rnethod of any one of claims 272 or 274-277, wherein the platinum-based chemotherapeutic agent is cisplatin.

279. The method of any one of claims 272-278, wherein the MIBC is surgically operable.

280. The method of claim 279, wherein the method further comprises a surgery.

281. The method of claim 280, wherein at least one dosing cycle is initiated prior to the surgery.

282. The method of claim 280, wherein at least 1, 2, or 3 dosing cycles are completed prior to the surgery.

283. The method of any one of claims 280-282, wherein at least one dosing cycle is initiated between 4-6 weeks after the surgery.

284. The method of claim 283, wherein 1-17 dosing cycles are completed after the surgery.

285. The rnethod of any one of claims 280-284, wherein the surgery is a cystectomy and/or lymph node dissection.

286. The rnethod of any one of claims 272-285, wherein the treating results in a pathological complete response (pCR).

287. The rnethod of any one of claims 272-286, wherein the treating results in an increase in the recurrence-free survival (RFS) of the subject or subjects as compared to a reference RFS time, an increase in the event-free survival (EFS) of the subject or subjects as compared to a reference EFS time, or an increase in the overall survival (OS) of the subject or subjects as compared to a reference OS time.

288. The rnethod of claim 287, wherein:
(a) the reference RFS time is the median RFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody;
(b) the reference EFS time is the median EFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody; or (c) the reference OS time is the rnedian OS tirne of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody.

289. The rnethod of any one of claims 272-288, wherein the treating results in a pathological downstaging.

290. A method for treating a subject or population of subjects having an MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks, wherein the subject or subjects are cisplatin ineligible.

291. A method for treating a subject or population of subjects having an MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks, wherein the treatment is a perioperative treatment.

292. The rnethod of any one of claims 272-291, wherein the treatment results in an OR R of the population of subjects of at least about 13.4% to at least about 15%.

293. The rnethod of any one of claims 272-292, wherein the treatment results in a median OS of the population of subjects of about 7.9 months to about 8.6 months.

294. The rnethod of any one of claims 272-293, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP142 has been determined.

295. The rnethod of claim 294, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction with a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (lCs) greater than or equal to 5%.

296. The rnethod of claim 270, wherein the bladder cancer is a urothelial carcinoma (UC).

297. The rnethod of claim 296, wherein the UC is a metastatic urothelial carcinoma (mUC).

298. A method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of an anti-TIG IT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.

299. The rnethod of claim 298, wherein the subject or subjects have not received a prior cancer immunotherapy.

300. The rnethod of claim 298 or 299, wherein the treatment is a second-line treatment.

301. The rnethod of any one of claims 298-300, wherein the mUC has progressed during or following a platinum-containing therapy.

302. The rnethod of any one of claims 298-301, wherein the method further comprises administering to the subject or population of subjects a second dosing regimen after the subject or population of subjects have experienced disease progression or unacceptable toxicity.

303. The rnethod of claim 302, wherein the second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).

304. The rnethod of claim 303, wherein the ADC is (a) enfortumab vedotin or (b) sacituzumab govitecan.

305. The rnethod of claim 304, wherein (a) enfortumab vedotin is administered at a dose of 1.25 mg/kg every week for 2-weeks on/1 week off or (b) sacituzumab govitecan is administered at a dose of 10 mg/kg every week for 2-weeks on/1 week off.

306. A method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and atezolizumab at a dose of about 1200 mg every three weeks.

307. A method for treating a subject or population of subjects having an mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:
(a) the first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 rng every three weeks and atezolizumab at a dose of about 1200 mg every three weeks; and (b) the second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg every three weeks and (i) enfortumab vedotin is administered at a dose of 1.25 mg/kg every week for 2-weeks on/1 week off or (ii) sacituzumab govitecan is administered at a dose of 10 mg/kg every week for 2-weeks on/1 week off, wherein the second dosing regimen is administered to the subject or population of subjects after the subject or population of subjects have experienced disease progression or unacceptable toxicity during the first dosing regimen.

308. The method of any one of claims 298-307, wherein the treatment results in an ORR of the population of subjects of at least about 13.4% to at least about 31%.

309. The method of any one of claims 298-308, wherein the treatment results in a median OS of the population of subjects of about 7.9 months to about 16.3 months.

310. The rnethod of claim 69, wherein the cancer is a pancreatic cancer.

311. A method of treating a subject or population of subjects having a pancreatic cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of 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, and nab-paclitaxel at a dose of about 125 mg/m20n Days 1, 8, and 15 of each 28-day dosing cycle.

312. The rnethod of claim 310 or 311, wherein the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).

313. The method of claim 312, wherein the PDAC is a metastatic PDAC.

314. The method of any one of claims 310-313, wherein the subject or subjects have not received prior systemic therapy for metastatic PDAC.

315. The rnethod of any one of claims 310-314, wherein the treatment results in an ORR of the population of subjects of at least about 41.7% to about 46.7%.

316. The rnethod of any one of claims 310-315, wherein the treatment results in an increase in ORR
of at least about 20% compared to a treatrnent comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

317. The rnethod of any one of claims 310-316, wherein the treatment results in a median PFS of the population of subjects of at least about 5.5 months to about 7 months.

318. The rnethod of any one of claims 310-317, wherein the treatment results in a median OS of the population of subjects of at least about 8.5 months to about 10.6 months.

319. The rnethod of claim 69, wherein the cancer is an esophageal cancer.

320. A method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of an anti-TIGIT
antagonist antibody at a dose of between about 500 mg to about 700 mg on Day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg on Day 1 of each dosing cycle.

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

322. The rnethod of claim 320, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

323. The rnethod of claim 321 or 322, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during the previous treatment.

324. The rnethod of claim 320, wherein the 21-day dosing cycles further comprise a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

325. The rnethod of claim 324, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

326. The rnethod of any one of claims 321-325, wherein the platinum-based chemotherapeutic agent is cisplatin.

327. The rnethod of claim 326, wherein cisplatin is administered at a dose of about 80 mg/m2 on Day 1 of each dosing cycle.

328. The rnethod of any one of claims 321-327, wherein the non-platinum-based chemotherapeutic agent is an antimetabolite.

329. The rnethod of claim 328, wherein the antimetabolite is 5-fluorouracil.

330. The rnethod 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.

331. The rnethod of any one of claims 321-330, wherein the esophageal cancer is an advanced or metastatic esophageal cancer.

332. The rnethod of claim 320 or 331, wherein the subject or subjects have had no prior treatment for metastatic esophageal cancer.

333. A method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of 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 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 the dosing regimen after six doses.

334. A method for treating a subject or population of subjects having an advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein:
(a) the first dosing regimen comprises one or more 21-day dosing cycles of cisplatin at a dose of about 80 mg/m2 on Day 1 of each dosing 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 the dosing regimen after six doses; and (b) the second dosing regimen comprises one or rnore 21-day dosing cycles of tiragolurnab 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.

335. The rnethod of any one of claims 321-334, wherein the treatment results in an ORR of the population of subjects of at least about 14%.

336. The rnethod of any one of claims 47-335, wherein the anti-TIGIT
antagonist antibody comprises the following hypervariable regions (HVRs):
an HVR-H1 sequence comprising the arnino acid sequence of SNSAAWN (SEQ ID NO:
1);
an HVR-H2 sequence comprising the arnino acid sequence ot 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);
an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO:
5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO:
6).

337. The method of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FRs):
an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID
NO: 7);
an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC
(SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

338. The rnethod of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:
an FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS
(SEQ ID NO: 11), wherein X1 is E or Q;
an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVEYCTR
(SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

339. The rnethod of claim 338, wherein Xi is E.

340. The method of claim 338, wherein X, is Q.

341. The method of any one of claims 336-340, wherein the anti-TIGIT
antagonist antibody comprises:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain as in (a) and a VL domain as in (b).

342. The rnethod of any one of claims 336-341, wherein the anti-TIGIT
antagonist antibody comprises:
(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.

343. The method of any one of claims 336-339, 341, and 342, wherein the anti-TIGIT antagonist antibody comprises:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

344. The method of any one of claims 336-339 and 341-343, wherein the anti-TIGIT antagonist antibody comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.

345. The method of any one of claims 336-344, wherein the anti-TIGIT
antagonist antibody is a monoclonal antibody.

346. The rnethod of any one of claims 336-345, wherein the anti-TIGIT
antagonist antibody is a human antibody.

347. The method of any one of claims 336-346, wherein the anti-TIGIT
antagonist antibody is a full-length antibody.

348. The method of any one of claims 336-347, wherein the anti-TIGIT
antagonist antibody has intact Fc-mediated effector function.

349. The rnethod of any one of claims 336-339 and 341-348, wherein the anti-TIGIT antagonist antibody is tiragolumab.

350. The method of any one of claims 336-346, wherein the anti-TIGIT
antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab)2 fragments.

351. The method of any one of claims 336-349, wherein the anti-TIGIT
antagonist antibody is an IgG
class antibody.

352. The rnethod of claim 351, wherein the IgG class antibody is an IgG1 subclass antibody.

353. The rnethod of any one of claims 336-352, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

354. The rnethod of claim 353, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

355. The rnethod of claim 354, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

356. The rnethod of claim 355, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

357. The rnethod of any one of claims 354-356, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

358. The rnethod of claim 357, wherein the anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalurnab, avelumab, SHR-1316, CS1001, envafolimab, T0B2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolirnab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, R098, PDL-GEX, KD036, KY1003, YBL-007, or HS-636.

359. The rnethod of claim 358, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

360. The rnethod of claim 357, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:
an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID
NO: 20);
an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG
(SEQ ID
NO: 21);
an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO:
22);
an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID
NO: 23);
an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO:
24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:
25).

361. The rnethod of claim 360, wherein the anti-PD-L1 antagonist antibody comprises:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 26;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95%
sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) a VH domain as in (a) and a VL domain as in (b).

362. The rnethod of claim 361, wherein the anti-PD-L1 antagonist antibody comprises:
(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.

363. The method of claim 362, wherein the anti-PD-L1 antagonist antibody comprises:
(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.

364. The method of any one of claims 360-363, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

365. The method of any one of claims 360-364, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

366. The method of claim 364 or 365, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

367. The method of any one of claims 360-365, wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab)2 fragments.

368. The method of any one of claims 360-366, wherein the anti-PD-L1 antagonist antibody is an IgG
class antibody.

369. The method of claim 368, wherein the IgG class antibody is an IgG1 subclass antibody.

370. The method of claim 353, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

371. The method of claim 370, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

372. The rnethod of claim 371, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

373. The rnethod of any one of claims 370-372, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

374. The rnethod of claim 373, wherein the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZMO09, F520, SG001, AM0001, ENUM
244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.

375. The rnethod of any one of claims 370-372, wherein the PD-1 binding antagonist is an Fc fusion protein.

376. The rnethod of claim 375, wherein the Fc fusion protein is AMP-224.

377. The method of any one of claims 77-101, 103-116, 119-122, and 247-249, wherein the method comprises administering to the subject or population of subjects the anti-TIG
IT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks.

378. The method of any one of claims 57, 59, 60, 62-64, 101, 123-151, 160, 1 61, 224, 225, 247-255, 272-289, 298-305, 320-332, and 377, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 600 mg every three weeks.

379. The method of any one of claims 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT
antagonist antibody at a dose of about 700 mg to about 1 000 mg every four weeks.

380. The method of any one of claims 47, 56, 64, 258, and 379, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 840 mg every four weeks.

381. The rnethod of any one of claims 77, 78, 82, 83, and 256, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT
antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks.

382. The method of any one of claims 48, 190-213, 215-221, 256, and 381, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 420 mg every two weeks.

383. The rnethod of any one of claims 47-382, wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

384. The rnethod of any one of claims 77-100, 103-116, 119-122, and 243-245, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.

385. The rnethod of any one of claims 59, 60, 62-64, 123-151, 160, 161, 224, 225, 247-258, 272-289,298-305, 320-332, and 384, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1200 mg every three weeks.

386. The rnethod of any one of claims 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.

387. The rnethod of any one of claims 47, 56, 64, 259, and 386, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1680 mg every four weeks.

388. The rnethod of claim 77, 78, 82, 83, and 257, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of between about 600 mg to about 1200 mg every two weeks.

389. The rnethod of any one of claims 48, 190-213, 215-221, 257, and 388, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 840 mg every two weeks.

390. The rnethod of any one of claims 47-389, wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

391. The rnethod of claim 58, wherein the method comprises administering to the subject pembrolizumab at a fixed dose of about 400 mg every six weeks.

392. The rnethod of any one of claims 51, 57, 59, 60, 62, 77, 78, 82, 83, 103, and 161, wherein the length of each of the one or more dosing cycles is 21 days.

393. The rnethod of any one of claims 47, 56, 64, 77, 184-189, and 253-259, wherein the length of each of the one or more dosing cycles is 28 days.

394. The rnethod of any one of claims 47-393, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody on about Day 1 of each of the one or more dosing cycles.

395. The rnethod of any one of claims 47-394, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist on about Day 1 of each of the one or more dosing cycles.

396. The rnethod of claim 256, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody on about Day 15 of each of the one or more dosing cycles.

397. The rnethod of claim 257, wherein the method comprises administering to the subject the PD-1 axis binding antagonist on about Day 15 of each of the one or more dosing cycles.

398. The rnethod of any one of claims 47-397, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody.

399. The rnethod of claim 398, wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist.

400. The rnethod of claim 399, wherein the first observation period is between about 30 minutes to about 60 minutes in length.

401. The rnethod of claim 399 or 400, wherein the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody.

402. The rnethod of claim 401, wherein the second observation period is between about 30 minutes to about 60 minutes in length.

403. The rnethod of any one of claims 47-397, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist simultaneously with the anti-TIG IT
antagonist antibody.

404. The rnethod of any one of claims 47-403, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously.

405. The rnethod of claim 404, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist by intravenous infusion over 30 10 minutes and/or over 60 10 minutes.

406. The rnethod of claim 404 or 405, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody by intravenous infusion over 30 10 minutes and/or over 60 10 minutes.

407. The rnethod of any one of claims 47-103 and 105-406, wherein a PD-L1 expression level of a tumor sample obtained from the subject or subjects have been determined.

408. The rnethod of claim 407, wherein the tumor sample obtained from the subject or subjects have been determined to have a detectable expression level of PD-L1.

409. The rnethod of claim 408, wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.

410. The rnethod of claim 409, wherein the detectable protein expression level of PD-L1 has been determined by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

411. The rnethod of claim 410, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, 5P142, 2203, or 28-8.

412. The rnethod of claim 410 or 411, wherein the detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana 5P142 IHC
assay, or a pharmDx 28-8 IHC assay.

413. The rnethod of any one any one of claims 47-102, 159, 181-223, and 245-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 has been determined.

414. The rnethod of any one any one of claims 47-189, 222-269, and 296-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP142 has been determined.

415. The rnethod of any one any one of claims 47-189 and 222-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C3 has been deterrnined.

416. The rnethod of any one any one of claims 47-103 and 105-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined.

417. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a tumor-associated immune-cell (TIC) of greater than or equal to 5% in the tumor sample.

418. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 5% and less than 20% in the tumor sample.

419. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 10% in the tumor sample.

420. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 20% in the tumor sample.

421. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 10% and less than 50% in the turnor sample.

422. The rnethod of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 50% in the tumor sample.

423. The rnethod of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 1%.

424. The rnethod of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 30%.

425. The rnethod of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 1% and less than 50% in the tumor sample.

426. The rnethod of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 50%.

427. The rnethod of claim 414, wherein the PD-L1-positive tumor cell fraction is a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (lCs).

428. The rnethod of claim 414, wherein the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating ICs is greater than or equal to 1%.

429. The rnethod of claim 414, wherein the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating ICs is greater than or equal to 5%.

430. The rnethod of claim 415, wherein the detectable protein expression level of PD-L1 is a combined positive score (CPS) of greater than or equal to 1.

431. The method of claim 415, wherein the detectable protein expression level of PD-L1 is a CPS of greater than or equal to 10.

432. The rnethod of claim 415, wherein the detectable protein expression level of PD-L1 is a CPS of greater than or equal to 20.

433. The rnethod of any one of claims 427-429, wherein the IHC assay is a Ventana SP142 IHC
assay.

434. The rnethod of claim 408, wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1.

435. The rnethod of claim 434, wherein the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qF'CR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

436. The rnethod of any one of claims 47-335, wherein the treating results in an increase in overall survival (OS) of the subject as compared to a reference OS time and/or progression-free survival (PFS) of the subject as compared to a reference PFS time.

437. The rnethod of claim 436, wherein:
(a) the reference OS time is the median OS time of a population of subjects who have received 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 reference PFS time is the median PFS time of a population of subjects who have received 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.

438. The rnethod of any one of claims 49, 141, and 190, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

439. The rnethod of claim 438, wherein the platinum-based chemotherapeutic agents is carboplatin or cisplatin.

440. The rnethod of claim 66, 89, 116, 145, 212, and 439, wherein the carboplatin is administered at a dose sufficient to achieve an AUC = 5 mg/ml/rnin or an AUC = 6 mg/ml/rnin.

441. The rnethod of claim 66, 116, 145, 147, 149, 151, 278, and 326, wherein the cisplafin is administered at a dose of about 75 mg/m2 or 80 mg/m2.

442. The rnethod of any one of claims 438-441, wherein the one or more non-platinum-based chemotherapeutic agents are an antimetabolite, a taxane, or a topoisomerase 11 inhibitor.

443. The rnethod of claim 59 or 442, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

444. The rnethod of any one of claims 66, 116, 145, and 443, wherein the pemetrexed is administered at a dose of about 500 mg/m2.

445. The rnethod of claim any one of claims 60, 61, 145, 316, and 443, wherein the gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.

446. The rnethod of claim 59 or 443, wherein the antimetabolite is capecitabine.

447. The rnethod of claim 443 or 446, wherein the capecitabine is administered at a dose of about 1250 mg/m2.

448. The rnethod of any one of claims 193, 202, 203, and 442-447, wherein the taxane is paclitaxel or nab-paclitaxel.

449. The rnethod of any one of claims 66, 145, and 448, wherein the paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.

450. The rnethod of any one of claims 60, 61, 212, 316, and 448, wherein the nab-paclitaxel is administered at a dose of about 100 mg/m2.

451. The rnethod of any one of claims 77, 78, 82, 83, 192, 193, and 442-450, wherein the topoisomerase 11 inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331.

452. The method of any one of claims 66, 89, and 451, wherein the etoposide is administered at a dose of about 100 mg/m2.

453. The method of any one of claims 438-452, wherein the one or more chemotherapeutic agents are each administered once per week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

454. The method of any one of claims 438-453, wherein the one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.

455. The method of any one of claims 443-454, wherein the gemcitabine is administered three times every four weeks.

456. The method of any one of claims 443-455, wherein the gemcitabine is administered on Days 1, 8, and/or 15 of one or more dosing cycles.

457. The method of any one of claims 443-456, wherein the capecitabine is administered daily for two weeks.

458. The method of any one of claims 443-457, wherein the capecitabine is administered on Days 1-14 of one or more dosing cycles.

459. The rnethod of any one of claims 448-458, wherein the nab-paclitaxel is administered three times every four weeks.

460. The method of any one of claims 448-459, wherein the nab-paclitaxel is administered on Days 1, 8, and 15 of one or more dosing cycles.

461. The method of any one of claims 451-460, wherein the etoposide is administered on Days 1-3 every three weeks.

462. The method of any one of claims 451-461, wherein the etoposide is administered on Days 1-3 of one or more dosing cycles.

463. The method of any one of claims 438-462, wherein the one or more chemotherapeutic agents are administered before the PD-1 axis binding antagonist and/or the anti-TIGIT
antagonist antibody.

464. The method of any one of claims 438-463, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or the anti-TIGIT
antagonist antibody.

465. The method of any one of claims 438-464, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

466. The method of any one of claims 62, 248, and 249, wherein the VEGF
antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.

467. The method of claim 250 or 466, wherein the 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 the VEGF antagonist is administered at a dose of about 15 mg/kg every three weeks.

469. The method of any one of claims 62, 248-250, 253-255, and 466-468, wherein the VEGF
antagonist is an anti-VEGF antibody.

470. The method of claim 469, wherein the anti-VEGF antibody is bevacizumab.

471. The method of any one of claims 62, 248-250, and 253-255, wherein the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab.

472. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the method comprises administering to the subject the VEGF antagonist on Day 1 of one or more dosing cycles.

473. The method of any one of claims 253-255, wherein the method comprises administering to the subject the VEGF antagonist on Day 15 of one or more dosing cycles.

474. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the VEGF
antagonist is administered intravenously.

475. The rnethod of claim 474, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90 ~ 15 rninutes.

476. The method of any one of claims 62, 248-250, 253-255, and 466-475, wherein the method comprises administering to the subject the PD-1 axis binding antagonist before the VEGF antagonist and the VEGF antagonist before the anti-TIGIT antagonist antibody.

477. The rnethod of claim 476, wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist, a second observation period following administration of the VEGF antagonist, and a third observation period following administration of the anti-TIGIT
antagonist antibody.

478. The rnethod of claim 477, wherein the first observation period, the second observation period, and the third observation period are each between about 30 minutes to about 120 minutes in length.

479. The method of any one of claims 102, 117, 118, 152, 153, 177, 184, 214, 226, 267, 290, 291, 306, 307, 311, 333, and 334, wherein tiragolumab and atezolizumab are combined in an IV bag prior to administration.

480. The method of any one of claims 47-479, wherein the subject is a human.

481. A kit comprising a PD-1 axis binding antagonist and/or an anti-TIGIT
antagonist antibody for treating a subject having a cancer according to the method of any one of claims 47-160, 162-224, and 226-480.

482. A kit comprising a PD-1 axis binding antagonist for use in combination with an anti-TIGIT
antagonist antibody for treating a subject having a cancer according to the method of any one of claims 47-160, 162-224, and 226-480.

483. The kit of claim 482, wherein the kit further comprises an anti-TIGIT
antagonist antibody.

484. The kit of any one of claims 481-483, wherein the anti-TIGIT antagonist antibody is tiragolumab.

485. The kit of any one of claims 481-484, wherein the PD-1 axis binding antagonist is atezolizumab.

486. A kit comprising an anti-TIG IT antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to the method of any one of claims 47-160, 162-224, and 226-480.

487. The kit of claim 486, wherein the kit further comprises a PD-1 axis binding antagonist.

488. The kit of claim 486 or 487, wherein the PD-1 axis binding antagonist is atezolizumab.

489. The kit of any one of claims 486-488, wherein the anti-TIGIT antagonist antibody is tiragolumab.

490. The kit of any one of claims 486-489, wherein the kit further comprises one or more chemotherapeutic agents.

491. The kit of claim 490, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

492. The kit of claim 491, wherein the one or more platinum-based chemotherapeutic agents are carboplatin or cisplatin.

493. The kit of claim 491 or 492, wherein the one or more non-platinum-based chemotherapeutic agent are an antimetabolite, a taxane, or a topoisomerase II inhibitor.

494. The kit of claim 493, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

495. The kit of claim 493 or 494, wherein the taxane is paclitaxel or nab-paclitaxel.

496. The kit of any one of claims 493-495, wherein the topoisomerase II
inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331.

497. The kit of any one of claims 481-496, wherein the kit further comprises a VEGF antagonist.

498. The kit of claim 497, wherein the VEGF antagonist is an anti-VEGF
antibody.

499. The kit of claim 498, wherein the anti-VEGF antibody is bevacizumab.

500. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having a cancer, wherein the method is according to any one of claims 47-160, 162-224, and 226-480.

501. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject or population of subjects having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of claims 47-160, 162-224, and 226-480.

502. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

503. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.