For example, in some aspects, the adjuvant platinum-based chemotherapy comprises cisplatin. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, and the cisplatin is administered at a dose of about 75-80 mg/m² (e.g., at a dose of about 75 mg/m²) intravenously on Day 1 of each 21 -day dosing cycle. In other aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, and the cisplatin is administered at a dose of about 50 mg/m² on Days 1 and 8 of each 28-day dosing cycle or at a dose of 50 mg/m² on Day 1 of each 28-day dosing cycle.

In some aspects, the adjuvant platinum-based chemotherapy comprises carboplatin. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, and the carboplatin is administered at a target dose of about area under the free carboplatin plasma concentration versus time curve (AUC) 5 or AUC 6 intravenously on Day 1 of each 21 -day dosing cycle.

In some aspects, the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents, e.g., a vinca alkaloid, a taxane, an anti-metabolite, or a combination thereof. In some aspects, the vinca alkaloid is vinorelbine; the taxane is docetaxel; or the anti-metabolite is gemcitabine or pemetrexed.

In some aspects, the subject has a non-squamous NSCLC, and the platinum-based adjuvant chemotherapy comprises cisplatin and pemetrexed. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and pemetrexed are administered to the subject.

In some aspects, the subject has a squamous NSCLC, and the platinum-based adjuvant chemotherapy comprises cisplatin and gemcitabine. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle, and gemcitabine is administered at a dose of about 1250 mg/m² on Days 1 and 8 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and gemcitabine are administered to the subject. In some aspects, the subject has a squamous NSCLC, and the platinum-based adjuvant chemotherapy comprises cisplatin and docetaxel. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle, and docetaxel is administered at a dose of about 75 mg/m² on Day 1 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and docetaxel are administered to the subject.

In some aspects, the platinum-based adjuvant chemotherapy comprises cisplatin and vinorelbine.

In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, wherein cisplatin is administered at a dose of about 50 mg/m² intravenously on Days 1 and 8 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 25 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle. In other aspects, cisplatin is administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle. In some aspects, 4 cycles of cisplatin and vinorelbine are administered to the subject.

In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75-80 mg/m² intravenously on Days 1 and 8 of each 21 -day dosing cycle, and vinorelbine is administered at a dose of about 25-30 mg/m² on Days 1 and 8 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and vinorelbine are administered to the subject.

In some aspects, the platinum-based adjuvant chemotherapy comprises cisplatin and etoposide. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, wherein cisplatin is administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28- day dosing cycle, and etoposide is administered at a dose of about 100 mg/m² on Days 1 -3 of each 28- day dosing cycle. In some aspects, 4 cycles of cisplatin and etoposide are administered to the subject.

In some aspects, the platinum-based adjuvant chemotherapy comprises carboplatin and paclitaxel. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 6 intravenously on Day 1 of each 21 -day dosing cycle, and paclitaxel is administered at a dose of about 200 mg/m² on Day 1 of each 21 - day dosing cycle. In some aspects, 4 cycles of cisplatin and paclitaxel are administered to the subject.

In some aspects, the platinum-based adjuvant chemotherapy comprises carboplatin and gemcitabine. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle, and gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and gemcitabine are administered to the subject.

In some aspects, the platinum-based adjuvant chemotherapy comprises carboplatin and pemetrexed. In some aspects, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21 - day dosing cycle. In some aspects, 4 cycles of cisplatin and pemetrexed are administered to the subject. C. Adjuvant treatment comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist

Following surgical resection and adjuvant chemotherapy as described above, subjects treated according to the methods provided herein are administered an adjuvant therapy comprising administration of one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab).

In some aspects, a subject who is administered the adjuvant therapy comprising the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist has not experienced recurrence of the NSCLC (e.g., has not experienced recurrence of the NSCLC following the complete resection or during or following the adjuvant chemotherapy).

In some aspects, the subject begins adjuvant chemotherapy within 12 weeks of their surgery date (e.g., the one or more dosing cycles of the adjuvant chemotherapy are initiated within one week, two weeks, six weeks, seven weeks, or eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks (e.g., within 1 -2 weeks, 2-4 weeks, 4-6 weeks, or 6-8 weeks, 8-10 weeks, or 10-12 weeks) of the surgery date.

In some aspects, the subject has not received an anti-cancer therapy for the NSCLC other than the surgical resection and adjuvant chemotherapy. In some aspects, the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.

Timing of surgery and adjuvant therapy

The one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist may be initiated at any appropriate time following the completion of the surgical resection and the adjuvant chemotherapy (e.g., at a time when the subject has recovered adequately from the surgery and adjuvant chemotherapy). For example, in some aspects, the one or more dosing cycles of the anti- TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated at least six weeks after the surgical resection (e.g., are initiated at least 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 weeks after the surgical resection (e.g., are initiated at least 6-8 weeks, 8-10 weeks, 10-12 weeks, 12-14 weeks, 14-16 weeks, 16-18 weeks, 18-20 weeks, 20-22 weeks, 22-24 weeks, 24-26 weeks, 26-28 weeks, or 28-30 weeks after the surgical resection) or are initiated more than 30 weeks after the surgical resection). In other aspects, the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated less than six weeks after the surgical resection (e.g., are initiated within 1 , 2, 3, 4, 5, or 6 weeks of the surgical resection). In some aspects, the one or more dosing cycles are initiated within 26 weeks of the surgical resection.

In some aspects, the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD- 1 axis binding antagonist are initiated within 10 weeks (e.g., within 70 days) after the last administered dose of the adjuvant chemotherapy). For example, in some aspects, the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated within 1 day, 5 days, 1 week, two weeks, six weeks, seven weeks, eight weeks, nine weeks, or ten weeks (e.g., within 1 -2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, or 8-10 weeks) of the last administered dose of the adjuvant chemotherapy. In other aspects, the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated more than 10 weeks after the last administered dose of the adjuvant chemotherapy.

Dosing and administration order

PD- 1 axis binding antagonist

In some aspects, in each of the one or more dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab), the PD-1 axis binding antagonist (e.g., atezolizumab) is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on about Day 1 (e.g., on Day 1 ± 3 days, e.g., on Day 1 ) of each of one or more 28-day dosing cycles). Exemplary PD-1 axis binding antagonists, and dosing regimens for the same, are provided in Section III, below.

In some aspects, the PD-1 axis binding antagonist is atezolizumab, and the atezolizumab is administered at a fixed dose of about 1680 mg (e.g., a fixed dose of 1680 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and the atezolizumab is administered on about Day 1 (e.g., on Day 1 ± 3 days, e.g., on Day 1 ) of each 28-day dosing cycle. Accordingly, in some aspects, the methods provided herein comprise administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.

In some aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered intravenously. In other aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered subcutaneously.

Anti-TIGIT antagonist antibody

In some aspects, in each of the one or more dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab), the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on about Day 1 (e.g., on Day 1 ± 3 days, e.g., on Day 1 ) of each of one or more 28-day dosing cycles). Exemplary anti-TIGIT antagonist antibodies, and dosing regimens for the same, are provided in Section IV, below.

In some aspects, the anti-TIGIT antagonist antibody is tiragolumab, and the tiragolumab is administered at a fixed dose of about 840 mg (e.g., a dose of 840 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and the tiragolumab is administered on about Day 1 (e.g., on Day 1 ± 3 days,, e.g., on Day 1 ) of each 28-day dosing cycle. Accordingly, in some aspects, the methods provided herein comprise administering to the subject tiragolumab at a fixed dose of about 840 mg every four weeks.

In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered intravenously. In other aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered subcutaneously. Administration order and co-administration

In some aspects, the method comprises co-administering the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (e.g., comprises co-administering tiragolumab and atezolizumab).

For example, in some aspects, the method comprises intravenous (IV) co-infusion of tiragolumab and atezolizumab. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs), e.g., are combined in an IV bag prior to administration. In other aspects, the co-infused tiragolumab and atezolizumab are formulated together (i.e. , are not mixed by the physician administering the drugs) and are administered as an IV-administered fixed dose combination (FDC). In some aspects, the IV- administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1680 mg and tiragolumab at a dose of 840 mg. Accordingly, in some aspects, the methods provided herein comprise co-administering to the subject atezolizumab and tiragolumab by intravenous co-infusion.

In some aspects, the method comprises SC co-infusion of tiragolumab and atezolizumab. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs). In other aspects, the coinfused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an SC-administered FDC. In some aspects, the SC- administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 880 mg. In other aspects, the SC-administered coinfusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 1000 mg.

In some aspects, the method comprises both IV and SC administration of tiragolumab and/or atezolizumab, e.g., comprises one or more IV-administered doses and one or more SC-administered doses of tiragolumab and/or atezolizumab. For example, in some aspects, the method comprises administering at least one dose of tiragolumab and atezolizumab as an IV-administered FDC and comprises administering at least one dose of tiragolumab and atezolizumab as an SC-administered FDC.

Exemplary IV and SC FDC doses and formulations of tiragolumab and atezolizumab are provided in PCT Pub. No. WO 2023/122665 and in U.S. Provisional Patent Application Nos. 63/493,691 (filed March 31 , 2023) and 63/494,983 (filed April 7, 2023) (both titled “Methods of Treating Tumors with Anti- TIGIT Antibodies”), each of which is incorporated herein by reference in its entirety.

Alternatively, in some aspects, the method comprises (i) administering (e.g., intravenously administering) to the subject the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody (e.g., atezolizumab before tiragolumab) or (ii) administering (e.g., intravenously administering) to the subject the anti-TIGIT antagonist antibody before the PD-1 axis binding antagonist (e.g., atezolizumab before tiragolumab). Number of dosing cycles

The methods provided herein may comprise administering one or more dosing cycles of the anti- TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) to the subject, e.g., may comprise administering a single dosing cycle or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, or more than 25 (e.g., 1 -5, 5-10, 10-15, 15-20, or 20-25) dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) to the subject. In some aspects, up to 13 dosing cycles (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or 13 dosing cycles, e.g., 1 -3, 3-5, 5-7, 7-9, 9-11 , or 11 -13 dosing cycles) of the anti- TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are administered to the subject. In some aspects, 13 dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are administered to the subject. In some aspects, dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are administered to the subject for up to one year (e.g., are administered continuously for up to one year, e.g., are administered once every two weeks, three weeks, or four weeks for up to one year).

D. Benefit from treatment

Increased duration of disease-free survival

In some aspects, treating a subject according to any one of the methods provided herein (e.g., treating with one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD- 1 axis binding antagonist (e.g., atezolizumab) as provided herein) results in an increase in disease-free survival (DFS) as compared to a reference DFS. In some aspects, the reference DFS is a DFS in a population of subjects (e.g., is the mean or median DFS of a population of subjects) who have received a control treatment.

In some embodiments, a treatment described herein extends the DFS of the subject compared to a reference DFS 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, 5.1 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 DFS 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, 1 1 months, 1 1 .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 DFS 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, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some aspects, the reference DFS is a DFS (e.g., a mean or median duration of DFS) in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage I IIB NSCLC) who have been treated according to a method comprising administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIG IT antagonist antibody (e.g., tiragolumab), and wherein, prior to the administration of the anti-TIG IT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy).

In other aspects, the reference DFS is a DFS (e.g., a mean or median duration of DFS) in a population of subjects having an NSCLC (e.g., a Stage IIB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC) who have been treated according to a method comprising administering to the subject (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has not received an adjuvant chemotherapy.

In another aspect, the reference DFS is a DFS (e.g., a mean or median duration of DFS) in a population of subjects having an NSCLC (e.g., a Stage IIB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC) in which the NSCLC has been completely resected and the subject has not received any adjuvant treatment for the NSCLC. Increased duration of OS

In some aspects, treating a subject according to any one of the methods provided herein (e.g., treating with one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD- 1 axis binding antagonist (e.g., atezolizumab) as provided herein) results in an increase in overall survival (OS) as compared to a reference OS. In some aspects, the reference OS is an OS in a population of subjects (e.g., is the mean or median OS of a population of subjects) who have received a control treatment.

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 as compared to a reference OS (e.g., by 2-120 months, by 3-1 10 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, 1 1 months, 1 1 .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, 1 1 months, 1 1 .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, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some aspects, the reference OS is an OS (e.g., a mean or median duration of OS) in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC) who have been treated according to a method comprising administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIG IT antagonist antibody (e.g., tiragolumab), and wherein, prior to the administration of the anti-TIG IT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy).

In other aspects, the reference OS is an OS (e.g., a mean or median duration of OS) in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC) who have been treated according to a method comprising administering to the subject (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has not received an adjuvant chemotherapy.

In another aspect, the reference OS is an OS (e.g., a mean or median duration of OS) in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC) in which the NSCLC has been completely resected and the subject has not received any adjuvant treatment for the NSCLC.

Increased DFS rate

In some aspects, treating a subject according to any one of the methods provided herein (e.g., treating with one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD- 1 axis binding antagonist (e.g., atezolizumab) as provided herein) results in an increase in the disease- free survival (DFS) rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) as compared to a reference DFS rate. In some aspects, the reference DFS rate is an RO resection rate in a population of subjects (e.g., is the mean or median DFS rate of a population of subjects) who have received a control treatment.

In some embodiments, the treatment results in a 3-year DFS rate of the population of subjects of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 1 1 %, 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%, 50%, 51 %, 52%,

53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,

75%, 80%, 85%, 90%, 95%, or 100%)).

In some embodiments, the treatment results in a 5-year DFS rate of the population of subjects of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%,

75%, 80%, 85%, 90%, 95%, or 100%)).

In some embodiments, the treatment results in a 7-year DFS rate of the population of subjects of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 1 1 %, 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%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%)).

In some embodiments, a treatment described herein increases the DFS rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) of a population of subjects treated according to the method compared to a reference DFS rate by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100%, e.g., increases DFS rate by 5%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% relative to a reference DFS rate.

In some aspects, the reference DFS rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) is a DFS resection rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage I HA NSCLC, or a T3N2 Stage IIIB NSCLC) who have been treated according to a method comprising administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIG IT antagonist antibody (e.g., tiragolumab), and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy).

In other aspects, the reference DFS rate is a DFS rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage I II A NSCLC, or a T3N2 Stage IIIB NSCLC) who have been treated according to a method comprising administering to the subject (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has not received an adjuvant chemotherapy.

In another aspect, the reference DFS rate is a DFS rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage III A NSCLC, or a T3N2 Stage IIIB NSCLC) in which the NSCLC has been completely resected and the subject has not received any adjuvant treatment for the NSCLC.

E. Assessment of PD-L1 Expression

The expression of PD-L1 may be assessed in a subject treated according to any of the methods, uses, and compositions for use described herein. The methods, uses, and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample, e.g., an NSCLC sample) obtained from the subject. In some examples, the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject has been determined prior to initiation of treatment or after initiation of treatment. PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application Pub. Nos. US 2018/0030138A1 and US 2018/0037655A1 . Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample. For example, PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 . It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody). Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28- 8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 . In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD- L1 antibody is 28-8.

In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.

In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

In some examples, tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table 2 and/or Table 3, respectively.

Table 2. Tumor-infiltrating immune cell (IC) IHC diagnostic criteria

Table 3. Tumor cell (TC) IHC diagnostic criteria

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 proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) is greater than or equal to 5% 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 proportion of tumor area occupied by PD-L1 expressing immune cells (ICs) greater than or equal to 5% by an immunohistochemical (IHC) assay. In some instances, the IHC assay uses the anti-PD-L1 antibody SP142, SP263, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 28-8.

In some instances, the proportion of tumor area occupied by PD-L1 -expressing 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 IC score has been determined to be 2 or 3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing 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 proportion of tumor area occupied by PD-L1 -expressing 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 proportion of tumor area occupied by PD-L1 -expressing 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 proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% 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 tumor-infiltrating immune cells that comprise greater than, or equal to, 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, 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% 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 tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1 % 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, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., a PD-L1 high (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody). In some instances, the PD-L1 selected tumor is a PD-L1 high selected tumor. In some instances, the PD-L1 selected tumor is a tumor that has been determined to have TPS greater than or equal to 50% by an immunohistochemical (IHC) assay.

In some instances, the TPS has been determined to be greater than, or equal to, 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1 % (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1 % and less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).

In some instances, the IHC assay uses the anti-PD-L1 antibody SP263, SP142, 22C3, 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, 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 SP263. In some instances, the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction greater than, or equal to, 50% of the tumor sample. In some instances, the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction less than 50% of the tumor sample. In some instances, the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction greater than, or equal to, 1 % and less than 50% of the tumor sample.

In some instances, the IHC assay uses the anti-PD-L1 antibody 22C3. In some instances, the IHC assay is the pharmDx 22C3 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has been determined to have a combined positive score (CPS) of greater than, or equal to, 10 or a tumor proportion score (TPS) of greater than or equal to 1 % in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 10 or a TPS of greater than or equal to 1 % and less than 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 20 or a TPS of greater than or equal to 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, tumor samples that have been determined to have a CPS of greater than, or equal to, 1 are comparable to tumor samples that have a TIC of greater than, or equal to, 5%.

In some instances, the IHC assay uses the anti-PD-L1 antibody 28-8. In some instances, the IHC assay is the pharmDx 28-8 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 28-8.

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.

III. PD-1 AXIS BINDING ANTAGONISTS

PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used for treating a subject having a cancer (e.g., an NSCLC, e.g., a Stage IIB NSCLC, a Stage II IA NSCLC, or a T3N2 Stage IIIB NSCLC).

A. PD-L1 Binding Antagonists

In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1 . The PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 ). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some instances, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some instances, the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299. In some instances, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD- L1 antibodies are contemplated and described herein. In any of the instances herein, the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example a human PD-L1 as shown in UniProtKB/Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof. In some instances, the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1 . In some instances, the anti-PD-L1 antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , 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, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

In some instances, the anti-PD-L1 antibody comprises:

(a) an HVR-H1 , HVR-H2, and HVR-H3 sequence of GFTFSDSWIH (SEQ ID NO: 3), AWISPYGGSTYYADSVKG (SEQ ID NO: 4) and RHWPGGFDY (SEQ ID NO: 5), respectively, and

(b) an HVR-L1 , HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO: 6), SASFLYS (SEQ ID NO: 7) and QQYLYHPAT (SEQ ID NO: 8), respectively.

In one embodiment, the anti-PD-L1 antibody comprises:

(a) a heavy chain variable region (VH) comprising the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 9), and

(b) the light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10).

In some instances, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 9; (b) a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 10; or (c) a VH as in (a) and a VL as in (b).

In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

(a) the heavy chain amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1 ), and

(b) the light chain amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO: 2).

In some instances, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG 1 kappa anti-PD- L1 antibody (Medlmmune, AstraZeneca) described in WO 2011/066389 and US 2013/034559.

In some instances, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.

In some instances, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti- PD-L1 antibody.

In some instances, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is singledomain antibody (dAB) generated from a camel phage display library.

In some instances, the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen-binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some instances, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

In some instances, the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Pat. No. 9,205,148, WO 2013/181634, or WO 2016/061142.

In a still further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In still a further instance, the effector-less Fc mutation is an N297A substitution in the constant region. In some instances, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

B. PD- 1 Binding Antagonists

In some instances, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 . In other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In yet other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). For example, in some instances, the PD-1 binding antagonist is an Fc-fusion protein. In some instances, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD- L2-Fc fusion soluble receptor described in WO 2010/027827 and WO 2011/066342. In some instances, the PD-1 binding antagonist is a peptide or small molecule compound. In some instances, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011 /161699. In some instances, the PD-1 binding antagonist is a small molecule that inhibits PD-1 .

In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the instances herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof. In some instances, the anti-PD-1 antibody is a monoclonal antibody. In some instances, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 .

In some instances, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS- 936558, and OPDI VO®, is an anti-PD-1 antibody described in WO 2006/121168.

In some instances, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853- 91 -4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335. In some instances, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized lgG4 anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis). PDR001 is a humanized lgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

In some instances, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is BGB-108 (BeiGene).

In some instances, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some instances, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti- PD-1 antibody.

In some instances, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human lgG4 anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some instances, the anti-PD-1 antibody is TSR-042 (also known as ANB011 ; Tesaro/AnaptysBio).

In some instances, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

In some instances, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking binding of PD-L1 to PD-1.

In some instances, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1 .

In some instances, the anti-PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302.

In a still further specific aspect, the anti-PD-1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some instances, the isolated anti-PD-1 antibody is aglycosylated.

C. PD-L2 Binding Antagonists

In some instances, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some instances, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partners. In a specific aspect, the PD-L2 binding ligand partner is PD-1 . The PD-L2 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

In some instances, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the instances herein, the anti-PD-L2 antibody can bind to a human PD-L2 or a variant thereof. In some instances, the anti-PD-L2 antibody is a monoclonal antibody. In some instances, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L2 antibody is a humanized antibody. In other instances, the anti-PD-L2 antibody is a human antibody. In a still further specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some instances, the isolated anti-PD-L2 antibody is aglycosylated.

D. Dosing of PD- 1 axis binding antagonists

As a general proposition, the therapeutically effective amount of a PD-1 axis binding antagonist (e.g., atezolizumab) administered to a subject having a cancer (e.g., a non-small cell lung cancer (NSCLC)) will be in the range of about 0.01 to about 50 mg/kg of subject body weight, whether by one or more administrations.

Exemplary doses and dosing regimens for PD-1 axis binding antagonists are provided, e.g., in PCT Application Pub. No. WO 2021/154761 , which is incorporated herein by reference in its entirety.

In some instances, the PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist as disclosed herein, e.g., atezolizumab) is 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 is atezolizumab, and atezolizumab is administered to the subject intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg of every 4 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 1680 mg every 4 weeks. For example, in some aspects, atezolizumab is administered to the subject intravenously at a dose of 1200 mg every 3 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 840 mg every 2 weeks.

In some instances, a subject is administered a total of 1 to 60 doses of a PD-1 axis binding antagonist (e.g., atezolizumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses,

30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 doses, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses,

45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In particular instances, the doses may be administered intravenously.

The PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered sequentially (on different days) or concurrently (on the same day or during the same treatment cycle). In some instances, the PD-1 axis binding antagonist is administered prior to the additional therapeutic agent. In other instances, the PD-1 axis binding antagonist is administered after the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered on the same day. In some instances, the PD-1 axis binding antagonist may be administered prior to an additional therapeutic agent that is administered on the same day. For example, the PD-1 axis binding antagonist may be administered prior to chemotherapy on the same day. In another example, the PD-1 axis binding antagonist may be administered prior to both chemotherapy and another drug on the same day. In other instances, the PD-1 axis binding antagonist may be administered after an additional therapeutic agent 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 additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is in a separate composition as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is in the same composition as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is administered through a separate intravenous line from any other therapeutic agent administered to the subject on the same day.

The PD-1 axis binding antagonist and any additional therapeutic agent(s) 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 additional therapeutic agent is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

In a preferred embodiment, the PD-1 axis binding antagonist is administered intravenously. 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.

E. Co-administration of anti-TIGIT antagonist antibodies and PD- 1 axis binding antagonists

In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are co-administered. For example, in some aspects, tiragolumab and atezolizumab are co-administered intravenously. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs), e.g., are combined in an IV bag prior to administration. In other aspects, the coinfused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an IV-administered fixed dose combination (FDC). In some aspects, the IV-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1680 mg and tiragolumab at a dose of 840 mg. In some aspects, tiragolumab and atezolizumab are co-infused intravenously every four weeks (Q4W) at a dose of 1680 mg of atezolizumab and a dose of 840 mg of tiragolumab. In some aspects, the IV-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1200 mg and tiragolumab at a dose of 600 mg. In some aspects, tiragolumab and atezolizumab are co-infused intravenously every three weeks (Q3W) at a dose of 1200 mg of atezolizumab and a dose of 600 mg of tiragolumab.

In some aspects, tiragolumab and atezolizumab are co-infused simultaneously. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs). In other aspects, the co-infused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an SC-administered FDC. In some aspects, the SC-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 880 mg. In other aspects, the SC-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 1000 mg.

Exemplary IV and SC FDC doses and formulations of tiragolumab and atezolizumab are provided in PCT Application Pub. No. WO 2023/1 2665 and in U.S. Provisional Patent Application Nos. 63/493,691 (filed March 31 , 2023) and 63/494,983 (filed April 7, 2023) (both titled “Methods of Treating Tumors with Anti-TIGIT Antibodies”), each of which is incorporated herein by reference in its entirety.

IV. ANTI-TIGIT ANTAGONIST ANTIBODIES

The invention provides anti-TIG IT antagonist antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., an NSCLC, e.g., a resectable NSCLC).

In some instances, the anti-TIG IT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

In certain instances, the anti-TIG IT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 16), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 11 -16.

In some instances, anti-TIG IT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 16). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 27) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 28); and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 29). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 27 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 29. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 27 and a VL domain comprising the amino acid sequence of SEQ ID NO: 29. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 28 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 29. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 28 and a VL domain comprising the amino acid sequence of SEQ ID NO: 29.

In some instances, the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33); and (b) the light chain comprises the amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC (SEQ ID NO: 34).

In some instances, the anti-TIG IT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and/or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 17-20. In some instances, for example, the antibody further comprises an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20).

In some instances, the anti-TIG IT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 21 ), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21 -24. The anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 22- 25. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24). In another instance, for example, the anti-TIG IT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 22-24 and 26. In some instances, the anti-TIG IT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24).

In another aspect, an anti-TIGIT antagonist antibody is provided, wherein the antibody comprises a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications.

In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIG IT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.

In some instances, the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).

In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR). In some instances, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM). In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction. In some instances, the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM). In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT. In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

In some instances, the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above. For example, the method may include administering an isolated anti-TIG IT antagonist antibody that competes for binding to TIGIT with an anti-TIG IT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 16). The methods described herein may also include administering an isolated anti-TIG IT antagonist antibody that binds to the same epitope as an anti-TIGIT antagonist antibody described above.

In some aspects, the anti-TIGIT antagonist antibody exhibits Fc-mediated effector function, e.g., participates in antibody-dependent cellular cytotoxicity (ADCC). In some aspects, the anti-TIGIT antagonist antibody is an antibody having intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EQS084448, or TJ-T6) or enhanced effector function (e.g., SGN-TGT).

In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902).

In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some aspects, the anti-TIGIT antagonist antibody is an IgG 1 class antibody, e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EQS084448 (EOS-448), TJ-T6, or AB308. In some aspects, the antibody is a human monoclonal full-length IgG 1 class antibody comprising an Fc region.

In some aspects, the anti-TIGIT antagonist antibody is a human, monoclonal full-length IgG 1 subclass antibody comprising a human IgG 1 Fc region, a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 29.

In other aspects, the anti-TIGIT antagonist antibody is an lgG4 class antibody, e.g., ASP8374 or COM902.

The anti-TIGIT antagonist antibodies (e.g., tiragolumab) useful in this invention, including compositions containing such antibodies, may be used in combination with a PD-1 axis binding antagonist (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab), PD-1 binding antagonists (e.g., anti-PD-1 antagonist antibodies, e.g., pembrolizumab), and PD-L2 binding antagonists (e.g., anti-PD-L2 antagonist antibodies)), as described herein.

In some embodiments, the anti-TIGIT antagonist antibody functions to inhibit TIGIT signaling. In some embodiments, the anti-TIGIT antagonist antibody inhibits the binding of TIGIT to its binding partners. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2), and CD113 (PVRL3 or Nectin-3). In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD155. In some embodiments, the anti-TIGIT antagonist antibody may inhibit binding between TIGIT and CD112. In some embodiments, the anti-TIGIT antagonist antibody inhibits binding between TIGIT and CD113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cellular signaling in immune cells. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (e.g., when engaging a FcyR).

In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some embodiments, the anti-TIGIT antibody is a humanized antibody. In some embodiments, the anti-TIGIT antibody is a human antibody. In some embodiments, the anti-TIGIT antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

In some embodiments, the anti-TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201 ), EOS884448 (EOS-448), SEA-TGT (SGN-TGT)), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, domvanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131 , NB6253, HLX301 , HLX53, SL-9258 (TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti- TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201 ), EOS-448, and SEA-TGT (SGN-TGT). The anti-TIGIT antibody may be tiragolumab (MTIG7192A, RG6058 or RO7092284).

In some embodiments, the anti-TIGIT antibody comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six HVRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six HVRs of any one of the antibodies selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any one of the anti- TIGIT antibodies disclosed herein and the light chain comprises a light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIGIT antibody comprises the VH and VL of an anti- TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises the heavy chain and the light chain of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the heavy chain and the light chain of an anti-TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK- 7684), and SEA-TGT (SGN-TGT).

A. Dosing of anti-TIGIT antagonist antibodies

As a general proposition, the therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered to a subject having a cancer (e.g., an NSCLC) will be in the range of about 0.01 to about 50 mg/kg of subject body weight, whether by one or more administrations. In some embodiments, the therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered to a subject is in the range of 0.01 to 50 mg/kg of subject body weight, whether by one or more administrations.

Exemplary doses and dosing regimens for anti-TIG IT antagonist antibodies are provided, e.g., in PCT Application Pub. No. WO 2021/154761 , which is incorporated herein by reference in its entirety.

In some instances, the anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is 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 effective amount of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every four 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 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 fixed dose of 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 fixed dose of about 420 mg every two weeks (e.g., 420 mg ± 10 mg, e.g., 420 ± 6 mg, e.g., 420 ± 5 mg, e.g., 420 ± 3 mg, e.g., 420 ± 1 mg, e.g., 420 ± 0.5 mg, e.g., 420 mg every two 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. Alternatively, in some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered subcutaneously. In some instances, tiragolumab is administered to the subject intravenously at a dose of about 420 mg every 2 weeks, about 600 mg every 3 weeks, or about 840 mg of every 4 weeks. In some instances, tiragolumab is administered to the subject intravenously at a dose of 420 mg every 2 weeks, 600 mg every 3 weeks, or 840 mg every 4 weeks.

In some instances, a subject is administered a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), 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, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, or 60 doses. In some instances, a subject is administered a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 60 doses, 25 to 55 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 doses, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses, 45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In particular instances, the doses may be administered intravenously.

The anti-TIGIT antagonist antibody may be administered in any suitable manner known in the art. In some instances, the anti-TIGIT antagonist antibody is 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 anti-TIGIT antagonist antibody may be administered on the same day. 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 anti-TIGIT antagonist antibody 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 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 is administered intravenously or subcutaneously.

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 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.

V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, AND KITS

Any of the anti-cancer agents described herein (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tiragolumab) can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tiragolumab) can be prepared by mixing one or both agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers {Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m- cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH- 20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and PCT Application Pub. No. WO 2006/044908, the latter formulations including a histidine-acetate buffer.

An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, with a pH of 5.8. For example, atezolizumab may be provided in a 20 mL vial containing 1200 mg of atezolizumab that is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821 .6 mg), with a pH of 5.8. In another example, atezolizumab may be provided in a 14 mL vial containing 840 mg of atezolizumab that is formulated in glacial acetic acid (11 .5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8.

An exemplary tiragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine, and WFI. Tiragolumab may be provided in a 15-mL vial containing 10 mL of tiragolumab drug product at an approximate concentration of tiragolumab antibody of 60 mg/mL.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

In some aspects, the invention provides kits that include (a) a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIG IT antagonist antibody for use in combination with a PD-1 axis binding antagonist, or (c) a PD-1 axis binding antagonist and an anti- TIGIT antagonist antibody for treating a subject having a cancer (e.g., a non-small cell lung cancer (NSCLC)) according to any of the methods described herein. In some instances, the article of manufacture or kit further comprises package insert comprising instructions for using (a) a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist or (c) a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody to treat or delay progression of a cancer (e.g., an NSCLC) in a patient.

Accordingly, in some aspects, the invention provides kits that include (a) atezolizumab for use in combination with tiragolumab, (b) tiragolumab for use in combination with atezolizumab, or (c) atezolizumab and tiragolumab for treating a subject having a cancer (e.g., an NSCLC) according to any of the methods described herein. In some instances, the article of manufacture or kit further comprises package insert comprising instructions for using (a) atezolizumab in combination with tiragolumab, (b) tiragolumab in combination with atezolizumab, or (c) atezolizumab and tiragolumab to treat or delay progression of a cancer (e.g., an NSCLC) in a patient.

In some instances, a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags and syringes. The container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). In some instances, the container holds the formulation and the label on, or associated with, the container may indicate directions for use. The article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some instances, the article of manufacture further includes one or more of another agent (e.g., an additional chemotherapeutic agent or anti-neoplastic agent). Suitable containers for the one or more agents include, for example, bottles, vials, bags and syringes.

VI. EXAMPLES

Example 1 : A Phase III, Randomized, Double-Blind Study of Tiragolumab Plus Atezolizumab Compared with Placebo Plus Atezolizumab in Participants With Completely Resected Stage IIB, IIIA, or Select IIIB, PD-L1 Positive, Non-Small Cell Lung Cancer Who Have Received Adjuvant Platinum-Based Chemotherapy

G045006 is a Phase III, randomized, double-blind, global, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of tiragolumab plus atezolizumab compared with placebo plus atezolizumab administered to participants with PD-L1 positive (percentage of tumor cells with any membrane staining above background > 1% (>1% TC) as determined using the investigational VENTANA PD-L1 (SP263) CDx assay) Stage IIB, IIIA, or select IIIB (T3N2 only) non-small cell lung cancer (NSCLC) following resection and adjuvant platinum-based chemotherapy. NSCLC staging is determined according to the American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) non-small cell lung cancer (NSCLC) Staging, 8th edition (AJCC 8^th edition (Detterbeck et al., Chest, 151 : 193-203, 2017); see, e.g., Table 4 herein). T3N2 Stage 11 IB NSCLC is NSCLC in which the primary tumor is T3 (i.e., is > 5 cm but < 7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, and parietal pericardium) and the lymph node status is N2 (i.e., regional lymph node involvement is characterized as metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)).

Table 4. AJCC/UICC Non Small Cell Lung Cancer Staging, 8th Edition

PD-L1 positive subjects have > 1% TC as determined using the investigational VENTANA PD-L1 (SP263) CDx assay). PD-L1 high subjects have > 50% TC as determined using the investigational VENTANA PD-L1 (SP263) CDx assay. Table 5 presents the primary objectives for the study expressed using the estimand framework in accordance with the International Council for Harmonisation (ICH) E9(R1 ) statistical principles for clinical trials (ICH 2020) and select secondary objective and corresponding endpoints. Table 6 presents further secondary and exploratory objectives and corresponding endpoints. Table 5. Primary and Secondary Objectives and Corresponding Estimands/Endpoints

Table 6. Other Secondary and Exploratory Objectives and Endpoints

Example 2: Study Design

A study schema for the G045006 study is provided in Fig. 1 .

Male and female participants age > 18 years old with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 who have had a complete surgical resection of Stage IIB, IIIA, or select IIIB (T3N2 only) NSCLC with PD-L1 > 1% TC expression, followed by adjuvant platinum-based chemotherapy, with no evidence of recurrent disease, are eligible for participation in the study.

Screening tests and evaluations, except central PD-L1 tissue testing (and/or EGFR or ALK as applicable), must be performed after the last dose of chemotherapy and within 28 days of randomization. During pre-screening or screening, tumor tissue from each potentially eligible participant is tested for PD- L1 expression by a central laboratory using the investigational VENTANA PD-L1 (SP263) CDx Assay. Only participants with PD L1 expression > 1% TC as determined by the investigational VENTANA PD-L1 (SP263) CDx assay are eligible for enrollment.

Participants whose tumors have a known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement are excluded from enrollment in the study. Participants with non-squamous NSCLC who have an unknown EGFR or ALK status are required to be tested at screening. Participants with squamous NSCLC who have unknown EGFR or ALK status are eligible and are not required to be tested at pre-screening or screening. EGFR and/or ALK status may be assessed locally or at a central laboratory.

Approximately 1150 participants (approximately 700 participants (approximately 60%) having PD- L1 > 50% TC, and approximately 450 participants (approximately 40%) having PD-L1 >1% and <50% TC) are enrolled in the study. Enrollment of a specific PD-L1 population is capped once it hits its specified target. Participants who discontinue study treatment prematurely are not replaced.

Randomization must be completed 70 days at the latest after the final dose of chemotherapy. Eligible participants are randomized in a 1 :1 ratio to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. Participants receive their first dose of study treatment on the day of randomization, if possible. If this is not possible, the first dose should occur within 5 days of randomization.

Eligible participants are stratified by tumor histology (squamous vs. non-squamous), disease stage (Stage I IB vs. Stage 11 IA + select II IB (T3N2 only)) and PD-L1 status (>1% and <50% TC vs. > 50% TC). Enrollment into the PD-L1 >1% and <50% TC sub-group is capped at approximately 450 participants (approximately 40% of participants), and enrollment into the PD-L1 > 50% TC sub-group is capped at approximately 700 participants (approximately 60% of participants).

In the experimental arm, tiragolumab at a dose of 840 mg plus atezolizumab at a dose of 1680 mg is administered by IV co-infusion (tiragolumab and atezolizumab are mixed and administered in one IV bag) on Day 1 of each 28-day cycle for a total of 13 cycles (approximately 1 year). In the comparator arm, placebo plus atezolizumab at a dose of 1680 mg is administered by IV co-infusion on Day 1 of each 28-day cycle for a maximum of 13 cycles.

Crossover from the placebo plus atezolizumab arm to the tiragolumab plus atezolizumab arm is not allowed.

Treatment is continued for a maximum of 13 cycles (approximately 1 year) in the absence of disease recurrence or unacceptable toxicity.

All participants undergo scheduled disease assessment scans by computed tomography (CT) at screening and every 16 weeks (± 2 weeks) starting at Cycle 1 , Day 1 in the first year, every 26 weeks (± 4 weeks) in Years 2-5, and annually thereafter (low-dose non-contrast CT recommended after 5 years). Disease assessments continue per schedule regardless of whether study treatment is completed or held or discontinued (for any reason) until disease recurrence, withdrawal of consent, death, or study termination, whichever occurs first. Disease recurrence must be determined radiographically as evidenced by local/regional recurrence, distant metastasis, or a second primary NSCLC. If a disease assessment shows disease recurrence, it must be confirmed pathologically, unless not clinically feasible.

Safety assessments include the incidence, nature, and severity of adverse events, graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

Participants are asked to complete participant-reported outcome (PRO) questionnaires during study treatment, at treatment discontinuation/completion, and at disease assessment time points during post-treatment follow-up.

During the study, serum samples are collected to monitor atezolizumab and tiragolumab pharmacokinetics and to detect the presence of antibodies to atezolizumab and tiragolumab. Participant samples, including archival and fresh tumor tissue, serum, plasma, and blood samples, are also collected for exploratory biomarker assessments.

After initiation of study treatment, all adverse events are reported until 30 days after the final dose of study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first. Serious adverse events continue to be reported until 90 days after the final dose of study treatment or until initiation of a new systemic anti-cancer therapy, whichever occurs first. In addition, adverse events of special interest continue to be reported until 90 days after the final dose of study treatment, regardless of initiation of new anti-cancer therapy. After this period, investigators report serious adverse events that are believed to be related to prior treatment with study drug(s). The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the participant is lost to follow-up, or the participant withdraws consent.

After discontinuation of treatment, participants enter the post-treatment follow-up period of the study. Post-treatment follow-up consists of ongoing assessments as described above. Follow-up information is collected until death, loss to follow-up, or study termination, whichever occurs first.

A. Rationale for study design

Rationale for study population

The study enrolls participants with PD-L1 > 1% TC Stage I IB, 11 IA, or select I IIB (T3N2) NSCLC. With cancer immunotherapy (CIT) and targeted therapies becoming available for resectable NSCLC, treatment options for some patients have improved over chemotherapy-based regimens. Nevertheless, a significant proportion of patients will still experience disease recurrence and will die from their disease, highlighting the need to continue to build on the recent successes.

Rationale for primary endpoint

While OS is the gold standard for establishing benefit in oncology clinical trials, the time necessary for an OS readout in the adjuvant NSCLC setting could lead to an unacceptable delay in making a new effective therapy available to participants. DFS (the primary efficacy endpoint in this study) is a meaningful and reliable efficacy endpoint with earlier time to evaluation compared to OS. DFS appears strongly correlated with OS in the adjuvant NSCLC setting, as demonstrated in several metaanalyses with chemotherapy (Michiels et al., Journal of Clinical Oncology, 29(15): 7004, 2011 ; Mauguen et al., Lancet Oncol, 14: 619-626, 2013). Furthermore, DFS is recommended by the FDA as a surrogate endpoint for both accelerated and traditional approval and has as such been used as the primary basis for approval for adjuvant therapy in several indications including for adjuvant CIT in NSCLC (FDA Guidance to Industry, 2018; and KEYTRUDA® U.S. Package Insert).

Secondary efficacy endpoints, including DFS rates at specific timepoints and OS, provide supportive measures of efficacy.

B. End of study and duration of participation

The end of the study occurs when the last patient, last visit has occurred or the date at which the last data point required for statistical analysis (i.e., final analysis for DFS) or safety follow-up is received from the last participant, whichever occurs later. The total length of study, from randomization of the first participant to the end of study, is expected to be approximately 15 years.

Participation continues until withdrawal or death due to any cause. Example 3: Study Population

Approximately 1 150 participants (approximately 700 participants with PD-L1 > 50% TC and approximately 450 participants with PD-L1 >1% and <50% TC by the investigational VENTANA PD-L1 (SP263) CDx assay) with completely resected Stage 11 B, 111 A, or select 11 IB (T3N2) NSCLC who have received adjuvant platinum-based doublet chemotherapy are enrolled in the G045006 study.

A. Inclusion criteria

Potential participants are eligible to be included in the study only if all of the following criteria apply:

• Age > 18 years at the time of signing Informed Consent Form.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

• Histological or cytological diagnosis of Stage I IB, 111 A, or select 11 IB (T3N2) NSCLC (per the UICC/AJCC staging system, 8th edition; Detterbeck et al., Chest, 151 : 193-203, 2017) of either non-squamous or squamous histology.

• Participants with tumors of mixed NSCLC histology must be classified as being non-squamous or squamous on the basis of the major histologic component.

• Participants with tumors of mixed histology containing both NSCLC and small cell lung cancer are not eligible.

• NSCLC with histology of large cell neuroendocrine carcinoma, sarcomatoid carcinoma, or NSCLC not otherwise specified are not eligible.

• Participants must have had complete resection of NSCLC (no residual tumor and all surgical margins negative for invasive carcinoma).

• Accepted types of resection include any of the following: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Participants who have had only segmentectomies or wedge resections are not eligible for this study.

• At a minimum, mediastinal lymph node systematic sampling must have occurred, though complete mediastinal lymph node dissection (MLND) is preferred. Systematic sampling is defined as removal of at least one representative lymph node at specified levels. MLND entails resection of all lymph nodes at those same stations. Sampling or MLND at a minimum of 2 lymph node N2 stations is required. Exceptions are granted for the following situations:

• If mediastinoscopy or endobronchial ultrasound (EBUS) was performed preoperatively, diagnostic mediastinal lymph node sampling can be used to meet the minimum of 2 lymph node N2 stations.

• If there is clear documentation in the operative report or in a separately submitted addendum by the surgeon of exploration of the required lymph node areas, the participant is considered eligible if no lymph nodes are found in those areas.

• Participants must have received between one and four cycles (four preferred) of adjuvant histologybased platinum doublet chemotherapy: cisplatin (preferred) or carboplatin, with pemetrexed (non- squamous), gemcitabine, docetaxel, vinorelbine, etoposide, or paclitaxel Acceptable adjuvant chemotherapy regimens are described in the NCCN/ESMO guidelines (National Comprehensive Cancer Network. NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, 2023) and in Table 1 . • Participants must have recovered adequately from surgery and from adjuvant chemotherapy (no Grade > 2 unresolved toxicity). Patients with an irreversible toxicity that is managed and is not expected to be exacerbated by study drug treatment may be included (e.g., hearing loss).

• Patients must begin adjuvant chemotherapy within 12 weeks of their surgery date.

• Patients must be randomized no more than 70 days (10 weeks) from last dose of chemotherapy (Day 1 of last cycle).

• Tumor PD-L1 expression with a percentage of tumor cells with any membrane staining above background > 1% (> 1% TO) as determined by the investigational VENTANA PD-L1 (SP263) CDx Assay, documented through central testing of a representative tumor tissue specimen.

• A representative formalin-fixed, paraffin-embedded (FFPE) existing resected tumor specimen in a paraffin block (preferred) or at least 15-20 slides containing unstained, freshly cut, serial sections is submitted along with an associated pathology report prior to study enrollment. If central testing for EGFR mutations and/or ALK translocations is required, an additional five unstained slides are provided.

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization:

• Absolute neutrophil count (ANC) > 1.5 x 10⁹/L (> 1500/pL) without granulocyte colony-stimulating factor support, with one exception: Participants with benign ethnic neutropenia (BEN): ANC > 1 .3 x

10⁹/L (> 1300/pL) are eligible. BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al., Blood Rev, 37: 100586, 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.

• Lymphocyte count > 0.5 x 10⁹/L (> 500/pL).

• Platelet count > 100 x 10⁹/L (> 100,000/pL) without transfusion.

• Hemoglobin > 90 g/L (> 9 g/dL). Participants may be transfused to meet this criterion.

• AST, ALT, and ALP < 2.5 x upper limit of normal (ULN).

• Total bilirubin < 1 .5 x ULN with the following exception: participants with known Gilbert disease: total bilirubin < 3 x ULN.

• Creatinine clearance > 30 mL/min (calculated by institutional standards or through use of the Cockcroft-Gault formula).

• Albumin > 25 g/L (> 2.5 g/dL).

• For participants not receiving therapeutic anticoagulation: INR and aPTT < 1 .5 x ULN. For participants receiving therapeutic anticoagulation: stable anticoagulant regimen.

• Negative HIV test at screening, with the following exception: participants with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count > 200/pL, and have an undetectable viral load.

• Participants must meet one of the following criteria for hepatitis B virus (HBV):

• Negative hepatitis B surface antigen (HBsAg) test at screening accompanied by either of the following: Positive hepatitis B surface antibody (HBsAb) or negative HBsAb and negative total hepatitis B core antibody (HBcAb).

• HBV DNA < 500 lU/mL at screening for participants with positive total HBcAb test and negative

HBsAb test. Participants with detectable HBV DNA should be managed per institutional guidelines.

• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test must be performed for participants who have a positive HCV antibody test.

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception.

• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm.

B. Exclusion criteria

Potential participants are excluded from the study if any of the following criteria apply:

• Any history of prior NSCLC within the last 5 years.

• Previous NSCLC must have been treated with surgery only.

• Any evidence of residual disease or disease recurrence following surgical resection of NSCLC, or during or following adjuvant chemotherapy.

• NSCLC known to have a mutation in the EGFR gene or an ALK fusion oncogene:

• Participants with non-squamous NSCLC who have an unknown EGFR or ALK status are required to be tested at pre-screening or screening.

• Participants with squamous NSCLC who have an unknown EGFR or ALK status are eligible and are not required to be tested at pre-screening or screening.

• EGFR and/or ALK status may be assessed locally or at a central laboratory. EGFR and or ALK status assessed locally must be performed on tissue using a validated health authority-approved or an appropriately validated next-generation sequencing (NGS) test performed in a Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified laboratory. EGFR test must detect mutations in exons 18-21 . If samples are submitted for central EGFR and/or ALK testing, an additional five slides must be provided.

• Prior treatment with systemic therapy (e.g., chemotherapy or immunotherapy) for the treatment of NSCLC, with the exception of adjuvant platinum-based chemotherapy as outlined in the inclusion criteria.

• Prior treatment with radiation therapy for NSCLC (including postoperative radiotherapy (PORT)), with the exception of localized symptom-directed radiation prior to surgical resection.

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain Barre syndrome, or multiple sclerosis, with the following exceptions:

• Participants with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study. • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

• Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: rash must cover < 10% of body surface area; disease is well controlled at baseline and requires only low-potency topical corticosteroids; there has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

• Positive Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening. An EBV polymerase chain reaction (PCR) test should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Participants with a positive EBV PCR test are excluded.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug- induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• Active tuberculosis.

• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.

• Major surgical procedure within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study treatment period.

• History of malignancy within 5 years prior to initiation of study treatment, with the exception of the cancer under investigation in the study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact participant safety.

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.

• Prior allogeneic stem cell or solid organ transplantation.

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications.

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine, during study treatment, for 90 days after the final dose of tiragolumab/placebo, and for 5 months after the final dose of atezolizumab.

• Treatment with investigational therapy within 28 days prior to initiation of study treatment. • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-TIGIT, anti-PD-L1 , and anti-PD-1 therapeutic antibodies

• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.

• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-a (TNF-a) agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

• Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.

• Participants who received mineralocorticoids (e.g., fludrocortisone), inhaled or lowdose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.

• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation.

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, within 90 days of the last dose dose of tiragolumab/placebo or within 5 months after the final dose of atezolizumab

• Any condition that, in the opinion of the investigator, would interfere with the participant’s safe participation in and completion of the study, the evaluation of the study drug, or the interpretation of participant safety or study results.

Example 4: Study Treatment and Concomitant Therapy

Table 7 provides a description of assigned study treatments for the G045006 study.

Table 7. Study Treatment Description

Q4W = every 4 weeks.

The treatment regimens are summarized below. "Study treatment" as used herein refers to the combination of treatments assigned to participants as part of the study (e.g., atezolizumab plus tiragolumab). Administration of study treatment is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.

A. Tiragolumab and atezolizumab or placebo and atezolizumab

Tiragolumab/atezolizumab and placebo/atezolizumab co-infusions are administered per the instructions outlined in Table 8.

Tiragolumab or placebo is administered by IV infusion at a fixed dose of 840 mg together with 1680 mg of atezolizumab mixed in the same IV bag for co-infusion on Day 1 of each 28-day cycle.

Except for Day 1 of Cycle 1 and the 6 and 12 months after treatment discontinuation (or 6 months after disease recurrence), all other study visits and assessments during the treatment period may performed within ± 3 days of the scheduled date. Thus, tiragolumab/atezolizumab and placebo/atezolizumab co-infusions may be administered on Day 1 ± 3 days of each 28-day cycle, with the exception of Cycle 1 .

Table 8. Administration of First and Subsequent Infusions of Atezolizumab Mixed with

Tiragolumab/Placebo

B. Treatment assignment and blinding

Treatment assignment

The study is a randomized, double-blind study.

Randomization must be completed within 70 days (10 weeks) after the final dose of chemotherapy. Eligible participants are randomized in a 1 :1 ratio to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. Participants receive their first dose of study treatment on the day of randomization, if possible. If this is not possible, the first dose should occur within 5 days of randomization.

Eligible participants are stratified by tumor histology (squamous vs. non-squamous), disease stage (Stage II vs. Stage I HA + select II IB (T3N2)), and PD-L1 status ((>1 % and <50% TC vs. > 50% TC) by the investigational VENTANA PD-L1 (SP263) CDx assay. A permuted-block randomization is applied to ensure a balanced assignment to each treatment arm within levels of the stratification factors.

C. Concomitant therapy

Permitted therapy

Participants are permitted to use the following therapies during the study:

• Oral contraceptives with a failure rate of < 1 % per year.

• Hormone-replacement therapy.

• Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or low-molecular- weight heparin).

• Vaccinations (such as influenza, COVID 19). Live, attenuated vaccines are not permitted.

• Megestrol acetate administered as an appetite stimulant.

• Mineralocorticoids (e.g., fludrocortisone).

• Corticosteroids administered for COPD or asthma.

• Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency.

Premedication with antihistamines, antipyretic medications, and/or analgesics may be administered for the second and subsequent infusions, at the discretion of the investigator.

In general, investigators manage a participant's care (including preexisting conditions) with supportive therapies other than those defined below as cautionary or prohibited therapies as clinically indicated, per local standard practice. Participants who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress are managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2-adrenergic agonists).

Cautionary therapy

Systemic corticosteroids, immunosuppressive medications, and TNF-a inhibitors may attenuate potential beneficial immunologic effects of treatment with tiragolumab and/or atezolizumab. Therefore, in situations in which systemic corticosteroids, immunosuppressive medications, or TNF-a inhibitors would be routinely administered, alternatives, including antihistamines, should be considered. If the alternatives are not feasible, systemic corticosteroids, immunosuppressive medications and TNF-a inhibitors may be administered at the discretion of the investigator.

Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion of the investigator, for the treatment of specific adverse events when associated with tiragolumab and/or atezolizumab therapy. Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety profiles, and potential drug-drug interactions are generally unknown. However, herbal therapies not intended for the treatment of cancer may be used during the study at the discretion of the investigator.

Prohibited therapy

Use of the following concomitant therapies is prohibited as described below:

• Concomitant therapy intended for the treatment of cancer (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy (RT), and herbal therapy), whether health authority- approved or experimental, for various time periods prior to starting study treatment, depending on the agent, and during study treatment, until disease recurrence is documented and the participant has discontinued study treatment.

• Investigational therapy within 28 days prior to initiation of study treatment and during study treatment

• Live, attenuated vaccines (e.g., FLUMIST®) within 4 weeks prior to initiation of study treatment, during study treatment, for 90 days after the final dose of tiragolumab/placebo. and for 5 months after the final dose of atezolizumab.

• Systemic immunostimulatory agents (including, but not limited to, IFNs and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with study treatment.

Example 5: Study Assessments and Procedures

Participants are closely monitored for safety throughout the study. Participants should be assessed for toxicity prior to each dose; treatment will be administered only if the clinical assessment and local laboratory test values are acceptable.

A. Efficacy Assessments

Screening and subsequent disease assessments include computed tomography (CT) scans with contrast of the chest and abdomen (including liver and adrenal glands). If a CT scan with contrast is contraindicated (e.g., in participants with impaired renal clearance), a non-contrast CT of the chest plus a magnetic resonance imaging (MRI) of the abdomen is preferred, and a chest/abdomen CT non-contrast is acceptable. MRI scan (preferred) or contrast CT of the brain must be done at screening to evaluate CNS metastasis in all participants (MRI scan must be performed if CT scan is contraindicated). An MRI scan of the brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT scan. Bone scans and CT scans of the neck should also be performed if clinically indicated.

The same radiographic modality (e.g. CT with contrast) and procedures (e.g., the same contrast protocol for CT scans) used at screening should be used for subsequent disease assessments. B. Clinical Outcome Assessments

Patient-reported outcome (PRO) instruments are completed to assess the patient-reported tolerability of tiragolumab plus atezolizumab at the selected dosages, and to confirm the safety profile of the doublet combination. In addition, PRO instruments enable the capture of each participant's direct experience with tiragolimab plus atezolizumab.

PRO data are collected through use of the following instruments: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, and PRO- CTCAE (selected items), and EQ-5D-5L.

The PROs are administered in the following order: EORTC QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, PRO-CTCAE (selected items), and EQ-5D-5L.

The QLQ-C30 is a validated, reliable self-reported measure (see Aaronson et al., J Natl Cancer Inst, 85: 365-376, 1993; Fitzsimmons et al., EurJ Cancer, 35: 939-941 , 1999).

The EORTC QLQ-LC13 is a self-reported PRO measure that is a lung cancer-specific module to the EORTC QLQ-C30 (Bergman et al., Eur J Cancer, 30A: 635-642, 1994).

The PRO-CTCAE is a validated item library that is used to characterize the presence, frequency of occurrence, severity, and/or degree of interference with daily function of 78 participant-reportable symptomatic treatment toxicities (Basch et al., J Natl Cancer Inst, 106: 1 -11 , 2014; Dueck et al., JAMA Oncol, 1 : 1051 -1059, 2015).

The EORTC IL46 is a validated single item from the EORTC Item Library which assesses the extent that participants have been troubled by the side effects from their treatment. It is rated on a 4-point scale, ranging from “not at all” to “very much.”

The EQ-5D-5L is a validated self-reported health status questionnaire that is used to calculate a health status utility score for use in health economic analyses (EuroQol Group, Health Policy, 16: 199- 208, 1990; Brooks, Health Policy, 37: 53-72, 1996; Herdman et al., Qual Life Res, 20: 1727-1736, 2011 ; Janssen et al., Qual Life Res, 22: 1717-1727, 2013)

Example 6: Statistical Considerations

Hypotheses are formally tested regarding the effect of tiragolumab plus atezolizumab compared to placebo plus atezolizumab on investigator-assessed disease-free survival (DFS) in the PD-L1 high analysis set (PHAS) (PD-L1 > 50% TC by SP263) and the full analysis set (FAS) (PD-L1 > 1% TC by SP263 CDx assay). The null (HO) and alternative (H1 ) hypotheses regarding investigator-assessed DFS in the PHAS and FAS is tested at a two-sided significance level of 0.038 and 0.012, respectively, and can be phrased in terms of the population hazard ratio X between the experimental arm and the control arm:

HO: X = 1 versus

All hypothesis tests are two-sided unless stated otherwise.

A. Sample size determination

A total of approximately 1150 participants (approximately 700 participants with PD-L1 > 50% TC and approximately 450 participants with PD-L1 >1% and <50% TC by investigational VENTANA PD-L1 (SP263) CDx assay) are randomized into the study. The detailed assumptions and calculations are listed below.

Type I error control

The overall type I error rate for the study is 0.05 (two-sided). The primary endpoints of investigator-assessed DFS in the PHAS and FAS are tested at a two-sided a level of 0.038 and 0.012, respectively.

If DFS is statistically significant in the PHAS, then the two-sided a of 0.038 is recycled to the FAS and the FAS is tested at two-sided a of 0.05.

If the DFS is statistically significant in the FAS, then the two-sided aof 0.012 is recycled to the PHAS to be tested at a two-sided a of 0.05 level.

The study is positive as long as any of the primary endpoints is positive.

Investigator-assessed disease-free survival

The final analysis for the primary endpoint of investigator-assessed DFS takes place when approximately 322 DFS events in the PHAS and approximately 652 DFS events in the FAS have been observed, whichever occurs later.

The estimated number of events required to demonstrate efficacy with regard to DFS in the PHAS are based on the following assumptions:

• 1 :1 randomization ratio.

• Two-sided a of 0.038.

• DFS curve follows the exponential distribution.

• Median DFS of 65 months for placebo plus atezolizumab arm.

• 85% power to detect a DFS HR of 0.70.

• One interim analysis is performed when approximately 249 DFS events in the PHAS have occurred. The stopping boundaries are computed using the Generalized Haybittle-Peto boundaries (Haybittie, Brit J Radiology, 44: 793-797, 1971 ) with unequal p-values of 0.0260 and 0.0252 at the interim and final DFS analyses, respectively.

• Enrollment period of approximately 64 months.

• Annual drop-out rate of 5%.

The estimated number of events required to demonstrate efficacy with regard to DFS in the FAS are based on the following assumptions:

• 1 :1 randomization ratio.

• Two-sided a of 0.012.

• D curve follows the exponential distribution.

• Median DFS of 51 months for placebo plus atezolizumab arm.

• 74% power to detect a DFS HR of 0.78.

• One interim analysis is performed when approximately 539 DFS events in the FAS have occurred. The stopping boundaries are computed using the Generalized Haybittle-Peto boundaries (Haybittie, Brit J Radiology, 44: 793-797, 1971 ) with unequal p-values of 0.0090 and 0.0071 (DFS analysis at the interim and final DFS analyses, respectively.

• Enrollment period of approximately 64 months.

• Annual drop-out rate of 5%.

With these assumptions, the final DFS analysis takes place approximately 120 months after the first participant is randomized. The minimum detectable difference in DFS HR at the final analysis is approximately 0.78 for the PHAS and 0.81 for the FAS. B. Analysis sets

The participant analysis sets for the purposes of analyses are defined in Table 9.

Table 9. Participant Analysis Sets

ADA= anti-drug antibody; FAS = full analysis set; PHAS = PD-L1 high analysis set; SAS = safety analysis set; PKAS = Phamacokinetic analysis set.

C. Statistical analyses

All efficacy analyses are performed on the PHAS and FAS, unless otherwise specified. All safety analyses are performed on the SAS, unless otherwise specified.

Estimation methods for the primary estimands

The primary objective for the study is to evaluate the efficacy of tiragolumab plus atezolizumab compared with placebo plus atezolizumab in participants with resected, Stage I IB, 111 A, or select 11 IB (T3N2 only) (AJCC 8th edition) PD-L1 > 50% TC and PD-L1 > 1% TC NSCLC who have received adjuvant platinum-based chemotherapy. The primary endpoints are investigator-assessed DFS in the PHAS and FAS. Investigator-assessed DFS is defined as the time from randomization to the occurrence of local/regional or distant recurrence of NSCLC, new primary NSCLC, or death from any cause (whichever occurs first), as determined by the investigator. Data for participants who have not experienced local/regional or distant recurrence of NSCLC, a new primary NSCLC, or death are censored at the date of the last tumor assessment. If no post-baseline data are available, DFS is censored at the date of randomization.

The stratified log-rank test is used to compare DFS between the two treatment arms. The HR for DFS is estimated using a stratified Cox regression model, along with the 95% Cl. Stratification factors for analysis in the FAS include histology (non squamous vs. squamous), stage of disease (Stage I IB vs. Stage IIIA + select IIIB (T3N2)) and PD-L1 status (>1% and <50% TC vs. >50% TC). Stratification factors for analysis in the PHAS include histology and stage of disease. Results of the unstratified analysis are also provided. Kaplan-Meier methodology is used to estimate the median DFS for each treatment arm, and the Kaplan-Meier curve is constructed to provide a visual description of the difference among arms. The Brookmeyer-Crowley methodology is used to construct the two-sided 95% Cl for the median DFS for each treatment arm.

Estimation methods for the secondary estimands

Overall survival

Overall survival after randomization is defined as the time from randomization to death from any cause. Data for participants who are not reported as having died at the date of analysis are censored at the date when they were last known to be alive. If no post-baseline data are available, OS is censored at the date of randomization.

The methodology for comparing OS between treatment arms in the PHAS and FAS is the same as the method used for treatment comparison for the primary endpoints of investigator-assessed DFS. Overall survival is analyzed at the time of the DFS analyses.

Investigator-assessed DFS 3- year, 5-year, and 7 -year rates

The investigator-assessed DFS rate at 3 years, 5 years, and 7 years is analyzed by treatment arm. The DFS rates are estimated by the Kaplan-Meier methodology for each treatment arm, with two- sided 95% Cis calculated using Greenwood’s formula.

Clinical outcome assessment analysis

The proportion of participants who maintained or meaningfully improved from baseline in patient- reported role, emotional, and physical functioning and GHS/QoL as measured by the EORTC QLQ-C30 is summarized by treatment arm. In general, a change of 10 points or more on scales of the EORTC QLQ- C30 was established by Osoba et al. (J Clin Oncol, 16: 139-144, 1998) to be clinically meaningful. This has been largely confirmed in studies with lung cancer patients, and specific estimates for individual scales of the EORTC QLQ-C30 and LC13 in lung cancer will be applied (Coon et al., Patient, 15: 691 - 702, 2022; Musoro et al., Eur J Cancer, 188: 171 -182, 2023). Maintenance of baseline is defined as a less than 10-point increase or decrease in deterioration of these domains. Safety analyses

Safety analyses are conducted in the SAS, defined as participants who receive at least one dose of tiragolumab/placebo or atezolizumab. Safety is assessed through summaries of exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.

Study treatment exposure (such as treatment duration, total dose received, and number of cycles and dose modifications) is summarized with descriptive statistics.

All verbatim adverse event terms are mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and adverse event severity is graded according to NCI CTCAE v5.0. Cytokine release syndrome (CRS) is graded according to the ASTCT CRS Consensus Grading Scale. All adverse events, serious adverse events, adverse events leading to death, adverse events of special interest, and adverse events leading to study treatment discontinuation that occur or worsen on or after the first dose of study treatment (i.e. , treatment-emergent adverse events) are summarized by mapped term, appropriate thesaurus level, and severity grade. For events of varying severity, the highest grade is used in the summaries. Deaths and causes of death are summarized.

Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, and temperature), and ECG data are displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests is used to summarize the baseline and maximum post-baseline severity grade. Changes in vital signs and ECGs are summarized.

Exploratory analyses

Clinical outcome assessment analyses

The analysis population for the EORTC QLQ-C30 and QLQ-LC13 is the FAS. Completion rates are summarized at each timepoint by treatment arm for the EORTC QLQ-C30, QLQ-LC13 and EQ-5D-5L using the FAS.

Summary statistics (mean, standard deviation (SD), median, 25th and 75th percentiles, and range) and the mean change from baseline of linear-transformed scores are reported for all of the items and subscales of the EORTC QLQ-C30 and EORTC QLQ-LC13. The number and proportion of participants who improved, worsened, or remained stable on each of the scales of the EORTC QLQ-C30 and QLQ-LC13 are summarized at each visit by treatment arm. Comparisons between treatment groups are made.

The analysis population for the PRO-CTCAE and EORTC IL46 is the SAS. Summaries of the data over time are based on the number of participants who provided data at each time point. Completion rates are summarized at each timepoint by treatment arm for the PRO-CTCAE and EORTC IL46 using the SAS population.

For patient-reported tolerability, the PRO-CTCAE analyses are primarily descriptive, with a focus on characterizing the pattern of symptomatic AE occurrence over the course of the study. PRO-CTCAE data are analyzed at the item level in accordance with current NCI recommendations for data handling (Basch et al., J Natl Cancer Inst, 106: 1 -11 , 2014). The number (percentage) of participants reporting symptoms by frequency, severity, and interference is reported at each visit by treatment arm. The change in the frequency of responses from baseline for each symptom is also summarized at each visit by treatment arm. Patient-reported bother with side effects, as measured by the EORTC IL46 item, is summarized descriptively at each assessment timepoint. The number (percentage) of participants reporting bother is reported at each visit by treatment arm. The change in the frequency of responses from baseline is also summarized at each visit by treatment arm.

Subgroup efficacy analyses

The effects of demographics (e.g., age, sex, race/ethinicity) and baseline prognostic characteristics (e.g., tumor stage, PD-L1 expression level by investigational VENTANA PD-L1 (SP263) CDx assay, chemotherapy regimen before randomization, histology, smoking history, and ECOG Performance Staus) on duration of investigator-assessed DFS and OS are examined in the PHAS and FAS. Summaries of DFS and OS, including unstratified HRs estimated from Cox proportional hazards models and Kaplan-Meier estimates of median survival time, are produced separately for each level of the cagegorical variables.

DFS and OS rate at landmark timepoints

In addition to the DFS 3-year, 5-year and 7-year rates as secondary endpoints, the DFS and OS rates (for example 3-year, 5-year, and 7-year rates) at various other timepoints in the PHAS and FAS are estimated by the Kaplan-Meier methodology for each treatment arm, with two-sided 95% Cis calculated using Greenwood’s formula for exploratory purposes.

Biomarker analysis

Exploratory biomarkers analysis including, but not limited to, tumor and immune-related gene signatures and circulating tumor DNA levels and dynamics are investigated. Additionally, ctDNA levels as an early indicator of disease recurrence are explored in the study.

Pharmacokinetic analyses

The pharmacokinetic (PK) analysis population for atezolizumab consists of all participants who received any dose of atezolizumab with at least 1 post-baseline atezolizumab PK assessment available. The PK analysis population for tiragolumab consists of all participants who received any dose of tiragolumab with at least 1 post-baseline tiragolumab PK assessment available. Samples are collected for PK analyses, and serum concentrations of atezolizumab and tiragolumab are reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation) by treatment arm and cycle, when appropriate and as data allow. Individual and median serum atezolizumab and tiragolumab concentrations are plotted for PK-evaluable participants by day.

Immunogenicity analyses

The immunogenicity analyses include participants with any ADA assessments, with participants grouped according to treatment received. The numbers and proportions of treatment-emergent ADApositive participants and ADA-negative participants for both tiragolumab and atezolizumab are summarized. The relationship between ADA status and safety, efficacy, and PK endpoints may be analyzed and reported via descriptive statistics.

D. Interim analyses

One interim analysis is planned for investigator-assessed DFS in the PHAS and FAS. The planned interim analysis of DFS is conducted when approximately 249 DFS events have occurred in the PHAS (77% of the total planned DFS events) and approximately 539 DFS events have occurred in the FAS (83% of the total planned DFS events), whichever occurs later. This interim analysis is estimated to occur approximately 90 months after the first participant is enrolled in the study.

The final DFS analysis is conducted when approximately 322 DFS events have occurred in the PHAS and approximately 652 DFS events have occurred in the FAS, whichever occurs later. This is estimated to occur approximately 120 months after the first participant is enrolled in the study.

The stopping boundaries for the interim and final analyses of DFS are computed using the Generalized Haybittle-Peto boundaries (Haybittie, Brit J Radiology, 44: 793-797, 1971 ) with unequal two- sided p-values of 0.0260 and 0.0252 for the PHAS, and 0.0090 and 0.0071 for the FAS, in the order of analysis. If the PHAS achieves statistical significance, then a is recycled to the FAS, and the two-sided p- values for the FAS are 0.0250 and 0.0436. If the FAS achieves statistical significance, then a is recycled to the PHAS, and the two-sided p-values for the PHAS are 0.0350 and 0.0331 .

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating a subject having a non-small cell lung cancer (NSCLC), the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.

2. A method of treating a subject having a non-small cell lung cancer (NSCLC), the method comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.

3. The method of claim 1 or 2, wherein the complete resection was a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy.

4. The method of any one of claims 1 -3, wherein the complete resection was a resection resulting in (i) no residual tumor and (ii) all surgical margins negative for invasive carcinoma.

5. The method of any one of claims 1 , 3, and 4, wherein the subject has received between one and four dosing cycles of the adjuvant chemotherapy.

6. The method of claim 5, wherein the subject has received four dosing cycles of the adjuvant chemotherapy.

7. The method of any one of claims 2-4, wherein the method comprises administering to the subject between one and four dosing cycles of the adjuvant chemotherapy.

8. The method of claim 7, wherein the method comprises administering to the subject four dosing cycles of the adjuvant chemotherapy.

9. The method of any one of claims 1 -8, wherein the adjuvant chemotherapy is a platinum-based adjuvant chemotherapy.

10. The method of claim 9, wherein the platinum-based adjuvant chemotherapy comprises cisplatin.

1 1 . The method of claim 9, wherein the platinum-based adjuvant chemotherapy comprises carboplatin.

12. The method of any one of claims 9-1 1 , wherein the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents.

13. The method of claim 12, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.

14. The method of claim 13, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.

15. The method of claim 9, wherein the platinum-based adjuvant chemotherapy is a platinum-based adjuvant doublet chemotherapy.

16. The method of claim 15, wherein the platinum-based adjuvant doublet chemotherapy comprises:

(i) cisplatin and pemetrexed administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21 -day dosing cycle;

(ii) cisplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is administered at a dose of about 1250 mg/m² on Days 1 and 8 of each 21 -day dosing cycle;

(Hi) cisplatin and docetaxel administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and docetaxel is administered at a dose of about 75 mg/m² on Day 1 of each 21 -day dosing cycle;

(iv) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered at a dose of about 50 mg/m² intravenously on Days 1 and 8 of each 28-day dosing cycle and vinorelbine is administered at a dose of about 25 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle;

(v) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle and vinorelbine is administered at a dose of about 30 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle;

(vi) cisplatin and vinorelbine administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75-80 mg/m² intravenously on Days 1 and 8 of each 21 -day dosing cycle and vinorelbine is administered at a dose of about 25-30 mg/m² on Days 1 and 8 of each 21 -day dosing cycle;

(vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle and etoposide is administered at a dose of about 100 mg/m² on Days 1 -3 of each 28-day dosing cycle;

(viii) carboplatin and paclitaxel administered in one or more 21 -day dosing cycles, wherein carboplatin is administered at AUC 6 intravenously on Day 1 of each 21 -day dosing cycle and paclitaxel is administered at a dose of about 200 mg/m² on Day 1 of each 21 -day dosing cycle;

(ix) carboplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21 -day dosing cycle; or

(x) carboplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21 -day dosing cycle.

17. The method of any one of claims 1 -16, wherein administration of the one or more dosing cycles of tiragolumab and atezolizumab is initiated within ten weeks of the last administered dose of the adjuvant chemotherapy.

18. The method of any one of claims 1 -17, wherein the subject has not experienced recurrence of the NSCLC following the complete resection.

19. The method of any one of claims 1 -18, wherein the subject has not experienced recurrence of the NSCLC following the adjuvant chemotherapy.

20. The method of any one of claims 1 -19, wherein the method comprises administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.

21 . The method of any one of claims 1 -20, wherein the method comprises administering to the subject tiragolumab at a fixed dose of about 840 mg every four weeks.

22. The method of any one of claims 1 -21 , wherein the length of each of the one or more dosing cycles of tiragolumab and atezolizumab is 28 days.

23. The method of claim 22, wherein the method comprises administering to the subject atezolizumab on about Day 1 of each 28-day dosing cycle.

24. The method of claim 22 or 23, wherein the method comprises administering to the subject tiragolumab on about Day 1 of each 28-day dosing cycle.

25. The method of any one of claims 1 -24, wherein the method comprises co-administering to the subject atezolizumab and tiragolumab.

26. The method of claim 25, wherein the method comprises co-administering to the subject atezolizumab and tiragolumab by intravenous co-infusion.

27. The method of claim 26, wherein atezolizumab and tiragolumab are formulated together and are administered intravenously as a fixed dose combination (FDC).

28. The method of any one of claims 1 -24, wherein the method comprises administering to the subject atezolizumab before tiragolumab.

29. The method of any one of claims 1 -24, wherein the method comprises administering to the subject tiragolumab before atezolizumab.

30. The method of claim 28 or 29, wherein the method comprises administering to the subject tiragolumab and atezolizumab intravenously.

31 . The method of any one of claims 1 -30, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

32. The method of claim 31 , wherein NSCLC staging is per the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8^th edition.

33. The method of any one of claims 1 -32, wherein the NSCLC is squamous NSCLC.

34. The method of any one of claims 1 -32, wherein the NSCLC is non-squamous NSCLC.

35. The method of any one of claims 1 -34, wherein the PD-L1 -positive tumor cell fraction of a tumor sample obtained from the subject has been determined by an immunohistochemical (IHC) assay.

36. The method of claim 35, 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, 22C3, SP142, or 28-8.

37. The method of claim 36, wherein the PD-L1 -positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28- 8 IHC assay.

38. The method of any one of claims 35-37, wherein the PD-L1 -positive tumor cell fraction has been determined using a Ventana SP263 IHC assay.

39. The method of claim 38, wherein the tumor sample obtained from the subject has been determined to have a percentage of tumor cells with any membrane staining above background (TC) of equal to or greater than 1%.

40. The method of claim 39, wherein the tumor sample obtained from the subject has been determined to have a TC of equal to or greater than 50%.

41 . The method of any one of claims 1 -40, wherein the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.

42. The method of any one of claims 1 -33 and 35-40, wherein the subject has a squamous NSCLC and has not been assessed for an EGFR or ALK genomic tumor aberration.

43. The method of any one of claims 1 -42, wherein the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.

44. The method of any one of claims 1 -43, wherein up to 13 dosing cycles of tiragolumab and atezolizumab are administered to the subject.

45. The method of any one of claims 1 -44, wherein dosing cycles of tiragolumab and atezolizumab are administered to the subject for up to one year.

46. The method of any one of claims 1 -45, wherein the treating results in an increase in the duration of disease-free survival (DFS) as compared to a reference DFS duration.

47. The method of claim 46, wherein the reference DFS duration is the mean or median DFS duration of a population of subjects who have received a control treatment.

48. The method of any one of claims 1 -47, wherein the treating results in an increase in the duration of overall survival (OS) as compared to a reference OS duration.

49. The method of claim 48, wherein the reference OS duration is the mean or median OS duration of a population of subjects who have received a control treatment.

50. The method of any one of claims 1 -49, wherein the treating results in an increase in the DFS rate as compared to a reference DFS rate.

51 . The method of claim 50, wherein the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7- year DFS rate.

52. The method of claim 50 or 51 , wherein the reference DFS rate is the DFS rate of a population of subjects who have received a control treatment.

53. The method of any one of claims 47, 49, and 52, wherein the control treatment is atezolizumab monotherapy.

54. A method of treating a subject having an NSCLC, the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

55. A method of treating a subject having an NSCLC, the method comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

56. The method of any one of claims 1 -55, wherein the subject is a human.

57. Use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.

58. Use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.

59. The use of claim 57 or 58, wherein the complete resection was a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy.

60. The use of any one of claims 57-59, wherein the complete resection was a resection resulting in (i) no residual tumor and (ii) all surgical margins negative for invasive carcinoma.

61 . The use of any one of claims 57, 59, and 60, wherein the subject has received between one and four dosing cycles of the adjuvant chemotherapy.

62. The use of claim 61 , wherein the subject has received four dosing cycles of the adjuvant chemotherapy.

63. The use of any one of claims 57-60, wherein between one and four dosing cycles of the adjuvant chemotherapy are to be administered to the subject.

64. The use of claim 63, wherein four dosing cycles of the adjuvant chemotherapy are to be administered to the subject.

65. The use of any one of claims 57-64, wherein the adjuvant chemotherapy is a platinum-based adjuvant chemotherapy.

66. The use of claim 65, wherein the platinum-based adjuvant chemotherapy comprises cisplatin.

67. The use of claim 65, wherein the platinum-based adjuvant chemotherapy comprises carboplatin.

68. The use of any one of claims 65-67, wherein the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents.

69. The use of claim 68, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.

70. The use of claim 69, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.

71 . The use of claim 65, wherein the platinum-based adjuvant chemotherapy is a platinum-based adjuvant doublet chemotherapy.

72. The use of claim 71 , wherein the platinum-based adjuvant doublet chemotherapy comprises:

(i) cisplatin and pemetrexed administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and pemetrexed is to be administered at a dose of about 500 mg/m² on Day 1 of each 21 -day dosing cycle;

(ii) cisplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is to be administered at a dose of about 1250 mg/m² on Days 1 and 8 of each 21 -day dosing cycle;

(Hi) cisplatin and docetaxel administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and docetaxel is to be administered at a dose of about 75 mg/m² on Day 1 of each 21 -day dosing cycle;

(iv) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is to be administered at a dose of about 50 mg/m² intravenously on Days 1 and 8 of each 28-day dosing cycle and vinorelbine is to be administered at a dose of about 25 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle;

(v) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is to be administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle and vinorelbine is to be administered at a dose of about 30 mg/m² on Days 1 , 8, 15, and 22 of each 28-day dosing cycle;

(vi) cisplatin and vinorelbine administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75-80 mg/m² intravenously on Days 1 and 8 of each 21 -day dosing cycle and vinorelbine is to be administered at a dose of about 25-30 mg/m² on Days 1 and 8 of each 21 - day dosing cycle;

(vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is to be administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle and etoposide is to be administered at a dose of about 100 mg/m² on Days 1 -3 of each 28-day dosing cycle; (viii) carboplatin and paclitaxel administered in one or more 21 -day dosing cycles, wherein carboplatin is to be administered at AUC 6 intravenously on Day 1 of each 21 -day dosing cycle and paclitaxel is to be administered at a dose of about 200 mg/m² on Day 1 of each 21 -day dosing cycle;

(ix) carboplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein carboplatin is to be administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is to be administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21 -day dosing cycle; or

(x) carboplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein carboplatin is to be administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle and pemetrexed is to be administered at a dose of about 500 mg/m² on Day 1 of each 21 -day dosing cycle.

73. The use of any one of claims 57-72, wherein administration of the one or more dosing cycles of tiragolumab and atezolizumab is to be initiated within ten weeks of the last administered dose of the adjuvant chemotherapy.

74. The use of any one of claims 57-73, wherein the subject has not experienced recurrence of the NSCLC following the complete resection.

75. The use of any one of claims 57-74, wherein the subject has not experienced recurrence of the NSCLC following the adjuvant chemotherapy.

76. The use of any one of claims 57-75, wherein atezolizumab is to be administered at a fixed dose of about 1680 mg every four weeks.

77. The use of any one of claims 57-76, wherein tiragolumab is to be administered at a fixed dose of about 840 mg every four weeks.

78. The use of any one of claims 57-77, wherein the length of each of the one or more dosing cycles of tiragolumab and atezolizumab is 28 days.

79. The use of claim 78, wherein atezolizumab is to be administered to the subject on about Day 1 of each 28-day dosing cycle.

80. The use of claim 78 or 79, wherein tiragolumab is to be administered to the subject on about Day 1 of each 28-day dosing cycle.

81 . The use of any one of claims 57-80, wherein atezolizumab and tiragolumab are to be coadministered to the subject.

82. The use of claim 81 , wherein atezolizumab and tiragolumab are to be co-administered to the subject by intravenous co-infusion.

83. The use of claim 82, wherein atezolizumab and tiragolumab are to be formulated together and administered intravenously as a fixed dose combination (FDC).

84. The use of any one of claims 57-80, wherein atezolizumab is to be administered to the subject before tiragolumab.

85. The use of any one of claims 57-80, wherein tiragolumab is to be administered to the subject before atezolizumab.

86. The use of claim 84 or 85, wherein tiragolumab and atezolizumab are to be administered to the subject intravenously.

87. The use of any one of claims 57-86, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

88. The use of claim 87, wherein NSCLC staging is per the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8^th edition.

89. The use of any one of claims 1 -88, wherein the NSCLC is squamous NSCLC.

90. The use of any one of claims 1 -88, wherein the NSCLC is non-squamous NSCLC.

91 . The use of any one of claims 1 -90, wherein the PD-L1 -positive tumor cell fraction of a tumor sample obtained from the subject has been determined by an immunohistochemical (IHC) assay.

92. The use of claim 91 , 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, 22C3, SP142, or 28-8.

93. The use of claim 92, wherein the PD-L1 -positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay.

94. The use of any one of claims 91 -93, wherein the PD-L1 -positive tumor cell fraction has been determined using a Ventana SP263 IHC assay.

95. The use of claim 94, wherein the tumor sample obtained from the subject has been determined to have a percentage of tumor cells with any membrane staining above background (TC) of equal to or greater than 1%.

96. The use of claim 95, wherein the tumor sample obtained from the subject has been determined to have a TC of equal to or greater than 50%.

97. The use of any one of claims 57-96, wherein the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.

98. The use of any one of claims 57-89 and 91 -97, wherein the subject has a squamous NSCLC and has not been assessed for an EGFR or ALK genomic tumor aberration.

99. The use of any one of claims 57-98, wherein the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.

100. The use of any one of claims 57-99, wherein up to 13 dosing cycles of tiragolumab and atezolizumab are to be administered to the subject.

101 . The use of any one of claims 57-100, wherein dosing cycles of tiragolumab and atezolizumab are to be administered to the subject for up to one year.

102. The use of any one of claims 57-101 , wherein the treatment results in an increase in the duration of disease-free survival (DFS) as compared to a reference DFS duration.

103. The use of claim 102, wherein the reference DFS duration is the mean or median DFS duration of a population of subjects who have received a control treatment.

104. The use of any one of claims 57-103, wherein the treatment results in an increase in the duration of overall survival (OS) as compared to a reference OS duration.

105. The use of claim 104, wherein the reference OS duration is the mean or median OS duration of a population of subjects who have received a control treatment.

106. The use of any one of claims 57-105, wherein the treatment results in an increase in the DFS rate as compared to a reference DFS rate.

107. The use of claim 106, wherein the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.

108. The use of claim 106 or 107, wherein the reference DFS rate is the DFS rate of a population of subjects who have received a control treatment.

109. The use of any one of claims 103, 105, and 108, wherein the control treatment is atezolizumab monotherapy.

1 10. Use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

1 1 1 . Use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

1 12. The use of any one of claims 57-1 1 1 , wherein the subject is a human.

1 13. Tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.

1 14. Tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.

1 15. The tiragolumab and/or atezolizumab for use of claim 1 13 or 114, wherein the complete resection was a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy.

1 16. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-115, wherein the complete resection was a resection resulting in (i) no residual tumor and (ii) all surgical margins negative for invasive carcinoma.

1 17. The tiragolumab and/or atezolizumab for use of any one of claims 1 13, 1 14, and 1 16, wherein the subject has received between one and four dosing cycles of the adjuvant chemotherapy.

1 18. The tiragolumab and/or atezolizumab for use of claim 1 17, wherein the subject has received four dosing cycles of the adjuvant chemotherapy.

1 19. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-116, wherein between one and four dosing cycles of the adjuvant chemotherapy are to be administered to the subject.

120. The tiragolumab and/or atezolizumab for use of claim 1 19, wherein four dosing cycles of the adjuvant chemotherapy are to be administered to the subject.

121 . The tiragolumab and/or atezolizumab for use of any one of claims 1 13-120, wherein the adjuvant chemotherapy is a platinum-based adjuvant chemotherapy.

122. The tiragolumab and/or atezolizumab for use of claim 121 , wherein the platinum-based adjuvant chemotherapy comprises cisplatin.

123. The tiragolumab and/or atezolizumab for use of claim 121 , wherein the platinum-based adjuvant chemotherapy comprises carboplatin.

124. The tiragolumab and/or atezolizumab for use of any one of claims 120-123, wherein the platinumbased adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents.

125. The tiragolumab and/or atezolizumab for use of claim 124, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.

126. The tiragolumab and/or atezolizumab for use of claim 125, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.

127. The tiragolumab and/or atezolizumab for use of claim 121 , wherein the platinum-based adjuvant chemotherapy is a platinum-based adjuvant doublet chemotherapy.

128. The tiragolumab and/or atezolizumab for use of claim 127, wherein the platinum-based adjuvant doublet chemotherapy comprises:

(ii) cisplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is to be administered at a dose of about 1250 mg/m² on Days 1 and 8 of each 21 -day dosing cycle; (iii) cisplatin and docetaxel administered in one or more 21 -day dosing cycles, wherein cisplatin is to be administered at a dose of about 75 mg/m² intravenously on Day 1 of each 21 -day dosing cycle and docetaxel is to be administered at a dose of about 75 mg/m² on Day 1 of each 21 -day dosing cycle;

(vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is to be administered at a dose of about 100 mg/m² intravenously on Day 1 of each 28-day dosing cycle and etoposide is to be administered at a dose of about 100 mg/m² on Days 1 -3 of each 28-day dosing cycle;

(viii) carboplatin and paclitaxel administered in one or more 21 -day dosing cycles, wherein carboplatin is to be administered at AUC 6 intravenously on Day 1 of each 21 -day dosing cycle and paclitaxel is to be administered at a dose of about 200 mg/m² on Day 1 of each 21 -day dosing cycle;

129. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-128, wherein administration of the one or more dosing cycles of tiragolumab and atezolizumab is to be initiated within ten weeks of the last administered dose of the adjuvant chemotherapy.

130. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-129, wherein the subject has not experienced recurrence of the NSCLC following the complete resection.

131 . The tiragolumab and/or atezolizumab for use of any one of claims 1 13-130, wherein the subject has not experienced recurrence of the NSCLC following the adjuvant chemotherapy.

132. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-131 , wherein atezolizumab is to be administered at a fixed dose of about 1680 mg every four weeks.

133. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-132, wherein tiragolumab is to be administered at a fixed dose of about 840 mg every four weeks.

134. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-133, wherein the length of each of the one or more dosing cycles of tiragolumab and atezolizumab is 28 days.

135. The tiragolumab and/or atezolizumab for use of claim 134, wherein atezolizumab is to be administered to the subject on about Day 1 of each 28-day dosing cycle.

136. The tiragolumab and/or atezolizumab for use of claim 134 or 135, wherein tiragolumab is to be administered to the subject on about Day 1 of each 28-day dosing cycle.

137. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-136, wherein atezolizumab and tiragolumab are to be co-administered to the subject.

138. The tiragolumab and/or atezolizumab for use of claim 137, wherein atezolizumab and tiragolumab are to be co-administered to the subject by intravenous co-infusion.

139. The tiragolumab and/or atezolizumab for use of claim 138, wherein atezolizumab and tiragolumab are to be formulated together and administered intravenously as a fixed dose combination (FDC).

140. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-136, wherein atezolizumab is to be administered to the subject before tiragolumab.

141 . The tiragolumab and/or atezolizumab for use of any one of claims 1 13-136, wherein tiragolumab is to be administered to the subject before atezolizumab.

142. The tiragolumab and/or atezolizumab for use of claim 140 or 141 , wherein tiragolumab and atezolizumab are to be administered to the subject intravenously.

143. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-142, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

144. The tiragolumab and/or atezolizumab for use of claim 143, wherein NSCLC staging is per the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8^th edition.

145. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-144, wherein the NSCLC is squamous NSCLC.

146. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-144, wherein the NSCLC is non-squamous NSCLC.

147. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-146, wherein the PD-L1 - positive tumor cell fraction of a tumor sample obtained from the subject has been determined by an immunohistochemical (IHC) assay.

148. The tiragolumab and/or atezolizumab for use of claim 147, 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, 22C3, SP142, or 28-8.

149. The tiragolumab and/or atezolizumab for use of claim 148, wherein the PD-L1 -positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay.

150. The tiragolumab and/or atezolizumab for use of any one of claims 147-149, wherein the PD-L1 - positive tumor cell fraction has been determined using a Ventana SP263 IHC assay.

151 . The tiragolumab and/or atezolizumab for use of claim 150, wherein the tumor sample obtained from the subject has been determined to have a percentage of tumor cells with any membrane staining above background (TC) of equal to or greater than 1 %.

152. The tiragolumab and/or atezolizumab for use of claim 151 , wherein the tumor sample obtained from the subject has been determined to have a TC of equal to or greater than 50%.

153. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-152, wherein the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.

154. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-145 and 147-153, wherein the subject has a squamous NSCLC and has not been assessed for an EGFR or ALK genomic tumor aberration.

155. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-154, wherein the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.

156. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-155, wherein up to 13 dosing cycles of tiragolumab and atezolizumab are to be administered to the subject.

157. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-156, wherein dosing cycles of tiragolumab and atezolizumab are to be administered to the subject for up to one year.

158. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-157, wherein the treating results in an increase in the duration of disease-free survival (DFS) as compared to a reference DFS duration.

159. The tiragolumab and/or atezolizumab for use of claim 158, wherein the reference DFS duration is the mean or median DFS duration of a population of subjects who have received a control treatment.

160. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-159, wherein the treating results in an increase in the duration of overall survival (OS) as compared to a reference OS duration.

161 . The tiragolumab and/or atezolizumab for use of claim 160, wherein the reference OS duration is the mean or median OS duration of a population of subjects who have received a control treatment.

162. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-161 , wherein the treating results in an increase in the DFS rate as compared to a reference DFS rate.

163. The tiragolumab and/or atezolizumab for use of claim 162, wherein the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.

164. The tiragolumab and/or atezolizumab for use of claim 162 or 163, wherein the reference DFS rate is the DFS rate of a population of subjects who have received a control treatment.

165. The tiragolumab and/or atezolizumab for use of any one of claims 159, 161 , and 164, wherein the control treatment is atezolizumab monotherapy.

166. Tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

167. Tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:

(a) a Stage IIB NSCLC;

(b) a Stage IIIA NSCLC; or

(c) a T3N2 Stage IIIB NSCLC.

168. The tiragolumab and/or atezolizumab for use of any one of claims 1 13-167, wherein the subject is a human.