This is a randomized, Phase II/III, global, multicenter, double-blind study designed to evaluate the efficacy and safety of tiragolumab in combination with atezolizumab plus pemetrexed and carboplatin/cisplatin compared with placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin in patients with previously untreated, locally advanced unresectable or metastatic non-squamous NSCLC.

PROTOCOL NUMBER: BO42592

The selection of carboplatin or cisplatin is per investigator’s choice. The choice of carboplatin or cisplatin should be made prior to randomization and cannot be changed after Day 1 of Cycle 1. Previously untreated male and female patients age  18 years with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 who have locally advanced unresectable or metastatic non-squamous NSCLC, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic aberrations, are eligible.

After providing informed consent, patients will undergo screening procedures as outlined in the Schedule of Activities. Patients who do not meet the criteria for participation in this study (screen failure) may qualify for 1 re-screening opportunity (for a total of 2 screenings per participant) at the investigator's discretion. Patients are not required to re-sign the Consent Form if they are re-screened within 60 days after previously signing the Consent Form. For patients who are rescreened, all eligibility criteria must be re-evaluated and the screening assessment should be repeated as applicable to meet eligibility criteria. The investigator will record reasons for screen failure in the screening log.

Patients whose tumors have a known EGFR or ALK rearrangement will be excluded from the study. Patients with tumors with unknown EGFR or ALK mutational status will be required to be tested prior to enrollment.

To enable an adequate representation of all PD-L1 expression subgroups (tumor proportion score [TPS]/tumor cell [TC]  1%, 1%49%, and  50%) and reflect natural distribution of PD-L1 expression observed in patients with 1L NSCLC, the proportion of patients enrolled into each PD-L1 subgroup will be capped at approximately 40% of the total planned enrollment) per central testing with an investigational VENTANA PD-L1 (SP263) Companion Diagnostic (CDx) Assay (e.g., approximately 80 patients during Phase II enrollment and approximately 200 patients if expansion to Phase III is ungated). To account for differences in local and central results, selective enrollment based on local PD-L1 status will be implemented if enrollment into a subgroup, as defined by central results, is on a trajectory to exceed the cap limits.

Induction treatment with tiragolumab in combination with atezolizumab plus pemetrexed and cisplatin/carboplatin (Arm A) or placebo in combination with pembrolizumab plus pemetrexed and cisplatin/carboplatin (Arm B) will be administered on a 21-day cycle for 4 cycles. Following the induction phase, patients will continue maintenance therapy with either tiragolumab in combination with atezolizumab and pemetrexed (Arm A) or placebo in combination with pembrolizumab and pemetrexed (Arm B).

A safety review of unblinded data will be performed by an independent Data Monitoring Committee (iDMC) after approximately 6 months from the time of randomization of the first patient. Subsequent iDMC safety reviews will occur approximately every 6 months thereafter until the study data are unblinded or the study is terminated by the Sponsor. Patients will undergo tumor assessment at baseline and every 6 weeks ( 7 days) for 48 weeks following Cycle 1, Day 1, regardless of treatment dose delays. After completion of the Week 48 tumor assessment, tumor assessments will be required every 9 weeks ( 7 days) thereafter, regardless of dose delays, until radiographic disease progression per RECIST v1.1, withdrawal of consent, study termination by Sponsor, or death, whichever occurs first. Patients who are treated beyond disease progression per RECIST v1.1 will undergo tumor assessments every 6 weeks ( 2 weeks) after initial documentation of progression, or more frequently if clinically indicated, regardless of time on study, until treatment is discontinued. Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments at the same frequency as would have been followed if the patient had remained on study treatment (i.e., every 6 weeks [  7 days] for 48 weeks following Cycle 1, Day 1, and then every 9 weeks [  7 days] thereafter, until radiographic disease progression per RECIST v1.1, withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first), regardless of whether the patient starts a new anti-cancer therapy. All primary imaging data used for tumor assessments will be collected by the Sponsor. A centralized, blinded review of responses and endpoints by an independent review facility (IRF) may be conducted.

Patients randomized during the Phase II part of the study will be asked to complete PRO questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL46) during treatment until study treatment discontinuation, and at the study treatment discontinuation visit. If Phase III expansion is ungated, patients randomized after the gating decision will be asked to complete PRO questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13, EORTC IL46, and EQ-5D-5L) during treatment, at the study treatment discontinuation visit, and during survival follow-up.

Safety assessments at study visits will include the incidence, nature, and severity of adverse events, protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified tests that are deemed critical to the safety evaluation of the study. During the study, serum samples will be collected to monitor tiragolumab and atezolizumab pharmacokinetics and to detect the presence of antibodies to tiragolumab and atezolizumab. Patient samples, including archival and fresh tumor tissue, serum, plasma, and blood samples will also be collected for exploratory biomarker assessments.

During the study, patients who meet criteria for disease progression per RECIST v1.1 and show evidence of clinical benefit may continue treatment with tiragolumab/placebo and atezolizumab/pembrolizumab at the investigator’s discretion, provided that the patients meet all of the following criteria:

• Evidence of clinical benefit, as assessed by the investigator

• Absence of symptoms and signs (including worsening of laboratory values [e.g., new or worsening hypercalcemia]) indicating unequivocal progression of disease

• No decline in ECOG Performance Status that can be attributed to disease progression

• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical interventions

• Patients must provide written informed consent to acknowledge deferring other treatment options in favor of continuing study treatment at the time of initial radiographic progression per RECIST v1.1

Treatment will be discontinued if clinical deterioration due to disease progression occurs at any time, or if disease progression is confirmed on the follow-up scans performed 4 8 weeks later. Investigator assessment of overall tumor response at all timepoints will be based only on RECIST v1.1.

Approximately 200 patients will be enrolled in the Phase II part of the study. After patients enrolled in the Phase II part of the study have undergone at least two postbaseline tumor assessments (approximately 3 months after the last patient of the Phase II part is enrolled), an interim analysis for efficacy will be conducted by the iDMC. Following the interim efficacy data review, the iDMC will provide a recommendation as to whether to ungate expansion of the Phase III part of the study. If the study is expanded to Phase III, additional patients will be enrolled so that the expanded Phase III study includes approximately 500 patients in total, and the Sponsor will remain blinded until the Phase III endpoints are evaluated.

During both the Phase II part and Phase III expansion of the study, eligible patients will be randomized 1:1 to receive tiragolumab in combination with atezolizumab plus pemetrexed and cisplatin/carboplatin (Arm A) or placebo in combination with pembrolizumab plus pemetrexed and cisplatin/carboplatin (Arm B). The randomization scheme is designed to ensure that an approximately equal number of patients will be enrolled in each treatment arm within the baseline characteristics of the following stratification factors:

• PD-L1 expression (TPS/TC  1% vs. 1%49% vs.  50% by local or central assay)

• Geographic region (Asia vs. Non-Asia)

• ECOG Performance Status (0 vs. 1)