A Study of Tiragolumab in Combination With Atezolizumab Plus Pemetrexed and Carboplatin/Cisplatin Versus Pembrolizumab Plus Pemetrexed and Carboplatin/Cisplatin in Participants With Previously Untreated Advanced Non-Squamous Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of tiragolumab in combination with atezolizumab plus pemetrexed and carboplatin/cisplatin (Arm A) compared with placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin (Arm B) in participants with previously untreated, locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC). Eligible participants will be randomized in a 1:1 ratio to receive one of the following treatment regimens during the induction phase: Arm A: Tiragolumab plus atezolizumab plus pemetrexed and carboplatin or cisplatin Arm B: Placebo plus pembrolizumab plus pemetrexed and carboplatin or cisplatin Following the induction phase, participants 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).

Official Title
-----------------
A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study of Tiragolumab in Combination With Atezolizumab Plus Pemetrexed and Carboplatin/Cisplatin Versus Pembrolizumab Plus Pemetrexed and Carboplatin/Cisplatin in Patients With Previously Untreated Advanced Non-Squamous Non-Small-Cell Lung Cancer

Conditions
-----------------
Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
-----------------
* Drug: Tiragolumab
* Drug: Atezolizumab
* Drug: Pemetrexed
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Tiragolumab Matching Placebo
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy No prior systemic treatment for metastatic non-squamous NSCLC Known tumor programmed death-ligand 1 (PD-L1) status Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) Life expectancy >= 12 weeks Adequate hematologic and end-organ function Negative human immunodeficiency virus (HIV) test at screening Serology test negative for active hepatitis B virus or active hepatitis C virus at screening. Key Exclusion Criteria: Mutations in epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene Pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis History of malignancy other than NSCLC within 5 years prior to randomization, with the exception of malignancies with a negligible risk of metastasis or death Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety 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-cytotoxic T lymphocyte-associated protein 4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment Known allergy or hypersensitivity or other contraindication to any component of the chemotherapy regimen the participant may receive during the study Women who are pregnant, or breastfeeding Known targetable c-ROS oncogene 1 (ROS1) or BRAFV600E genomic aberration.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiragolumab+Atezolizumab+Pemetrexed+Carboplatin or Cisplatin<br>Induction treatment with tiragolumab in combination with atezolizumab plus pemetrexed and cisplatin or carboplatin will be administered to participants on Day 1 of each 21-day cycle for 4 cycles. Following the induction phase, participants will continue maintenance therapy with tiragolumab in combination with atezolizumab and pemetrexed on Day 1 of each 21-day cycle. | Drug: Tiragolumab<br>* Tiragolumab at a fixed dose of 600 milligrams (mg), administered by intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21-day cycle.<br>* Other names: MTIG7192A;Drug: Atezolizumab<br>* Atezolizumab at a fixed dose of 1200 mg, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Pemetrexed<br>* Pemetrexed 500 milligrams per square meter (mg/m^2), administered by IV infusion, Q3W on Day 1 of each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin at dose of area under the concentration-time curve (AUC) of 5, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.<br>|
| Placebo Comparator: Placebo+Pembrolizumab+Pemetrexed+Carboplatin or Cisplatin<br>Induction treatment with placebo in combination with pembrolizumab plus pemetrexed and cisplatin or carboplatin will be administered to participants on Day 1 of each 21-day cycle for 4 cycles. Following the induction phase, participants will continue maintenance therapy with placebo in combination with pembrolizumab and pemetrexed on Day 1 of each 21-day cycle. | Drug: Pemetrexed<br>* Pemetrexed 500 milligrams per square meter (mg/m^2), administered by IV infusion, Q3W on Day 1 of each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin at dose of area under the concentration-time curve (AUC) of 5, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2, administered by IV infusion, Q3W on Day 1 of each 21-day cycle for 4 cycles.<br>Drug: Tiragolumab Matching Placebo<br>* Matching placebo, administered by IV infusion, Q3W on Day 1 of each 21-day cycle.<br>Drug: Pembrolizumab<br>* Pembrolizumab at a fixed dose of 200 mg, administered by IV infusion, Q3W, on Day 1 of each 21-day cycle.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-Assessed Confirmed Objective Response Rate (ORR) (Phase 2) |  | Up to approximately 5 years | 
| Investigator-Assessed Progression-Free Survival (PFS) (Phase 2 and Phase 3) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 5 years [Phase 2], up to approximately 7 years [Phase 3]) | 
| Overall Survival (Phase 3) |  | From randomization to death from any cause (up to approximately 7 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Phase 2) |  | From randomization to death from any cause (up to approximately 5 years) | 
| PFS as Determined by an Independent Review Facility (IRF) (Phase 3) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 7 years) | 
| Investigator-assessed PFS in Participants With PD-L1 Expression at TC ≥50% and TC ≥1% Cut-off, as Determined by Central Testing With Ventana PD-L1 (SP263) Assay (Phase 3) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 7 years) | 
| OS in Participants With PD-L1 Expression at TC ≥50% and TC ≥1% Cut-off, as Determined by Central Testing With Ventana PD-L1 (SP263) Assay (Phase 3) |  | From randomization to death from any cause (up to approximately 7 years) | 
| Investigator-Assessed PFS at 6 Months and 12 Months (Phase 3) |  | 6 months, 12 months | 
| OS Rate at 12 Months and 24 Months (Phase 3) |  | 12 months, 24 months | 
| Investigator-Assessed Confirmed ORR (Phase 3) |  | Up to approximately 7 years | 
| Investigator-Assessed Duration of Response (DOR) (Phase 2 and Phase 3) |  | From first occurrence of a documented confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 5 years [Phase 2]; up to approximately 7 years [Phase 3]) | 
| Time to Confirmed Deterioration (TTCD) in Participant-Reported Physical Functioning and Global Health Status (GHS)/Quality of Life (QoL) as Measured by European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (Phase 2 and Phase 3) | TTCD using EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30) is an initial 10-point decrease in GHS and physical functioning from baseline that must be held for at least two consecutive assessments or an initial clinically meaningful decrease above baseline followed by death. EORTC QLQ-C30: a self-reported measure, consisting of 30 questions that assess 5 aspects of participants functioning (physical, emotional, role, cognitive and social), 3 symptom scales (fatigue, nausea/vomiting and pain), GHS and QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) with a recall period of the previous week. Functioning items are scored on a 4-point scale: 1=Not at all to 4=Very much, with higher score indicating worse outcome. Symptom items (GHS and QoL) are scored on a 7-point scale: 1=Very poor to 7=Excellent. Scores will be linearly transformed with a minimum score of 0 and maximum score of 100. Higher score indicates better outcome. | Up to approximately 5 years (Phase 2); up to approximately 7 years (Phase 3) | 
| TTCD in Participant-Reported Lung Cancer Symptoms for Cough, Dyspnea, and Chest Pain, as Measured by EORTC QLQ-LC13 (Phase 2 and Phase 3) | TTCD using EORTC Quality-of-Life Questionnaire Lung Cancer Module (QLQ-LC13) is an initial 10-point increase in symptom score from baseline that must be held for at least two consecutive assessments or an initial clinically meaningful decrease above baseline followed by death. EORTC QLQ-LC13 consists of 13 lung cancer specific items and includes 11 disease-specific scales/items (dyspnea, coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, pain in other parts, pain medication). Each item is scored on a 4-point scale of 1=Not at all to 4=Very much. Scores will be linearly transformed to a score range of 0 to 100. Higher score indicates worsening of symptoms. | Up to approximately 5 years (Phase 2); up to approximately 7 years (Phase 3) | 
| Percentage of Participants With Adverse Events (AEs) (Phase 2 and Phase 3) |  | Up to approximately 5 years (Phase 2); up to approximately 7 years (Phase 3) | 
| Participants' Response to Side Effects of Treatment as Assessed by EORTC IL46 (Phase 2 and Phase 3) | EORTC Item List 46 (IL46) is a validated single-item question that assesses overall side effect impact. Each item is scored on a 4-point scale of 1=Not at all to 4=Very much. Scores will be linearly transformed to a score range of 0 to 100. Higher score indicates a worse outcome. | Up to approximately 5 years (Phase 2); up to approximately 7 years (Phase 3) | 
| Serum Concentration of Tiragolumab (Phase 2 and Phase 3) |  | Cycle 1 (each cycle=21 days), Day 1: predose, 0.5 hour (h) postdose; Cycles 2, 3, 4, 8, 12, 16, Day 1: predose and at treatment discontinuation (TD) visit (up to approximately 5 years [Phase 2]; up to approximately 7 years [Phase 3]) | 
| Serum Concentration of Atezolizumab (Phase 2 and Phase 3) |  | Cycle 1 (each cycle=21 days), Day 1: predose, 0.5 hour (h) postdose; Cycles 2, 3, 4, 8, 12, 16, Day 1: predose and at TD visit (up to approximately 5 years [Phase 2]; up to approximately 7 years [Phase 3]) | 
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Tiragolumab (Phase 2 and Phase 3) |  | Predose on Day 1 of Cycles (each cycle=21 days) 1, 2, 3, 4, 8, 12, 16 and at TD visit (up to approximately 5 years [Phase 2]; up to approximately 7 years [Phase 3]) | 
| Percentage of Participants With ADAs to Atezolizumab (Phase 2 and Phase 3) |  | Predose on Day 1 of Cycles (each cycle=21 days) 1, 2, 3, 4, 8, 12, 16 and at TD visit (up to approximately 5 years [Phase 2]; up to approximately 7 years [Phase 3]) |