A Study of Atezolizumab and Tiragolumab Compared With Durvalumab in Participants With Locally Advanced, Unresectable Stage III Non-Small Cell Lung Cancer (NSCLC)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of atezolizumab in combination with tiragolumab compared with durvalumab in participants with locally advanced, unresectable Stage III non-small cell lung cancer (NSCLC) who have received at least two cycles of concurrent platinum-based chemoradiotherapy (CRT) and have not had radiographic disease progression.

Official Title
-----------------
A Phase III, Open-Label, Randomized Study of Atezolizumab and Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable Stage III Non-Small Cell Lung Cancer Who Have Not Progressed After Concurrent Platinum-Based Chemoradiation

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

Intervention / Treatment
-----------------
* Drug: Atezolizumab
* Drug: Tiragolumab
* Drug: Durvalumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Histologically or cytologically documented NSCLC with locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology Whole-body Positron Emission Tomography-Computed Tomography (PET-CT) scan, performed prior and within 42 days of the first dose of concurrent chemoradiotherapy (cCRT) At least two prior cycles of platinum-based chemotherapy administered concurrently with radiotherapy (RT), which must be completed within 1 to 42 days prior to randomization in the study (one cycle of cCRT is defined as 21 or 28 days) The radiotherapy (RT) component in the cCRT must have been at a total dose of radiation of 60 (±10 percent [%]) gray (Gy) (54 Gy to 66 Gy) administered by intensity modulated RT (preferred) or 3D-conforming technique No progression during or following concurrent platinum-based CRT A known PD-L1 result Life expectancy >/= 12 weeks Adequate hematologic and end-organ function Female participants must be willing to avoid pregnancy for 90 days after the final dose of tiragolumab and 5 months after the final dose of atezolizumab, or for 3 months after the final dose of durvalumab Male participants must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of tiragolumab Male participants must not donate sperm during the treatment period and for 90 days after the final dose of tiragolumab Exclusion Criteria: Any history of prior NSCLC and/or any history of prior treatment for NSCLC (participants must be newly diagnosed with unresectable Stage III disease) NSCLC known to have a mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene Any evidence of Stage IV disease Treatment with sequential CRT for locally advanced NSCLC Participants with locally advanced NSCLC who have progressed during or after the definitive cCRT prior to randomization Any Grade >2 unresolved toxicity from previous CRT Grade >= 2 pneumonitis from prior CRT 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 screening with the exception of malignancies with a negligible risk of metastasis or death Prior allogeneic stem cell or solid organ transplantation Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening 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-T-cell immunoreceptor with Ig and ITIM domains (anti-TIGIT), anti-PD-1 and anti-PD-L1 Any prior Grade >/= 3 immune-mediated adverse event or any unresolved Grade > 1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents Treatment with systemic immunosuppressive medication Women who are pregnant, or breastfeeding

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab + Tiragolumab<br>Participants will receive atezolizumab administered intravenously (IV) on Day 1 of each 28-day cycle followed by tiragolumab administered IV on Day 1 of each 28-day cycle for a maximum of 13 cycles. | Drug: Atezolizumab<br>* Atezolizumab 1680 mg every 4 weeks (Q4W) will be administered IV on Day 1 of each 28-day cycle.<br>* Other names: Tecentriq; RO5541267;Drug: Tiragolumab<br>* Tiragolumab 840 mg Q4W will be administered IV on Day 1 of each 28-day cycle.<br>* Other names: MTIG7192A; RO7092284;|
| Active Comparator: Durvalumab<br>Participants will receive durvalumab administered IV during each 28-day cycle for a maximum of 13 cycles. | Drug: Durvalumab<br>* Durvalumab will be administered based on weight at 10 mg/kg IV every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle, or will be administered at a fixed dose of 1500 mg IV every 4 weeks (Q4W) (for participants whose weight >/= 30 kg) on Day 1 of each 28-day cycle.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Independent Review Facility (IRF)-assessed Progression Free Survival (PFS) in the PD-L1-positive Analysis Set (PPAS) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 
| IRF-assessed PFS in the Full Analysis Set (FAS) |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the PPAS |  | From randomization to death from any cause (up to approximately 114 months) | 
| Investigator-assessed PFS in the PPAS |  | Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first first (up to approximately 114 months) | 
| IRF-assessed Confirmed Objective Response Rate (ORR) in the PPAS |  | From randomization up to approximately 114 months | 
| Investigator-assessed Confirmed ORR in the PPAS |  | From randomization up to approximately 114 months | 
| IRF-assessed Duration of Response (DOR) in the PPAS |  | From first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 
| Investigator-assessed DOR in the PPAS |  | From first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 
| Time to Confirmed Deterioration (TTCD) Assessed Using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core (QLQ-C30) Score in the PPAS | TTCD using EORTC QLQ-C30 is an initial 10-point decrease in global health status (GHS) and physical functioning from baseline that must be held for all subsequent assessment timepoints or followed by death attributable to cancer progression. 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 and vomiting and pain), GHS and quality of life (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 114 months | 
| OS in the FAS |  | From randomization to death from any cause (up to approximately 114 months) | 
| Investigator-assessed PFS in the FAS |  | Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first first (up to approximately 114 months) | 
| IRF-assessed Confirmed ORR in the FAS |  | From randomization up to approximately 114 months | 
| Investigator-assessed Confirmed ORR in the FAS |  | From randomization up to approximately 114 months | 
| IRF-assessed DOR in the FAS |  | From first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 
| Investigator-assessed DOR in the FAS |  | From first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 114 months) | 
| TTCD Assessed Using EORTC QLQ-C30 Score in the FAS | TTCD using EORTC QLQ-C30 is an initial 10-point decrease in global health status (GHS) and physical functioning from baseline that must be held for all subsequent assessment timepoints or followed by death attributable to cancer progression. 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 and vomiting and pain), GHS and quality of life (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 114 months | 
| IRF-assessed PFS Rates at 12 Months, 18 Months and 24 Months in the PPAS |  | 12, 18 and 24 months | 
| IRF-assessed PFS Rates at 12 Months, 18 Months and 24 Months in the FAS |  | 12, 18 and 24 months | 
| Investigator-assessed PFS Rates at 12 Months, 18 Months and 24 Months in the PPAS |  | 12, 18 and 24 months | 
| Investigator-assessed PFS Rates at 12 Months, 18 Months and 24 Months in the FAS |  | 12, 18 and 24 months | 
| OS Rates at 12 Months, 24 Months, 36 Months and 48 Months in the PPAS |  | 12, 24, 36 and 48 months | 
| OS Rates at 12 Months, 24 Months, 36 Months and 48 Months in the FAS |  | 12, 24, 36 and 48 months | 
| Investigator-assessed Time to Death or Distant Metastasis (TTDM) in the PPAS |  | From randomization until the first date of distant metastasis or death in the absence of distant metastasis (up to approximately 114 months) | 
| Investigator-assessed TTDM in the FAS |  | From randomization until the first date of distant metastasis or death in the absence of distant metastasis (up to approximately 114 months) | 
| Percentage of Participants With Adverse Events |  | Up to approximately 114 months |