A Study of Atezolizumab in Combination With Carboplatin Plus (+) Paclitaxel With or Without Bevacizumab Compared With Carboplatin+Paclitaxel+Bevacizumab in Participants With Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This randomized, open-label study evaluated the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin+paclitaxel with or without bevacizumab compared with treatment with carboplatin+paclitaxel+bevacizumab in chemotherapy-naïve participants with Stage IV non-squamous NSCLC. Participants were randomized in a 1:1:1 ratio to Arm A (Atezolizumab+Carboplatin+Paclitaxel), Arm B (Atezolizumab+Carboplatin+Paclitaxel+Bevacizumab), or Arm C (Carboplatin+Paclitaxel+Bevacizumab).

Official Title
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A Phase III, Open-Label, Randomized Study of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Paclitaxel With or Without Bevacizumab Compared With Carboplatin + Paclitaxel + Bevacizumab in Chemotherapy-Naïve Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
* Drug: Bevacizumab
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group performance status 0 or 1 Histologically or cytologically confirmed, Stage IV non-squamous NSCLC Participants with no prior treatment for Stage IV non-squamous NSCLC Known PD-L1 status as determined by immunohistochemistry assay performed on previously obtained archival tumor tissue or tissue obtained from a biopsy at screening Measurable disease as defined by RECIST v1.1 Adequate hematologic and end organ function Exclusion Criteria: Cancer-Specific Exclusions: Active or untreated central nervous system metastases Malignancies other than NSCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome General Medical Exclusions: Pregnant or lactating women History of autoimmune disease History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted Positive test for human immunodeficiency virus Active hepatitis B or hepatitis C Severe infection within 4 weeks prior to randomization Significant cardiovascular disease Illness or condition that interferes with the participant's capacity to understand, follow and/or comply with study procedures Exclusion Criteria Related to Medications: Prior treatment with cluster of differentiation 137 agonists or immune checkpoint blockade therapies, anti-programmed death-1, and anti-PD-L1 therapeutic antibodies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Atezolizumab+Paclitaxel+Carboplatin)<br>Participants received intravenous (IV) infusion of atezolizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit. | Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody<br>* Atezolizumab was administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle until loss of clinical benefit.<br>* Other names: Tecentriq;Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>Drug: Paclitaxel<br>* Paclitaxel was administered as IV infusion at a dose of 200 milligrams per square meter (mg/m^2) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>|
| Experimental: Arm B (Atezolizumab+Bevacizumab+Paclitaxel + Carboplatin)<br>Participants received IV infusion of atezolizumab and bevacizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of atezolizumab until loss of clinical benefit and bevacizumab until progressive disease, unacceptable toxicity, or death during maintenance treatment phase. | Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody<br>* Atezolizumab was administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle until loss of clinical benefit.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab was administered as IV infusion at a dose of 15 milligrams per kilogram (mg/kg) on Day 1 of each 21-day cycle until progressive disease, unacceptable toxicity, or death.<br>Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>Drug: Paclitaxel<br>* Paclitaxel was administered as IV infusion at a dose of 200 milligrams per square meter (mg/m^2) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>|
| Active Comparator: Arm C (Bevacizumab+Paclitaxel+Carboplatin)<br>Participants received IV infusion of bevacizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of bevacizumab during maintenance treatment phase until progressive disease, unacceptable toxicity, or death. | Drug: Bevacizumab<br>* Bevacizumab was administered as IV infusion at a dose of 15 milligrams per kilogram (mg/kg) on Day 1 of each 21-day cycle until progressive disease, unacceptable toxicity, or death.<br>Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>Drug: Paclitaxel<br>* Paclitaxel was administered as IV infusion at a dose of 200 milligrams per square meter (mg/m^2) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS), as Determined by the Investigator in Arm B Versus Arm C in the Teff-high WT Population and ITT-WT Population | Progression Free Survival (PFS), as Determined by the Investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Arm B versus Arm C in the T-effector (Teff)-high wild type (WT) population and the intent-to-treat (ITT)-WT population. | Baseline until disease progression or death, whichever occurs first until data cut-off on 15 September 2017 (up to approximately 29 months) | 
| Overall Survival (OS) in Arm B Versus Arm C in ITT-WT Population | Overall Survival (OS) in Arm B Versus Arm C in ITT-WT Population | Baseline until death until data cut-off on 22 January 2018 (up to approximately 34 months) | 
| Overall Survival (OS) in Arm A Versus Arm C in ITT-WT Population | Overall Survival (OS) in Arm A Versus Arm C in ITT-WT Population | Baseline until death (up approximately 53 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS, as Determined by the Independent Review Facility (IRF) in Arm B Versus Arm C in Teff-High-WT Population and ITT-WT Population | PFS, as determined by the independent review facility (IRF) Using RECIST v1.1 in Arm B versus Arm C in the T-effector (Teff)-high wild type (WT) population and the intent-to-treat (ITT)-WT population. | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| PFS, as Determined by the Investigator in Arm B Versus Arm C in Teff High Population and ITT Population | PFS, as determined by the investigator according to RECIST v1.1, in Arm B versus C in the Teff high population and ITT population. | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| PFS, as Determined by the Investigator in Arm A Versus Arm B in Teff High-WT Population and ITT-WT Population | PFS, as determined by the investigator according to RECIST v1.1, in Arm A versus B in the Teff high-WT population and ITT-WT population. | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| PFS, as Determined by the Investigator in Arm B Versus Arm C by PD-L1 Subgroup | PFS as Determined by the Investigator according to RECIST v1.1, in Arm B Versus Arm C by PD-L1 Subgroup: TC2/3 or 1C2/3 and TC1/2/3 or IC1/2/3 (ITT-WT Population) | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| OS in Arm B Versus Arm C by PD-L1 Subgroup | OS in Arm B Versus Arm C by PD-L1 Subgroup: TC2/3 or 1C2/3 and TC1/2/3 or IC1/2/3 (ITT-WT Population) | Baseline until death (up to approximately 34 months) | 
| OS in Arm A Versus Arm C by PD-L1 Subgroup | OS in Arm A Versus Arm C by PD-L1 Subgroup: TC2/3 or 1C2/3 and TC1/2/3 or IC1/2/3 (ITT-WT Population) | Baseline until death (up approximately 53 months) | 
| OS in Arm B Versus Arm C in Teff High-WT Population, Teff High Population, and ITT Population |  | Baseline until death (up to approximately 34 months) | 
| OS in Arm A Versus Arm C in Teff High-WT Population, Teff High Population, and ITT Population |  | Baseline until death (up approximately 53 months) | 
| OS in Arm A Versus Arm B in Teff High-WT Population and ITT-WT Population |  | Baseline until death (up approximately 53 months) | 
| Duration of Response (DOR), as Determined By Investigator in Arm B Versus Arm C | DOR, as determined by investigator according to RECIST v1.1 in Arm B versus Arm C in the Teff high-WT population and the ITT-WT population. | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator in the Teff-High-WT Population and ITT-WT Population | Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator using RECIST v1.1 in the Teff-High-WT population and ITT-WT population. | Baseline until disease progression or death, whichever occurs first (up to approximately 29 months) | 
| OS Rates at Years 1 and 2 in Arm B Versus Arm C | OS at 1- and 2-year landmark timepoints in Teff-high WT population and ITT-WT population. | Baseline to 2 years or death, whichever occurs first. | 
| OS Rates at Years 1 and 2 in Arm A Versus Arm C | OS at 1- and 2-year landmark timepoints in Teff-high WT population and ITT-WT population. | Baseline to 2 years or death, whichever occurs first. | 
| Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms Determined by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30) Score | EORTC QLQ-C30 is a validated & reliable self-report measure (Aaronson et al.1993;Fitzsimmons et al.1999) that consists of 30 questions that assess 5 aspects of patient functioning (physical,emotional,role, cognitive,and social), 3 symptom scales (fatigue,nausea & vomiting, pain),global health/quality of life,and six single items (dyspnea,insomnia, appetite loss,constipation,diarrhea, and financial difficulties). EORTC QLQ-C30 is scored according to the EORTC scoring manual (Fayers et al. 2001). All EORTC scales and single-item measures are linearly transformed so that each score has a range of 0-100. A high score for a functional/global health status scale represents a high or healthy level of functioning/HRQoL (Health-Related Quality of Life);however a high score for a symptom scale or item represents a high level of symptomatology or problems. A ≥10-point change in the symptoms subscale score is perceived by patients as clinically significant (Osoba et al.1998). | Baseline up to approximately 29 months | 
| TTD in Patient-Reported Lung Cancer Symptoms as Determined by EORTC Quality-of-Life Questionnaire-Core Lung Cancer Module 13 (QLQ-LC13) Score | QLQ-LC13 Quality-of-Life Questionnaire Lung Cancer Module incorporates one multiple-item scale to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. The EORTC QLQ-LC13 is scored according to the EORTC scoring manual (Fayers et al. 2001). All EORTC scales and single-item measures are linearly transformed so that each score has a range of 0-100. A high score for a functional/global health status scale represents a high or healthy level of functioning/HRQoL (Health-Related Quality of Life); however, a high score for a symptom scale or item represents a high level of symptomatology or problems. A ≥10-point change in the symptoms subscale score is perceived by patients as clinically significant (Osoba et al. 1998). | Baseline up to approximately 29 months | 
| Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale | The SILC (Symptoms in Lung Cancer) scale was used to assess patient-reported severity of lung cancer symptoms (chest pain, dyspnea, and cough). The SILC scale is a 9-item content validated self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, and chest pain with a symptom severity score. The SILC questionnaire comprises three individual symptoms (dyspnea, cough, chest pain) and are scored at the individual symptom level, thus have a dyspnea score, chest pain score, and cough score. Each individual symptom score is calculated as the average of responses for the symptom items [e.g. Chest Pain Score=mean (item 1; item 2)]. An increase in score is suggestive of a worsening in symptomology (i.e. frequency or severity). A score change of ≥0.3 points for the dyspnea and cough symptom scores is considered to be clinically significant; whereas a score change of ≥0.5 points for the chest pain score is considered to be clinically significant. | Baseline up to approximately 29 months | 
| Percentage of Participants With Adverse Events | Percentage of participants with at least one adverse event. | Baseline up to data cutoff date 7 December 2020 (up to approximately 68 months) | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab |  | Baseline up to approximately 29 months | 
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Arm A and Arm B | The predose samples will be collected on the same day of treatment administration. The infusion duration of atezolizumab will be of 30-60 minutes. | Day 1 of Cycle 1 and 3 (Cycle length=21 days) | 
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Arm A and Arm B |  | Day 21 of Cycles 1, 2 3, and 7 (Cycle length=21 days) | 
| Plasma Concentrations for Carboplatin in Arm A, Arm B, and Arm C |  | Predose (same day of treatment administration), 5-10 minutes before end of carboplatin infusion, 1 h after carboplatin infusion (infusion duration=15 to 30 minutes) on D1 of Cy1,3 (Cycle length=21 days) | 
| Plasma Concentrations for Paclitaxel in Arm A, Arm B, and Arm C |  | Predose (same day of treatment administration), 5-10 minutes before end of paclitaxel infusion, 1 h after paclitaxel infusion (infusion duration=3 h) on D1 of Cy1,3 (Cycle length=21 days) | 
| Cmax of Bevacizumab in Arm B and Arm C |  | Cycle 1 Day 1 and Cycle 3 Day 1 (Cycle length=21 days) | 
| Cmin of Bevacizumab in Arm B and Arm C |  | Cycle 1 Day 1 and Cycle 2 Day 21 (Cycle length=21 days) |