A Study of Atezolizumab in Combination With Carboplatin Plus (+) Nab-Paclitaxel Compared With Carboplatin+Nab-Paclitaxel 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 Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin+nab-paclitaxel compared with treatment with carboplatin+nab-paclitaxel in chemotherapy-naive participants with Stage IV non-squamous NSCLC. Participants were randomized in a 2:1 ratio to Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) or Arm B (Nab-Paclitaxel+Carboplatin).

Official Title
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A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Squamous Non-Small Cell Lung

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group performance status of 0 or 1 Histologically or cytologically confirmed, Stage IV non-squamous NSCLC Participants with no prior treatment for Stage IV non-squamous NSCLC Previously obtained archival tumor tissue or tissue obtained from fresh 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+Nab-Paclitaxel+Carboplatin)<br>Participants received intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurred 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. Atezolizumab was administered to participants who were randomized to Arm A (Atezolizumab + Nab-Paclitaxel + Carboplatin) and to participants in Arm B (Nab-Paclitaxel + Carboplatin) who cross over at progression.<br>* Other names: MPDL3280A, RO5541267, Tecentriq;Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.<br>Drug: Nab-Paclitaxel<br>* Nab-paclitaxel was administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.<br>|
| Active Comparator: Arm B (Nab-Paclitaxel+Carboplatin)<br>Participants received IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurred first during induction treatment phase. Participants received best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. Participants who were consented prior to approval of protocol Version 5 were given the option to cross over to receive atezolizumab as monotherapy until disease progression. | 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. Atezolizumab was administered to participants who were randomized to Arm A (Atezolizumab + Nab-Paclitaxel + Carboplatin) and to participants in Arm B (Nab-Paclitaxel + Carboplatin) who cross over at progression.<br>* Other names: MPDL3280A, RO5541267, Tecentriq;Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.<br>Drug: Nab-Paclitaxel<br>* Nab-paclitaxel was administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.<br>Drug: Pemetrexed<br>* Switch maintenance to pemetrexed can be administered within 6 weeks of Day 1 of the last induction cycle.<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 Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first in the ITT-WT population. | Up to approximately 35 months after first patient enrolled | 
| Overall Survival (OS) in the ITT-WT Population | OS is defined as the time between the date of randomization and date of death from any cause in the ITT-WT population. | Up to approximately 35 months after first patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first. The ITT population was defined as all randomized participants, regardless of receipt of the assigned treatment. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation. | Up to approximately 35 months after first subject enrolled | 
| OS as Determined by the Investigator Using Recist v1.1 in the ITT Population | OS is defined as the time between the date of randomization and date of death from any cause in the ITT population. | Up to approximately 41 months after first subject enrolled | 
| OS as Determined by the Investigator Using RECIST v1.1 in the PD-L1 Expression Population and PD-L1 Expression WT Population | OS is defined as the time between the date of randomization and date of death from any cause in the PD-L1 Expression Population and PD-L1 Expression WT Population. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation. | Up to approximately 35 months after first patient enrolled | 
| 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 ITT-WT Population | ORR (confirmation not required) is defined as the proportion of participants with an objective response, either CR or PR, with the use of RECIST v1.1, as determined by the investigator in the ITT-WT population. | Up to approximately 41 months after first subject enrolled | 
| 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 ITT Population, PD-L1 Expression Population, and PD-L1 Expression WT Population | ORR (confirmation not required) is defined as proportion of participants with an objective response, either CR or PR, with the use of RECIST v1.1, as determined by investigator in ITT population, PD-L1 Expression population, and PD-L1 Expression WT population. ITT population was defined as all randomized participants, regardless of receipt of the assigned treatment. PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. PD-L1 expression WT population is defined as PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation. | Up to approximately 35 months after first subject enrolled | 
| Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population, ITT Population, and PD-L1 Expression Population and PD-L1 Expression WT Population | DOR,defined for participants with objective response (OR) as time from 1st documented OR to documented disease progression as determined by investigator using RECIST v1.1,or death from any cause,whichever occurs 1st.ITT defined as all randomized participants,regardless of receipt of assigned treatment.ITT-WT defined as ITT population excluding participants with activating EGFR mutation or ALK translocation.PD-L1 expression population is defined as one of following:PD-L1 IHC TC1/2/3 or IC1/2/3 population,defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue;PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue;PD-L1 IHC TC3 or IC3 population,defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue.PD-L1 expression WT is defined as PD-L1 expression population excluding participants with activating EGFR mutation or ALK translocation. | Up to approximately 35 months after first subject enrolled | 
| Event Free Rate (%) at Year 1 and 2 in ITT-WT Population and ITT Population | The OS rate at the 1- and 2-year landmark time points after randomization. | Up to 41 months after first patient enrolled, years 1 and 2 reported | 
| Event Free Rate (%) at Year 1 and 2 in PD-L1 Expression Population and PD-L1 Expression WT Population | The OS rate at the 1- and 2-year landmark time points after randomization in the PD-L1 Expression Population and PD-L1 Expression WT Population. The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 or IC1/2/3 population, defined as ITT participants with PD-L1 IHC TC1/2/3 or IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, defined as ITT participants with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT participants with PD-L1 IHC TC3 or IC3 expression in baseline tumor tissue. The PD-L1 expression WT population is defined as the PD-L1 expression population excluding participants with an activating EGFR mutation or ALK translocation. | Up to 35 months after first patient enrolled, years 1 and 2 reported | 
| Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population | Defined as time from randomization to confirmed deterioration (10-point change) on the combined European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core (EORTC QLQ-C30) and supplemental lung cancer module (EORTC QLQ-LC13) symptom subscales. | Up to approximately 35 months after first subject enrolled | 
| Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale | Change from baseline per SILC scale will be analyzed for each lung cancer symptoms scores. SILC questionnaire comprises 3 individual symptoms & are scored at individual symptom level, thus have a dyspnea score, chest pain score, & cough score. There are a total of 9 questions in SILC questionnaire, each question has a minimum value of 0 & maximum value of 4. Each individual symptom score is calculated as average of responses for symptom items. 'Chest pain' score is mean of question 1 & 2, 'Cough' score is mean of question 3 & 4 and 'Dyspnea' score is mean of question 5 to 9 in SILC questionnaire. An increase in score is suggestive of a worsening in symptomology. A score change of ≥0.3 points for dyspnea & cough symptom scores is considered to be clinically significant; whereas a score change of≥0.5 points for chest pain score is considered to be clinically significant. | Up to approximately 35 months after first subject enrolled | 
| Percentage of Participants With Adverse Events | Percentage of participants with at least one adverse event. Adverse event onset date before cross over. | Up to approximately 69 months after first patient enrolled | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab | Baseline prevalence and post-baseline incidence of anti-drug antibodies (ADA) to Atezolizumab in the Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) and Arm B Carboplatin+nab-paclitaxel Crossover Participants | Up to approximately 35 months after first subject enrolled | 
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab for Patients in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm | Predose samples will be collected on the same day of treatment administration. The infusion duration of atezolizumab will be of 30-60 minutes. | Cycle 1 Day 1 and Cycle 3 Day 1 (Cycle length = 21 days) | 
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplain+Nab-Paclitaxel | Predose samples will be collected on the same day of treatment administration. | Cycle 1 Day 21, Cycle 2 Day 21, Cycle 3 Day 21, and Cycle 7 Day 21 (Cycle length = 21 days) | 
| Plasma Concentrations of Carboplatin |  | Predose (same day of treatment administration), 5-10 minutes before end of carboplatin infusion, 1 hour after carboplatin infusion (infusion duration=15 to 30 minutes) on Day 1 of Cycle 1 and 3 (1 Cycle=21 days) (up to approximately 35 months) | 
| Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel |  | Predose (same day of treatment administration), 5-10 minutes before end of nab-paclitaxel infusion, 1 hour after nab-paclitaxel infusion (infusion duration=30 minutes) on Day 1 of Cycle 1 and 3 (1 Cycle=21 days) (up to approximately 35 months) |