A Study of Atezolizumab in Combination With Carboplatin + Paclitaxel or Carboplatin + Nab-Paclitaxel Compared With Carboplatin + Nab-Paclitaxel in Participants With Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC) [IMpower131]

Study Overview
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Brief Summary
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This randomized, open-label study will evaluate the safety and efficacy of atezolizumab (MPDL3280A) in combination with carboplatin + paclitaxel or carboplatin + nab-paclitaxel compared with treatment with carboplatin + nab-paclitaxel in chemotherapy-naive participants with Stage IV squamous NSCLC.

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

Conditions
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Squamous Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (anti-PD-L1) antibody
* Drug: Carboplatin
* Drug: Nab-Paclitaxel
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Histologically or cytologically confirmed, treatment-naïve Stage IV squamous NSCLC Previously obtained archival tumor tissue or tissue obtained from biopsy at screening Measurable disease as defined by RECIST v1.1 Adequate hematologic and end organ function Exclusion Criteria: Active or untreated central nervous system (CNS) metastasis 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 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 (CT) scan, History of radiation pneumonitis in the radiation field (fibrosis) is permitted Positive test for Human Immunodeficiency Virus (HIV) Active hepatitis B or hepatitis C Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibody Severe infection within 4 weeks prior to randomization Significant history of cardiovascular disease

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>The induction phase of the study will consist of four or six cycles; atezolizumab, paclitaxel, and carboplatin will be administered on Day 1 of each 21-day cycle. The Day 1 order of drug administration is as follows: atezolizumab, then paclitaxel, then carboplatin. Participants who experience no further clinical benefit at any time during the induction phase will discontinue all study treatments. In the absence of the above criteria, after the 4- or 6-cycle induction phase, participants will begin maintenance therapy with atezolizumab. Atezolizumab will be continued as long as there is a clinical benefit to the participant. | Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (anti-PD-L1) antibody<br>* Atezolizumab 1200 milligrams (mg) intravenous infusion (IV) on day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Carboplatin<br>* Carboplatin area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles.<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m^2 IV on Day 1 of each 21-day cycle for 4 or 6 cycles. Participants of Asian race/ethnicity will be administered paclitaxel 175 mg/m^2 IV.<br>|
| Experimental: Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin<br>The induction phase of the study will consist of four or six cycles; atezolizumab and carboplatin will be administered on Day 1 of each 21-day cycle. Nab-Paclitaxel will be administered on Days 1, 8, and 15 of each 21-day cycle. The Day 1 order of drug administration is as follows: atezolizumab, then nab-paclitaxel, then carboplatin. Participants who experience no further clinical benefit at any time during the induction phase will discontinue all study treatments. In the absence of the above criteria, after the 4- or 6-cycle induction phase, participants will begin maintenance therapy with atezolizumab. Atezolizumab will be continued as long as there is a clinical benefit to the participant. | Drug: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (anti-PD-L1) antibody<br>* Atezolizumab 1200 milligrams (mg) intravenous infusion (IV) on day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Carboplatin<br>* Carboplatin area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles.<br>Drug: Nab-Paclitaxel<br>* Nab-paclitaxel 100 milligrams per meter squared (mg/m^2) IV on Day 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles.<br>|
| Active Comparator: Arm C: Nab-Paclitaxel + Carboplatin<br>The induction phase of the study will consist of four or six cycles; carboplatin will be administered on Day 1 of each 21-day cycle, nab-paclitaxel will be administered on Days 1, 8, and 15 of each 21-day cycle. The Day 1 order of drug administration is as follows: nab-paclitaxel, then carboplatin. Participants who experience disease progression at any time during the induction phase will discontinue all study treatment. In the maintenance phase, participants will receive best supportive care. | Drug: Carboplatin<br>* Carboplatin area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles.<br>Drug: Nab-Paclitaxel<br>* Nab-paclitaxel 100 milligrams per meter squared (mg/m^2) IV on Day 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles.<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 Intent-to-Treat (ITT) Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first, in the ITT population. | Up to approximately 30 months after first participant enrolled | 
| Overall Survival (OS) 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 39 months after first participant enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS in the in the Teff Population | OS is defined as the time between the date of randomization and date of death from any cause in the in the Teff Population. | Up to approximately 39 months after first participant enrolled | 
| PFS as Determined by the Investigator Using RECIST v1.1 in the Teff Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first, in the Teff Population. | Up to approximately 30 months after first participant enrolled | 
| PFS as Determined by the Investigator Using RECIST v1.1 in the Tumor Cell (TC) 2/3 or Tumor-Infiltrating Immune Cell (IC) 2/3 Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first, in the Tumor Cell (TC) 2/3 or Tumor-Infiltrating Immune Cell (IC) 2/3 Population. | Up to approximately 30 months after first participant enrolled | 
| PFS as Determined by the Investigator Using RECIST v1.1 in the TC1/2/3 or IC1/2/3 Population | PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first, in the TC1/2/3 or IC1/2/3 Population. | Up to approximately 30 months after first participant enrolled | 
| OS in the TC2/3 or IC2/3 Population | OS is defined as the time between the date of randomization and date of death from any cause, in the TC2/3 or IC2/3 Population. | Up to approximately 39 months after first participant enrolled | 
| OS in the TC1/2/3 or IC1/2/3 Population | OS is defined as the time between the date of randomization and date of death from any cause in the TC1/2/3 or IC1/2/3 Population. | Up to approximately 39 months after first participant enrolled | 
| Percentage of Participants With Objective Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population | Proportion of participants with an objective response (CR or PR) in the ITT population. | Up to approximately 30 months after first participant enrolled | 
| Duration of Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population | Duration of response is defined as the time from the first documented objective response to documented PD or death from any cause, whichever occurred first, in the ITT Population. | Up to approximately 30 months after first participant enrolled | 
| Event Free Rate at 1 and 2 Years in the ITT Population | Event free rate at 1 and 2 years is defined as the proportion of participants alive at 1 and 2 years after randomization estimated using Kaplan-Meier (KM) methodology for the ITT population. | 1 and 2 years | 
| Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-C30 Symptom Subscales in the ITT Population | TTD in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-C30 Symptom Subscales in the ITT Population. The EORTC QLQ-C30 is a validated and reliable self-report measure that consists of 30 questions that assess five aspects of patient functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). EORTC scales and single-item measures will be linearly transformed so that each score has a range of 0-100. A high score for a functional scale represents a high or healthy level of functioning, and a high score for the global health status and HRQoL represents a high HRQoL; however, a high score for a symptom scale or item represents a high level of symptomatology or problems. | Up to approximately 30 months after first participant enrolled | 
| TTD in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-LC13 Symptom Subscales in the ITT Population | TTD was documented for a 3-symptom composite endpoint using the following EORTC QLQ-LC13 symptom scores: cough, chest pain, and dyspnea multi--item scale. In this instance, symptom deterioration will be determined as a >= 10-point increase above baseline in any of the listed symptom scores, whichever occurs first (cough, chest pain, and dyspnea multi-item scale). Confirmed clinically meaningful symptom deterioration will need to be held for the original symptom; a >= 10-point increase above baseline in a symptom score must be held for at least two consecutive assessments or an initial>=10-point increase above baseline followed by death within 3 weeks from the last assessment. A >= 10-point change in the EORTC scale score is perceived by patients as clinically significant. | Up to approximately 30 months after the first participant enrolled | 
| Change From Baseline in Patient-reported Lung Cancer Symptoms Score Using the SILC Scale Symptom Severity Score in the ITT Population | 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. (Note: PD=progression of disease) | Baseline up to approximately 30 months after first participant enrolled | 
| PFS as Determined by the Investigator Using RECIST v1.1 in the ITT Population (Arm A and Arm B) | PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first, in the ITT Population Arm A and Arm B. | Up to approximately 30 months after first participant enrolled | 
| OS in the ITT Population (Arm A and Arm B) | OS is defined as the time between the date of randomization and date of death from any cause in the ITT Population, Arm A and Arm B. | Up to approximately 39 months after first participant enrolled | 
| Percentage of Participants With Adverse Events | Percentage of participants with at least one adverse event. | Up to approximately 68 months after first participant enrolled | 
| Percentage of Participants With Anti-therapeutic Antibody (ATA) Response to Atezolizumab | Percentage of participants with Anti-therapeutic Antibody (ATA) response to atezolizumab. | Up to approximately 30 months after first participant enrolled | 
| Maximum Observed Serum Atezolizumab Concentration (Cmax) | Maximum observed serum atezolizumab concentration (Cmax). The 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 Atezolizumab Concentration (Cmin) | Minimum observed serum atezolizumab concentration (Cmin). The predose samples will be collected on the same day of treatment administration. | Predose on Day 1 of Cycles 1-4, 8, 16, every 8 cycle thereafter (up to 30 months), at treatment discontinuation (up to 30 months), and at 120 days after the last dose of atezolizumab (up to approximately 30 months, each cycle is 21 days) | 
| Plasma Concentrations for Paclitaxel | Plasma concentrations for paclitaxel. | Prior to infusion (within same day of treatment administration), 5-10 minutes before the end of infusion, and 1 hour after the end of infusion (infusion duration 180 minutes) on Day 1 of Cycles 1 and 3 (each cycle is 21 days) | 
| Plasma Concentrations for Nab-Paclitaxel | Plasma concentrations for nab-paclitaxel. | Prior to infusion (within same day of treatment administration), 5-10 minutes before the end of infusion, and 1 hour after the end of infusion (infusion duration 30 minutes) on Day 1 of Cycles 1 and 3 (each cycle is 21 days) | 
| Plasma Concentrations for Carboplatin | Plasma concentrations for carboplatin. | Prior to infusion (within same day of treatment administration), 5-10 minutes before the end of infusion, and 1 hour after the end of infusion (infusion duration 15 to 30 minutes) on Day 1 of Cycles 1 and 3 (each cycle is 21 days) |