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]

• Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (anti-PD-L1) antibody (Drug), also known as Tecentriq: Atezolizumab 1200 milligrams (mg) intravenous infusion (IV) on day 1 of each 21-day cycle.
• Carboplatin (Drug): 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.
• Nab-Paclitaxel (Drug): 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.
• Paclitaxel (Drug): 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.

Primary outcomes

• 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 [Up to approximately 30 months after first participant enrolled]: 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.
• Overall Survival (OS) in the ITT Population [Up to approximately 39 months after first participant enrolled]: OS is defined as the time between the date of randomization and date of death from any cause in the ITT population.

Secondary outcomes

• OS in the in the Teff Population [Up to approximately 39 months after first participant enrolled]: OS is defined as the time between the date of randomization and date of death from any cause in the in the Teff Population.
• PFS as Determined by the Investigator Using RECIST v1.1 in the Teff Population [Up to approximately 30 months after first participant enrolled]: 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.
• 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 [Up to approximately 30 months after first participant enrolled]: 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.
• PFS as Determined by the Investigator Using RECIST v1.1 in the TC1/2/3 or IC1/2/3 Population [Up to approximately 30 months after first participant enrolled]: 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.
• OS in the TC2/3 or IC2/3 Population [Up to approximately 39 months after first participant enrolled]: 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.
• OS in the TC1/2/3 or IC1/2/3 Population [Up to approximately 39 months after first participant enrolled]: 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.
• Percentage of Participants With Objective Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population [Up to approximately 30 months after first participant enrolled]: Proportion of participants with an objective response (CR or PR) in the ITT population.
• Duration of Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population [Up to approximately 30 months after first participant enrolled]: 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.
• Event Free Rate at 1 and 2 Years in the ITT Population [1 and 2 years]: 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.
• Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-C30 Symptom Subscales in the ITT Population [Up to approximately 30 months after first participant enrolled]: 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.
• TTD in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-LC13 Symptom Subscales in the ITT Population [Up to approximately 30 months after the first participant enrolled]: 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.
• Change From Baseline in Patient-reported Lung Cancer Symptoms Score Using the SILC Scale Symptom Severity Score in the ITT Population [Baseline up to approximately 30 months after first participant enrolled]: 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)
• PFS as Determined by the Investigator Using RECIST v1.1 in the ITT Population (Arm A and Arm B) [Up to approximately 30 months after first participant enrolled]: 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.
• OS in the ITT Population (Arm A and Arm B) [Up to approximately 39 months after first participant enrolled]: 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.
• Percentage of Participants With Adverse Events [Up to approximately 68 months after first participant enrolled]: Percentage of participants with at least one adverse event.
• Percentage of Participants With Anti-therapeutic Antibody (ATA) Response to Atezolizumab [Up to approximately 30 months after first participant enrolled]: Percentage of participants with Anti-therapeutic Antibody (ATA) response to atezolizumab.
• Maximum Observed Serum Atezolizumab Concentration (Cmax) [Cycle 1 Day 1 and Cycle 3 Day 1 (Cycle length = 21 days)]: 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.
• Minimum Observed Serum Atezolizumab Concentration (Cmin) [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)]: Minimum observed serum atezolizumab concentration (Cmin). The predose samples will be collected on the same day of treatment administration.
• 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 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 nab-paclitaxel.
• 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)]: Plasma concentrations for carboplatin.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• 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 (Primary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 5.6 (5.5 to 5.7); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 6.5 (5.7 to 7.1); Arm A: Atezolizumab + Paclitaxel + Carboplatin 5.6 (5.5 to 6.9) (p 0.0006)
• Overall Survival (OS) in the ITT Population (Primary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 13.5 (12.2 to 15.1); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 14.2 (12.3 to 16.8); Arm A: Atezolizumab + Paclitaxel + Carboplatin 12.6 (11.6 to 14.7) (p 0.1581)
• OS in the in the Teff Population (Secondary), Median, Month: Arm C: Nab-Paclitaxel + Carboplatin 16.4 (12.2 to 19.7); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 17.4 (12.3 to 23.8); Arm A: Atezolizumab + Paclitaxel + Carboplatin 15.2 (13.4 to 22.8) (p 0.4451)
• PFS as Determined by the Investigator Using RECIST v1.1 in the Teff Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 5.6 (5.1 to 5.7); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 7.0 (5.5 to 8.5); Arm A: Atezolizumab + Paclitaxel + Carboplatin 7.0 (5.6 to 9.7) (p 0.0006)
• 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 (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 5.6 (5.1 to 5.7); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 8.4 (6.8 to 10.4); Arm A: Atezolizumab + Paclitaxel + Carboplatin 7.0 (5.6 to 8.3) (p <.0001)
• PFS as Determined by the Investigator Using RECIST v1.1 in the TC1/2/3 or IC1/2/3 Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 5.6 (5.3 to 5.7); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 7.1 (5.8 to 8.3); Arm A: Atezolizumab + Paclitaxel + Carboplatin 7.0 (5.6 to 8.3) (p <.0001)
• OS in the TC2/3 or IC2/3 Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 14.5 (12.1 to 17.2); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 20.4 (13.8 to 24.1); Arm A: Atezolizumab + Paclitaxel + Carboplatin 14.8 (11.1 to 23.7) (p 0.0518)
• OS in the TC1/2/3 or IC1/2/3 Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 15.0 (12.4 to 17.2); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 14.8 (12.1 to 19.6); Arm A: Atezolizumab + Paclitaxel + Carboplatin 14.9 (12.5 to 18.2) (p 0.2956)
• Percentage of Participants With Objective Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population (Secondary), Number, Percentage of participants: Arm C: Nab-Paclitaxel + Carboplatin 41.0; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 49.7; Arm A: Atezolizumab + Paclitaxel + Carboplatin 49.3 (p 0.0248)
• Duration of Response as Determined by the Investigator Using RECIST v1.1 in the ITT Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 5.2 (4.4 to 5.6); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 7.2 (6.8 to 9.5); Arm A: Atezolizumab + Paclitaxel + Carboplatin 7.0 (5.7 to 8.3) (p <.0001)
• Event Free Rate at 1 and 2 Years in the ITT Population (Secondary), Number, Percentage of participants: Arm C: Nab-Paclitaxel + Carboplatin 56.28; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 56.34; Arm A: Atezolizumab + Paclitaxel + Carboplatin 52.30 (p 0.9871)
• Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-C30 Symptom Subscales in the ITT Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 3.2 (2.6 to 4.1); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 4.2 (3.2 to 5.6); Arm A: Atezolizumab + Paclitaxel + Carboplatin 3.0 (2.6 to 3.9) (p 0.0461)
• TTD in Patient-reported Lung Cancer Symptoms Using EORTC QLQ-LC13 Symptom Subscales in the ITT Population (Secondary), Median, Months: Arm C: Nab-Paclitaxel + Carboplatin 2.6 (2.2 to 3.0); Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 3.4 (2.7 to 5.1); Arm A: Atezolizumab + Paclitaxel + Carboplatin 2.8 (2.1 to 3.7) (p 0.0942)
• Change From Baseline in Patient-reported Lung Cancer Symptoms Score Using the SILC Scale Symptom Severity Score in the ITT Population (Secondary), Mean, Units on a scale: Arm C: Nab-Paclitaxel + Carboplatin 0.04 +/- 0.93; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 0.14 +/- 0.87; Arm A: Atezolizumab + Paclitaxel + Carboplatin 0.44 +/- 1.03
• PFS as Determined by the Investigator Using RECIST v1.1 in the ITT Population (Arm A and Arm B) (Secondary), Median, Months: Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 6.5 (5.7 to 7.1); Arm A: Atezolizumab + Paclitaxel + Carboplatin 5.6 (5.5 to 6.9) (p 0.4007)
• OS in the ITT Population (Arm A and Arm B) (Secondary), Median, Months: Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 14.2 (12.3 to 16.8); Arm A: Atezolizumab + Paclitaxel + Carboplatin 12.6 (11.6 to 14.7)
• Percentage of Participants With Adverse Events (Secondary), Number, Percentage of participants: Arm C: Nab-Paclitaxel + Carboplatin 97.0; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 99.4; Arm A: Atezolizumab + Paclitaxel + Carboplatin 97.9
• Percentage of Participants With Anti-therapeutic Antibody (ATA) Response to Atezolizumab (Secondary), Number, Percentage of participants: Arm A: Atezolizumab + Paclitaxel + Carboplatin 3.1; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 1.9
• Maximum Observed Serum Atezolizumab Concentration (Cmax) (Secondary), Mean, µg/mL: Arm A: Atezolizumab + Paclitaxel + Carboplatin 372 +/- 116; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin 378 +/- 124
• Minimum Observed Serum Atezolizumab Concentration (Cmin) (Secondary), Mean, µg/mL: Arm A: Atezolizumab + Paclitaxel + Carboplatin NA +/- NA; Arm B: Atezolizumab + Nab-Paclitaxel + Carboplatin NA +/- NA
• 3 more outcome measures not shown.

Adverse events

Time frame: From the first study drug administration to the data cutoff date: 17 February 2021 (up to approximately 68 months).

Serious adverse events by term

187 more terms not shown.

Other adverse events by term

1 more terms not shown.

142 more sites not listed.

• Results publication: Ton TGN, Pal N, Trinh H, Mahrus S, Bretscher MT, Machado RJM, Sadetsky N, Chaudhary N, Lu MW, Riely GJ. Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data. Clin Cancer Res. 2022 Jul 1;28(13):2844-2853. doi: 10.1158/1078-0432.CCR-22-0471. PMID 35511917

• Study Protocol (PDF, 2018-10-24)
• Statistical Analysis Plan (PDF, 2018-01-11)

• Clinical Trials, Study director, Hoffmann-La Roche

NIH grants: 2014