A Study of Atezolizumab in Combination With Carboplatin or Cisplatin + Pemetrexed Compared With Carboplatin or Cisplatin + Pemetrexed in Participants Who Are Chemotherapy-Naive and Have Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (IMpower 132)

Study Overview
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Brief Summary
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This is a randomized, Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab in combination with cisplatin or carboplatin + pemetrexed compared with treatment with cisplatin or carboplatin + pemetrexed in participants who are chemotherapy-naive and have Stage IV non-squamous NSCLC. Eligible participants will be randomized by a 1:1 ratio into 2 groups: Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) and Arm B (Carboplatin or Cisplatin + Pemetrexed). The study will be conducted in two phases: Induction Phase and Maintenance Phase.

Official Title
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A Phase III, Open-Label, Randomized Study of Atezolizumab (MPDL3280A, Anti-Pd-L1 Antibody) in Combination With Carboplatin or Cisplatin + Pemetrexed Compared With Carboplatin or Cisplatin + Pemetrexed in Patients Who Are Chemotherapy-Naive and Have Stage IV Non-Squamous Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically or cytologically confirmed, Stage IV non-squamous NSCLC. Participants with tumors of mixed non-small cell histology (i.e., squamous and non-squamous) are eligible if the major histological component appears to be non-squamous No prior treatment for Stage IV non-squamous NSCLC. Participants with a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or with an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded. Participants with unknown EGFR and ALK status require test results at screening from a local or central laboratory Participants who have received prior neo-adjuvant, radiotherapy, adjuvant chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from randomization since the last dose of chemotherapy and/or radiotherapy Participants should submit a pre-treatment tumor tissue sample if available before or within 4 weeks after enrollment. If tumor tissue is not available, participants are still eligible For participants enrolled in the extended China enrollment phase: current resident of mainland China, Hong Kong, or Taiwan and of Chinese ancestry Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end organ function For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 5 months after the last dose of atezolizumab or 6 months after the last dose of cisplatin For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm Exclusion Criteria: Cancer-Specific Exclusions Participants with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for greater than or equal to (>= 2) weeks prior to randomization Leptomeningeal disease Uncontrolled tumor-related pain Uncontrolled or symptomatic hypercalcemia (greater than [>] 1.5 millimole/Liter ionized calcium or calcium >12 milligrams/deciliter or corrected serum calcium >upper limit of normal) Malignancies other than NSCLC within 5 years prior to randomization Known tumor programmed death-ligand 1 (PD-L1) expression status from other clinical studies (e.g., participants whose PD-L1 expression status was determined during screening for entry into a study with anti-PD-1 or anti-PD L1 antibodies but were not eligible are excluded) General Medical Exclusions: History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins History of certain autoimmune disease History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis All participants will be tested for human immunodeficiency virus (HIV) prior to the inclusion into the study and HIV-positive participants will be excluded from the clinical study Severe infections within 4 weeks prior to randomization Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina Illness or condition that may interfere with a participant's capacity to understand, follow, and/or comply with study procedures Exclusion Criteria Related to Medications and Chemotherapy: Prior treatment with EGFR inhibitors or ALK inhibitors Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to initiation of study treatment Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies Treatment with systemic immunostimulatory agents within 4 weeks prior to randomization Treatment with systemic immunosuppressive medications Exclusion Criteria Related to Chemotherapy: History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds Participants with hearing impairment (cisplatin) Grade >=2 peripheral neuropathy as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria (cisplatin) Creatinine clearance (CRCL) <60 milliliters/minute (mL/min) for cisplatin or <45 mL/min for carboplatin

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 + Carboplatin or Cisplatin + Pemetrexed<br>Participants received intravenous (IV) infusion of 1200 milligrams (mg) of atezolizumab on Day 1 every 3 weeks (q3w), IV infusion of 500 milligrams per meter square (mg/m^2) pemetrexed on Day 1 q3w, and as per investigator's choice either IV infusion of carboplatin on Day 1 q3w with a dose calculated using 'Calvert formula' to obtain area under concentration versus time (AUC) = 6 milligrams per milliliter per minute (mg/mL/min) or IV infusion of 75 mg/m^2 cisplatin q3w on Day 1 q3w, during induction dosing period of 4 or 6 cycles (Cycle length=21 days). Participants who experienced clinical benefit during the induction phase began maintenance therapy. Participants will receive IV infusion of 1200 mg of atezolizumab and 500 mg/m^2 of pemetrexed on Day 1 q3w until disease progression in the maintenance period. | Drug: Atezolizumab<br>* Participants received IV infusion of 1200 mg atezolizumab on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period and until disease progression on Day 1 q3w in the maintenance dosing period.<br>* Other names: TECENTRIQ;Drug: Carboplatin<br>* Participants received IV infusion of carboplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period with doses calculated using Calvart formula.<br>Drug: Cisplatin<br>* Participants received IV infusion of 75 mg/m^2 cisplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period.<br>Drug: Pemetrexed<br>* Participants received IV infusion of 500 mg/m^2 pemetrexed on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period and until disease progression on Day 1 q3w in the maintenance dosing period.<br>|
| Active Comparator: Arm B (Carboplatin or Cisplatin + Pemetrexed)<br>Participants received IV infusion of 500 mg/m^2 pemetrexed on Day 1 q3w, and as per investigator's choice of either IV infusion of carboplatin on Day 1 q3w with a dose calculated using 'Calvert formula' to obtain AUC =6 mg/mL/min or IV infusion of 75 mg/m^2 cisplatin q3w on Day 1 q3w, during induction dosing period for 4 or 6 cycles (Cycle length=21 days). Participants who did not experience disease progression during the induction phase began maintenance therapy. Participants will receive IV infusion of 500 mg/m^2 of pemetrexed on Day 1 q3w until disease progression in the maintenance period. | Drug: Carboplatin<br>* Participants received IV infusion of carboplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period with doses calculated using Calvart formula.<br>Drug: Cisplatin<br>* Participants received IV infusion of 75 mg/m^2 cisplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period.<br>Drug: Pemetrexed<br>* Participants received IV infusion of 500 mg/m^2 pemetrexed on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period and until disease progression on Day 1 q3w in the maintenance dosing period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurred first. | Randomization up to approximately 39 months | 
| Overall Survival (OS) | OS is defined as time from randomization to death from any cause. | Randomization up to approximately 39 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate at Year 1 | The Overall Survival Rate at the 1-year landmark time point is defined as the probabilities that participants are alive 1-year after randomization. | Year 1 | 
| Overall Survival Rate Year 2 | The Overall Survival Rate at the 2-year landmark time point is defined as the probabilities that participants are alive 2-years after randomization. | Year 2 | 
| Percentage of Participants With an Objective Response (Complete Response [CR] or Partial Response [PR]) Assessed by the Investigator Using RECIST V1.1 | An objective response is defined as either an unconfirmed CR or a PR, as determined by the investigator using RECIST v1.1. Objective Response Rate is defined as the proportion of patients who had an objective response. | Randomization up to approximately 25 months | 
| Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 | DOR is defined as the time interval from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented, whichever occurs first. | Randomization up to approximately 25 months | 
| Change From Baseline in Patient-Reported Lung Cancer Symptoms as Assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30) Symptom Score | 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 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 3 and 6 months after disease progression or loss of clinical benefit (up to approximately 25 months) | 
| Change From Baseline in Patient-Reported Lung Cancer Symptoms as Assessed by EORTC Quality-of-Life Lung Cancer Module (QLQ-LC13) Symptom Score | The EORTC QLQ-LC13 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 3 and 6 months after disease progression or loss of clinical benefit (up to approximately 25 months) | 
| Change From Baseline in Patient-Reported Lung Cancer Symptoms as Reported Using the Symptoms in Lung Cancer (SILC) Scale Score | 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. | Baseline up to 3 and 6 months after disease progression or loss of clinical benefit (up to approximately 25 months) | 
| Minimum Observed Serum Atezolizumab Concentration (Cmin) | Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at selected cycles (Arm A) | Predose (Prd; 0 hour [h]) on D1 of Cy 2,3,4,8,16 (Cy length=21 days) and thereafter on D1 of every 8th cycle (up to approximately 25 months) | 
| Maximum Observed Serum Atezolizumab Concentration (Cmax) | Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arm A) | Day 1 of Cycle 1 (Cycle length=21 days) | 
| Plasma Concentrations for Carboplatin in Arm A(Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) |  | Prd (0 h), 5-10 minutes (mins) before end of carboplatin infusion (infusion duration=1-2 h), 1 h post-infusion on D1 of Cy1,3 (Cy length=21 days) | 
| Plasma Concentrations for Cisplatin in Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) |  | Prd (0 h), 5-10 mins before end of cisplatin infusion (infusion duration=30-60 mins), 1 h post-infusion on D1 of Cy1,3 (Cy length=21 days) | 
| Plasma Concentrations for Pemetrexed in Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) |  | Prd (0 h), 5-10 mins before end of pemetrexed infusion (infusion duration=10 mins), 1 h post-infusion on D1 of Cy1,3 (Cy length=21 days) | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) of Atezolizumab | Baseline prevalence and post-baseline incidence of anti-drug antibodies (ADA) to Atezolizumab in the Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) | Prd (0 h) on D1 of Cy1,2,3,4,8,16 (Cy length=21 days) and thereafter on D1 of every 8th cycle, at treatment discontinuation & then every 30 days (up to 120 days) after last dose of atezolizumab (up to app 25 months) |