A Study of Atezolizumab (MPDL3280A) Compared With a Platinum Agent (Cisplatin or Carboplatin) + (Pemetrexed or Gemcitabine) in Participants With Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer (NSCLC) [IMpower110]

Study Overview
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Brief Summary
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This randomized, open-label study will evaluate the efficacy and safety of atezolizumab compared with chemotherapy consisting of a platinum agent (cisplatin or carboplatin per investigator discretion) combined with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in programmed death-ligand 1 (PD-L1)-selected, chemotherapy-naive participants with Stage IV Non-Squamous or Squamous NSCLC.

Official Title
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A Phase III, Open Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Compared With a Platinum Agent (Cisplatin or Carboplatin) in Combination With Either Pemetrexed or Gemcitabine for PD-L1-Selected, Chemotherapy-Naive Patients With Stage IV Non-Squamous Or Squamous Non-Small Cell Lung Cancer

Conditions
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Non-Squamous Non-Small Cell Lung Cancer, Squamous Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, Stage IV non-squamous or squamous NSCLC No prior treatment for Stage IV non-squamous or squamous NSCLC. Participant known to have a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded from the study Tumor PD-L1 expression as determined by immunohistochemistry (IHC) assay of archival tumor tissue or tissue obtained at screening Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Adequate hematologic and end-organ function Exclusion Criteria: Known sensitizing mutation in the EGFR gene or ALK fusion oncogene Active or untreated central nervous system (CNS) metastases as determined by Computed Tomography (CT) or magnetic resonance imaging (MRI) evaluation 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 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 (CD) 137 agonists or immune checkpoint blockade therapies, anti PD1, 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 |
| --- | --- |
| Active Comparator: (Carboplatin/ Cisplatin) + (Pemetrexed/ Gemcitabine)<br>Participants with non-squamous NSCLC will receive chemotherapy with pemetrexed in combination with either cisplatin or carboplatin (per investigator discretion) on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by maintenance therapy with pemetrexed alone as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months). Participants with squamous NSCLC will receive chemotherapy with gemcitabine on Days 1 and 8 of each 21-day cycle in combination with either cisplatin or carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by best supportive care as per local standard of care until disease progression, unacceptable toxicity, or death (maximum up to approximately 58 months). | Drug: Carboplatin<br>* Carboplatin will be administered as intravenous infusion at a dose of area under the concentration-time curve (AUC) 6 when given in combination with pemetrexed or at a dose of AUC 5 when given in combination with gemcitabine, every 21 days for 4 or 6 cycles as per local standard of care.<br>Drug: Cisplatin<br>* Cisplatin will be administered as intravenous infusion at a dose of 75 mg per meter squared (mg/m^2) every 21 days for 4 or 6 cycles as per local standard of care.<br>Drug: Gemcitabine<br>* Gemcitabine will be administered as intravenous infusion at a dose of 1250 mg/m^2 (in combination with cisplatin) or 1000 mg/m^2 (in combination with carboplatin), on Days 1 and 8 of each 21-day cycle for 4 or 6 cycles as per local standard of care.<br>Drug: Pemetrexed<br>* Pemetrexed will be administered as intravenous infusion at a dose of 500 mg/m^2 on Day 1 of each 21-day cycle as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months).<br>|
| Experimental: Atezolizumab<br>Participants with squamous or non-squamous NSCLC will receive atezolizumab on Day 1 of each 21-day cycle until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months). | Drug: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody<br>* Atezolizumab 1200 milligram (mg) will be administered as intravenous infusion every 21 days until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months).<br>* Other names: MPDL3280A, RO5541267;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the TC3 or IC3-WT Populations | OS is defined as the time from randomization to death from any cause. | From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Overall Survival (OS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations | OS is defined as the time from randomization to death from any cause. | From randomization to death from any cause until data cut-off on 4 February 2020 (up to approximately 54.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in the TC3 or IC3-WT Populations | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first. PFS could not be formally tested. | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Progression-free Survival (PFS) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first. PFS could not be formally tested. | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 4 February 2020 (up to approximately 54.5 months) | 
| Percentage of Participants With Objective Response (ORR) in the TC3 or IC3-WT Populations | Objective response (partial response plus complete response) as determined by the investigator according to RECIST v1.1. | Every 6 weeks for 48 weeks following Day 1, thereafter every 9 weeks after completion of Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression until data cut-off on 10 Sep 2018 (up to approximately 38 months) | 
| Percentage of Participants With Objective Response (ORR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations | Objective response (partial response plus complete response) as determined by the investigator according to RECIST v1.1. | Every 6 weeks for 48 weeks following Day 1, thereafter every 9 weeks after completion of Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression until data cut-off on 4 Feb 2020 (up to approximately 54.5 months) | 
| Duration of Response (DOR) in the TC3 or IC3-WT Populations | DOR is defined as the time from the first occurrence of a documented objective response to the time of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first. | From first occurrence of a complete response or partial response, whichever occurs first, until first date that progressive disease or death is documented, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Duration of Response (DOR) in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations | DOR is defined as the time from the first occurrence of a documented objective response to the time of disease progression, as determined by the investigator with use of RECIST v1.1, or death from any cause, whichever occurs first. | From first occurrence of a complete response or partial response, whichever occurs first, until first date that progressive disease or death is documented, whichever occurs first until data cut-off on 4 February 2020 (up to approximately 54.5 months) | 
| Percentage of Participants Who Are Alive at 1 Year in the TC3 or IC3-WT Populations |  | Baseline to 1 year or death, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Percentage of Participants Who Are Alive at 2 Years in the TC3 or IC3-WT Populations |  | Baseline to 2 years or death, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Percentage of Participants Who Are Alive at 1 Year in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations |  | Baseline to 1 year or death, whichever occurs first until clinical cut-off date on 4 February 2020 (up to approximately 54.5 months) | 
| Percentage of Participants Who Are Alive at 2 Years in the TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT Populations |  | Baseline to 2 years or death, whichever occurs first until clinical cut-off date on 4 February 2020 (up to approximately 54.5 months) | 
| Time to Deterioration (TTD) in Patient-reported Lung Cancer Symptoms Score as Assessed by the Symptoms in Lung Cancer (SILC) Scale Symptom Score in the TC3 or IC3-WT Populations | TTD in each of the patient-reported lung cancer symptoms with use of the SILC scale. The SILC scale is a nine-item content valid self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, and chest pain with a total symptom severity score. Each SILC symptom scale (dyspnea, cough, chest pain) score was calculated as the average of the component items (range 0 to 4). An increase in score suggested worsening in symptomatology. A symptom score change of 0.3 points for the dyspnea and cough scores was considered to be clinically significant; whereas a symptom score change of 0.5 points for the chest pain score was considered to be clinically significant. | Baseline until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Change From Baseline in Patient-reported Lung Cancer Symptoms Score as Assessed by the SILC Scale Symptom Score in the TC3 or IC3-WT Populations | Change from baseline in each of the patient-reported lung cancer symptoms with use of the SILC scale. The SILC scale is a nine-item content valid self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, and chest pain with a total symptom severity score. Each SILC symptom scale (dyspnea, cough, chest pain) score was calculated as the average of the component items (range 0 to 4). An increase in score suggested worsening in symptomatology. A symptom score change of 0.3 points for the dyspnea and cough scores was considered to be clinically significant; whereas a symptom score change of 0.5 points for the chest pain score was considered to be clinically significant. | Baseline until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| TTD as Assessed Using EORTC QLQ Supplementary Lung Cancer Module (EORTC QLQ-LC13) in the TC3 or IC3-WT Populations | TTD in patient-reported lung cancer symptoms, defined as time from randomization to deterioration (10-point change) in any of the following symptom subscales (cough, dyspnea [multi-item scale], and chest pain), whichever occurs first, as measured by the EORTC QLQ-LC13. EORTC QLQ-LC13 module incorporates one multi-item scale to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. | Baseline until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| OS in Participants With PD-L1 Expression | OS is defined as the time from randomization to death from any cause. | From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Investigator-Assessed PFS in Participants With PD-L1 Expression According to RECIST v1.1 | Investigator-assessed PFS according to RECIST v1.1 in the PD-L1 (defined with SP263 IHC assay) | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| OS in Participants With Blood Tumor Mutational Burden (bTMB) | OS is defined as the time from randomization to death from any cause. | From randomization to death from any cause until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Investigator-Assessed PFS in Participants With bTMB According to RECIST v1.1 | PFS according to RECIST v1.1 in the bTMB subpopulations. | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first until data cut-off on 10 September 2018 (up to approximately 38 months) | 
| Minimum Observed Serum Concentration (Cmin) of Atezolizumab |  | Prior to infusion (0 hour) on Day 1 of Cycles 2, 3, 4, 8, 16, and every eighth cycle thereafter, and at treatment discontinuation until data cut-off on 10 September 2018 (up to approximately 38 months) (cycle duration = 21 days) | 
| Maximum Observed Serum Concentration (Cmax) of Atezolizumab |  | 0 hour (predose) and 30 minutes after atezolizumab infusion on Day 1 (infusion duration = up to 1 hour) | 
| Percentage of Participants With at Least One Adverse Event | Percentage of participants with at least one adverse event. | Baseline up to until data cut-off on 8 March 2022 (up to approximately 79.5 months) | 
| Percentage of Participants With Anti-therapeutic Antibodies (ATAs) |  | Baseline until data cut-off on 10 September 2018 (up to approximately 38 months) |