Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer [IMpower010]

Study Overview
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Brief Summary
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This is a Phase III, global, multicenter, open-label, randomized study to compare the efficacy and safety of 16 cycles (1 cycle duration=21 days) of atezolizumab (MPDL3280A) treatment compared with best supportive care (BSC) in participants with Stage IB-Stage IIIA non-small cell lung cancer (NSCLC) following resection and adjuvant chemotherapy, as measured by disease-free survival (DFS) as assessed by the investigator and overall survival (OS). Participants, after completing up to 4 cycles of adjuvant cisplatin-based chemotherapy, will be randomized in a 1:1 ratio to receive atezolizumab for 16 cycles or BSC.

Official Title
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A Phase III, Open-Label, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Best Supportive Care Following Adjuvant Cisplatin-Based Chemotherapy in Patients With Completely Resected Stage IB-IIIA Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Cisplatin
* Drug: Vinorelbine
* Drug: Docetaxel
* Drug: Gemcitabine
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for Enrollment Phase Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histological or cytological diagnosis of Stage IB (tumors greater than or equal to [>/=] 4 centimeters [cm])-IIIA (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) NSCLC (per the Union Internationale Contre le Cancer staging system (UICC)/American Joint Committee on Cancer staging system (AJCC) staging system, 7th edition; Detterbeck et al. 2009) Participants must have had complete resection of NSCLC 4-12 weeks (>/=28 days and less than or equal to [</=] 84 days) prior to enrollment and must be adequately recovered from surgery If mediastinoscopy was not performed preoperatively, it is required that, at a minimum, mediastinal lymph node systematic sampling will have occurred. Systematic sampling is defined as removal of at least one representative lymph node at specified levels. MLND entails resection of all lymph nodes at those same levels. For a right thoracotomy, sampling or MLND is required at levels 4 and 7 and for a left thoracotomy, levels 5 and/or 6 and 7. Exceptions will be granted if there is clear documentation in the operative report or in a separately submitted addendum by the surgeon of exploration of the required lymph node areas, the participant will be considered eligible if no lymph nodes are found in those areas; if participants have documented N2 disease in one level (per the UICC/AJCC staging system, 7th edition; Detterbeck et al. 2009), not all levels need to be sampled; if the preoperative staging imaging results (contrast computed tomography [CT] and positron emission tomography [PET] scans) do not suggest evidence of disease in the mediastinum, the participant will be considered eligible if N2 nodal sampling is not performed per surgeon's decision Eligible to receive a cisplatin-based chemotherapy regimen Adequate hematologic and end-organ function Women who are not postmenopausal (>/=12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of cisplatin-based chemotherapy Inclusion Criteria for Randomized Phase - Women who are not postmenopausal (>/=12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of atezolizumab or BSC Exclusion Criteria: Exclusion Criteria for Enrollment Phase Illness or condition that may interfere with a participant's capacity to understand, follow, and/or comply with study procedures Pregnant and lactating women Treatment with prior systemic chemotherapy: Chemotherapy for early stage of malignancy with curative intent, provided that the last dose received was more than 5 years prior to enrollment and low-dose chemotherapy for non-malignant conditions may be allowed upon approval by the Medical Monitor Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years before enrollment Treatment with any other investigational agent with therapeutic intent within 28 days prior to enrollment Participants with hearing impairment Known sensitivity to any component of the chemotherapy regimen the participant will be assigned to, or to mannitol Prior treatment with cluster of differentiation (CD) 137 (CD137) agonists or immune checkpoint blockade therapies, anti-programmed death-1 (PD-1), and anti programmed death ligand 1 (PD-L1) therapeutic antibodies Malignancies other than NSCLC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS greater than [>] 90 percent [%]) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis Positive test for human immunodeficiency virus (HIV) Participants with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C Active tuberculosis Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within the previous 3 months, unstable arrhythmias, or unstable angina History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan Prior allogeneic bone marrow transplantation or solid organ transplant Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications Known tumor PD-L1 expression status as determined by an immunohistochemistry (IHC) assay 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) Specific Exclusions for Pemetrexed Treatment - Participants with squamous cell histology Exclusion Criteria for Randomized Phase Signs or symptoms of infection within 14 days prior to randomization (severe infection within 28 days prior to randomization), including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to randomization Major surgical procedure within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation that such a live attenuated vaccine will be required during the study Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to randomization: Prior treatment with cancer vaccines is allowed Treatment with systemic corticosteroids or other immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization

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: Atezolizumab<br>Enrollment Phase: Participants will receive four 21-day cycles of cisplatin-based chemotherapy (cisplatin plus either vinorelbine or docetaxel or gemcitabine or pemetrexed [non-squamous cell NSCLC only]), unless unacceptable toxicity, disease relapse, or participant's decision to discontinue occur. Randomization Phase: Participants will receive atezolizumab 1200 milligrams (mg) intravenously (IV) every 3 weeks (Q3W) for sixteen 21-day cycles and will undergo periodic chest X-ray and CT scan. | Drug: Atezolizumab<br>* Participants will receive atezolizumab (1200 mg IV) Q3W for 16 cycles (cycle length=21 days).<br>* Other names: MPDL3280A; TECENTRIQ;Drug: Cisplatin<br>* Participants will receive cisplatin 75 milligrams per square meter (mg/m^2) IV on Day 1 of up to four 21-day cycles.<br>Drug: Vinorelbine<br>* Participants will receive vinorelbine 30 mg/m^2 IV on Days 1 and 8 of each of the four 21-day cycles.<br>Drug: Docetaxel<br>* Participants will receive docetaxel 75 mg/m^2 IV on Day 1 of each of the four 21-day cycles.<br>Drug: Gemcitabine<br>* Participants will receive gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each of the four 21-day cycles.<br>Drug: Pemetrexed<br>* Participants will receive pemetrexed 500 mg/m^2 IV on Day 1 of each of the four 21-day cycles. Pemetrexed will be administered only in participants with non-squamous cell NSCLC.<br>|
| Active Comparator: Best Supportive Care<br>Enrollment Phase: Participants will receive four 21-day cycles of cisplatin-based chemotherapy (cisplatin plus either vinorelbine or docetaxel or gemcitabine or pemetrexed [non-squamous cell NSCLC only]), unless unacceptable toxicity, disease relapse, or participant's decision to discontinue occur. Randomization Phase: After enrollment phase participants will receive only the best supportive care and will undergo periodic chest X-ray and CT scan. | Drug: Cisplatin<br>* Participants will receive cisplatin 75 milligrams per square meter (mg/m^2) IV on Day 1 of up to four 21-day cycles.<br>Drug: Vinorelbine<br>* Participants will receive vinorelbine 30 mg/m^2 IV on Days 1 and 8 of each of the four 21-day cycles.<br>Drug: Docetaxel<br>* Participants will receive docetaxel 75 mg/m^2 IV on Day 1 of each of the four 21-day cycles.<br>Drug: Gemcitabine<br>* Participants will receive gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each of the four 21-day cycles.<br>Drug: Pemetrexed<br>* Participants will receive pemetrexed 500 mg/m^2 IV on Day 1 of each of the four 21-day cycles. Pemetrexed will be administered only in participants with non-squamous cell NSCLC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS), Assessed Using Computed Tomography (CT)/Magnetic Resonance Imaging (MRI)/X-Ray | DFS will be assessed by the investigator in PD-L1 subpopulation within the Stage II-IIIA population, in all randomized patients with Stage II-IIIA NSCLC, and in the ITT population. | From randomization to the date of first recurrence of NSCLC, occurrence of new primary NSCLC, or death from any cause, whichever occurs first (up to approximately 131 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in the ITT Population |  | Baseline up to death from any cause (up to approximately 131 months) | 
| Percentage of Participants Who are Disease-Free at Year 3, Assessed Using CT/MRI/X-Ray | DFS rates will be measured in the PD-L1 subpopulation within the Stage II-IIIA population, in all randomized patients with Stage II-IIIA NSCLC, and in the ITT population. | Year 3 | 
| Percentage of Participants Who are Disease-Free at Year 5, Assessed Using CT/MRI/X-Ray | DFS rates will be measured in the PD-L1 subpopulation within the Stage II-IIIA population, in all randomized patients with Stage II-IIIA NSCLC, and in the ITT population. | Year 5 | 
| DFS Within Selected Populations | DFS rates will be measured within the PD-L1 subpopulation in patients with Stage II-IIIA NSCLC. | From randomization to the date of first recurrence of NSCLC, occurrence of new primary NSCLC, or death from any cause, whichever occurs first (up to approximately 67 months) | 
| Percentage of Participants with Adverse Events |  | Baseline up to approximately 131 months | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab |  | Predose (Hour 0) on Day (D) 1 of Cycles (Cy) 1, 2, 3, 4, 8, 16 (Cy length=21 days), at treatment discontinuation (TD) (up to 12 months), 120 days after last atezolizumab administration (up to 16 months) | 
| Maximum Plasma Concentration (Cmax) of Atezolizumab |  | Post-infusion on Day 1 of Cycle 1 (cy length = 21 days) | 
| Minimum Serum Concentration (Cmin) at Steady-State Within a Dosing Interval of Atezolizumab |  | Prior to infusion on D1 of Cy2, 3, 4, 8, 16 (Cy length = 21 days), and at study termination (up to approximately 131 months) |