A Study of Atezolizumab as Adjuvant Therapy in Participants With Renal Cell Carcinoma (RCC) at High Risk of Developing Metastasis Following Nephrectomy

Study Overview
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Brief Summary
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This is a Phase III, multicenter, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of atezolizumab versus placebo in participants with RCC who are at high risk of disease recurrence following nephrectomy.

Official Title
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A Phase III, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of Atezolizumab (Anti-PD-L1 Antibody) as Adjuvant Therapy in Patients With Renal Cell Carcinoma at High Risk of Developing Metastasis Following Nephrectomy

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Atezolizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG performance status of less than or equal to (</=) 1 Pathologically confirmed RCC with a component of either clear cell histology or sarcomatoid histology that has not been previously treated in the adjuvant or neoadjuvant setting and classified as being at high risk of RCC recurrence Radical or partial nephrectomy with lymphadenectomy in select participants Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Confirmation of disease-free status will be assessed by an independent central radiologic review of imaging data. Absence of brain metastasis, as confirmed by a negative CT with contrast or magnetic resonance imaging (MRI) scan of the brain, no more than 4 weeks prior to randomization. Applicable only to metastasectomy participants Full recovery from nephrectomy or metastasectomy within 12 weeks from randomization following surgery Exclusion Criteria: Bilateral synchronous tumors with inheritable forms of RCC including von Hippel-Lindau Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days or five half-lives of the investigational agent, whichever is longer, prior to enrollment Malignancies other than RCC within 5 years prior to Cycle 1, Day 1 History of autoimmune disease Participants with prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan Positive test for HIV Participants with active hepatitis B or hepatitis C Active tuberculosis Severe infections within 4 weeks prior to randomization including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 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 Prior treatment with cluster of differentiation (CD)137 agonists, anti-cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), or anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibody or pathway-targeting agents Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to randomization Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to randomization or anticipated need for systemic immunosuppressive medications during the study

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab<br>Participants will receive atezolizumab 1200 milligrams (mg) intravenous (IV) infusion every 3 weeks (q3w) for 16 cycles (each cycle=21 days) or 1 year (whichever occurs first). | Drug: Atezolizumab<br>* Atezolizumab 1200 mg IV infusion q3w<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo matching to atezolizumab q3w for 16 cycles (each cycle=21 days) or 1 year (whichever occurs first). | Other: Placebo<br>* Placebo matching to atezolizumab q3w<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Disease-Free Survival (DFS) | Investigator-assessed DFS, defined as the time from randomization to death from any cause or the first documented recurrence assessed by investigator, whichever occurred first. Recurrence was defined as any of the following: Local recurrence of renal cell carcinoma (RCC), new primary RCC, or distant metastasis of RCC. Investigator-assessed DFS was analyzed similarly to the analysis of IRF-assessed DFS. | From baseline up to first occurence of event by investigator assessment (up to approximately 64 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death from any cause. | From baseline up to death due to any cause (up to approximately 64 months) | 
| Investigator-assessed DFS in Participants With Tumor-Infiltrating Immune Cell (IC) 1/2/3 | Investigator assessed DFS for participants with PD-L1 expression of IC1/2/3 vs IC0, defined as the time from randomization to death from any cause or the first documented recurrence assessed by investigator, whichever occurred first. Investigator-assessed DFS was analyzed similarly to the analysis of IRF-assessed DFS. PD-L1 IC0 was defined as <1% and IC1/2/3 was defined as >=1% of tumor-infiltrating IC expressing PD-L1 as assessed by immunohistochemistry using SP142 assay. Recurrence was defined as any of the following: Local recurrence of renal cell carcinoma (RCC), new primary RCC, or distant metastasis of RCC. | From baseline until first occurrence of DFS event (up to approximately 64 months) | 
| Independent Review Facility (IRF)-Assessed DFS | IRF-assessed DFS was defined as the time from randomization to death from any cause or the first documented recurrence assessed by IRF, whichever occurred first. | From baseline until first documented recurrence event (up to approximately 64 months) | 
| IRF-assessed DFS in Participants With Tumor-Infiltrating IC 1/2/3 | IRF-assessed DFS was defined as the time from randomization to death from any cause or the first documented recurrence assessed by IRF, whichever occurred first. PD-L1 IC0 was defined as <1% and IC1/2/3 was defined as >=1% of tumor-infiltrating IC expressing PD-L1 as assessed by immunohistochemistry using SP142 assay. | From baseline until first occurrence of DFS event (up to approximately 64 months) | 
| IRF-assessed Event-free Survival (EFS) | IRF-assessed EFS was defined as the time from randomization to death from any cause, or the first documented recurrence in participants without baseline disease by IRF or the first documented disease progression in participants identified as having baseline disease by IRF, whichever occurred first. Disease progression was defined as either unequivocal progression of baseline disease or new unequivocal lesions. | From baseline until first documented recurrence event (up to approximately 64 months) | 
| Disease-Specific Survival | Disease-specific survival was defined as the time from randomization to death from renal cell carcinoma (RCC). | From baseline up to death due to RCC (up to approximately 64 months) | 
| Distant Metastasis-Free Survival | Distant metastasis-free survival, defined as the time from randomization to death from any cause or the date of diagnosis of distant (i.e., non-locoregional) metastases assessed by the investigator, whichever occurred first. | From baseline up to date of diagnosis of distant metastases or death due to any cause (up to approximately 64 months) | 
| Percentage of Participants Who Are Alive and IRF-assessed Recurrence Free at Year 1, 2, and 3 | IRF-assessed DFS was defined as the percentage of participants being alive and free of recurrence assessed by IRF at Year 1, 2, and 3 after randomization. | Up to 3 years | 
| Percentage of Participants Who Are Alive and Investigator-assessed Recurrence Free at Year 1, 2, and 3 | Investigator-assessed DFS rate was defined as the percentage of participants being alive and free of recurrence assessed by investigator at Year 1, 2, and 3 after randomization. | Up to 3 years | 
| Percentage of Participants With Adverse Events | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unitended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a pharmaceutical product whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as a AEs. | From baseline up to death due to any cause (up to approximately 71 months) | 
| Maximum Serum Concentration (Cmax) of Atezolizumab |  | Predose (Hour[hr]0), 0.5 hr after end of infusion (infusion duration=1 hr) on Cycle 1 Day 1; predose (hr 0) on Day 1 of Cycles 2, 3, 4, 8; at treatment discontinuation (up to 1 year); 90-120 days after last dose (last dose = up to 1 year) (Cycle=21 days) | 
| Minimum Serum Concentration (Cmin) of Atezolizumab |  | Predose (Hour[hr]0), 0.5 hr after end of infusion (infusion duration=1 hr) on Cycle 1 Day 1; predose (hr 0) on Day 1 of Cycles 2, 3, 4, 8; at treatment discontinuation (up to 1 year); 90-120 days after last dose (last dose = up to 1 year) (Cycle=21 days) | 
| Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab |  | Predose (hr 0) on Day 1 of Cycles 1, 2, 3, 4, 8; at treatment discontinuation (up to 1 year); 90-120 days after last dose (last dose = up to 1 year) (Cycle=21 days) |