As reported in JAMA Oncology by Robert J. Motzer, MD, and colleagues, the final overall survival analysis of the phase III IMmotion151 trial has shown no significant difference for atezolizumab plus bevacizumab vs sunitinib in previously untreated patients with metastatic renal cell carcinoma (RCC). Molecular analysis identified a combination of gene-expression clusters that appeared to confer a survival benefit with atezolizumab/bevacizumab.
Robert J. Motzer, MD
Study Details
In the open-label trial, 915 patients from sites in 21 countries were randomly assigned to receive atezolizumab at 1,200 mg and bevacizumab at 15 mg/kg every 3 weeks (n = 454) or sunitinib at 50 mg once daily in a 4-weeks-on/2-weeks-off schedule. Random assignment was stratified by presence of liver metastasis, tumor PD-L1 status, and Memorial Sloan Kettering Cancer Center/Motzer risk score. The co–primary endpoints were progression-free survival among patients with PD-L1–positive disease (expression on ≥ 1% of tumor-infiltrating immune cells; n = 362, 40% of total population) and overall survival in the intention-to-treat (ITT) population.
The previously reported progression-free survival analysis among patients with PD-L1–positive disease showed a significant benefit of atezolizumab/bevacizumab vs sunitinib (median = 11.2 vs 7.7 months, hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.57–0.96, P = .0217). At interim overall survival analysis, the hazard ratio was 0.93 (95% CI = 0.76–1.14), with the significance boundary not being crossed.
Overall Survival
At the time of data cutoff (February 14, 2020), the minimum follow-up was 40 months. In the ITT population, death occurred in 54.8% of patients in the atezolizumab/bevacizumab group vs 55.3% of the sunitinib group. Median overall survival was 36.1 months (95% CI = 31.5–42.3 months) in the atezolizumab/bevacizumab group vs 35.3 months (95% CI = 28.6–42.1 months) in the sunitinib group (stratified HR = 0.91, 95% CI = 0.76–1.08, P = .27).
In the PD-L1–positive population, death occurred in 53.9% of patients in the atezolizumab/bevacizumab group vs 56.5% of the sunitinib group. Median overall survival was 38.7 months (95% CI = 29.0–49.7 months) among 178 patients in the atezolizumab/bevacizumab group vs 31.6 months (95% CI = 23.3–42.1 months) among 184 patients in the sunitinib group (stratified HR = 0.85, 95% CI = 0.64–1.13).
Adverse Events
No new safety signals were identified. Adverse events leading to withdrawal from any study treatment occurred in 28% of the atezolizumab/bevacizumab group vs 12% of the sunitinib group. Grade 3 or 4 treatment-related adverse events occurred in 46% of the atezolizumab/bevacizumab group; the most commonly reported event occurring with a ≥ 2% incidence vs the sunitinib group was proteinuria (8%).
Biomarker Analysis
A total of 823 pretreatment tumors were transcriptionally profiled by RNA sequencing; 7 molecular clusters were identified, consisting of: angiogenic/stromal; angiogenic; complement/omega-oxidation; T-effector/proliferative; proliferative; stromal/proliferative; and small nucleolar RNA profiles.
Hazard ratios for overall survival favored atezolizumab/bevacizumab among 116 patients with the T-effector/proliferative cluster (median = 38.7 vs 23.3 months, HR = 0.66, 95% CI = 0.41–1.06) and among 74 patients with the proliferative cluster (21.7 months vs 15.5 months, HR = 0.66, 95% CI = 0.39–1.12). Among 190 patients with these two clusters, median overall survival was 34.0 months vs 19.5 months (HR = 0.69, 95% CI = 0.48–0.98). Among 218 patients with the T-effector/proliferative, proliferative, and small nucleolar RNA (n = 28) clusters, median overall survival was 35.4 vs 21.2 months (HR = 0.70, 95% CI = 0.50–0.98).
The investigators concluded, “The primary endpoint of progression-free survival was met at interim analyses, although no improvement in overall survival was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with metastatic RCC may benefit from combined anti–PD-L1 and anti-VEGF therapy.”
Dr. Motzer, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was funded by F. Hoffmann-La Roche Ltd. and Genentech, Inc. For full disclosures of the study authors, visit jamanetwork.com.
