Robert J. Motzer, MD

As reported in JAMA Oncology by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, the final overall survival analysis of the phase III IMmotion151 trial has shown no significant difference for the PD-L1 inhibitor atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma.¹ Molecular analysis identified gene-expression clusters that appeared to confer a survival benefit with atezolizumab plus bevacizumab.

Study Details

In the open-label trial, 915 patients from sites in 21 countries were randomly assigned between May 2015 and October 2016 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. Randomization was stratified by the 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).² At the 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 the atezolizumab 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 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 at final analysis. Grade 3 or 4 adverse events occurred in 60% of the atezolizumab/bevacizumab group vs 68% of the sunitinib group and were considered treatment-related in 46% vs 56%; the most commonly reported treatment-related event with atezolizumab/bevacizumab occurring with a at least a 2% incidence vs the sunitinib group was proteinuria (8%). Serious adverse events occurred in 42% vs 37% and were considered treatment-related in 22% vs 15%. Adverse events led to discontinuation of treatment in 28% of the atezolizumab/bevacizumab group (including atezolizumab in 16% and bevacizumab in 26%) vs 12% of the sunitinib group. Treatment-related death occurred in seven patients (2%) in the atezolizumab/bevacizumab group vs one patient (0.2%) in the sunitinib group.

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).

For other clusters, hazard ratios for atezolizumab/bevacizumab vs sunitinib were 0.94 (95% CI = 0.52–1.72) among 98 patients with the angiogenic/stromal cluster, 1.32 (95% CI = 0.91–1.91) among 245 with the angiogenic cluster, 0.99 (95% CI = 0.64–1.54) among 156 with the complement/omega-oxidative cluster, and 0.90 (95% CI = 0.57–1.40) among 106 with the stromal/proliferative cluster.

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 renal cell carcinoma] may benefit from combined anti−PD-L1 and anti-VEGF therapy.” 

DISCLOSURE: The study was funded by F. Hoffmann–La Roche and Genentech. Dr. Motzer has served as a consultant or advisor to Genentech/Roche, Pfizer, Novartis, Eisai, Exelixis, Lilly, Incyte, EMD Serono, and Merck; has received research support from Genentech/Roche, Bristol Myers Squibb, Novartis, Eisai, Exelixis, and Merck; and has received personal fees from an Aveo consulting/advisory board outside the submitted work.

REFERENCES

1. Motzer RJ, Powles T, Atkins MB, et al: Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol 8:275-280, 2022.

2. Rini BI, Powles T, Atkins MB, et al: Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomised controlled trial. Lancet 393:2404-2415, 2019.