Atezolizumab plus bevacizumab showed encouraging responses as a first-line approach to treatment of metastatic renal cell carcinoma (mRCC) in a phase 2 trial. Although the trial failed to meet its primary end point—significant improvement in progression-free survival (PFS) compared with sunitinib—the combination of atezolizumab plus bevacizumab reduced the risk of death or disease progression by 36% in patients enriched for programmed death-1 ligand 1 (PD-L1) expression. Median PFS was almost double in the PD-L1+ group treated with the combination versus sunitinib: 14.7 months versus 7.8 months, respectively.
“Results were impressive in PD-L1+ patients. This benefit of atezolizumab plus bevacizumab in the PD-L1+ patients is different from what was found with nivolumab and shows the importance of the biomarker in patients treated with atezolizumab. The combination of atezolizumab plus bevacizumab looks attractive in PD-L1+ patients. And the PD-L1 biomarker seems particularly marked with the combination. We could have predicted that the biomarker would be less important with the combination than with atezolizumab monotherapy, but that isn’t what happened,” said presenting author Trevor Powles, MD, Barts Cancer Institute, Queen Mary University, London, UK.
“This study is teaching us how to design and conduct our clinical trials in the future,” he stated.
The hypothesis-generating study was the first to evaluate frontline immunotherapy against the benchmark (ie, sunitinib), and the first study of frontline targeted therapy against the benchmark.
The phase 2 study randomized 305 patients with mRCC in a 1:1:1 ratio to standard-of-care sunitinib versus atezolizumab monotherapy versus atezolizumab plus bevacizumab. Crossover to the combination therapy arm was allowed at disease progression. Both atezolizumab-containing arms were compared with sunitinib.
In the overall intention-to-treat analysis, there was no significant difference in PFS with atezolizumab versus sunitinib or atezolizumab plus bevacizumab versus sunitinib. Median PFS was 6.1 months with atezolizumab alone, 8.4 months with sunitinib, and 11.7 months with the combination of atezolizumab plus bevacizumab.
However, a striking difference was observed in PD-L1+ patients (defined as 1% or greater PD-L1 expression on immunochemistry): a 36% reduction in risk of death or disease progression favoring the combination. In PD-L1+ patients, median PFS was 5.5 months for atezolizumab, 7.8 months for sunitinib, and 14.7 months for the combination.
At the time of data collection, 75% of patients treated with immunotherapy were in response.
In PD-L1+ patients, the overall response rate was 46% for the combination therapy and 28% for atezolizumab alone.
Tolerability was improved in the immunotherapy-containing arms versus sunitinib. The rate of grade 3/4 adverse events was 69% with sunitinib, 63% with the combination, and 40% with atezolizumab alone. Fewer all-cause adverse events were reported in the combination arm versus sunitinib, but more immune-related adverse events.
At progression, 78% of the sunitinib group and 60% of the atezolizumab group crossed over to the combination arm. Analysis of crossovers will be presented in the future.
The phase 2 study led to an ongoing phase 3 trial called IMmotion to evaluate the combination of atezolizumab plus bevacizumab as frontline treatment of mRCC in PD-L1+ patients.
The study was sponsored by F. Hoffmann-La Roche Ltd.