Combination of Atezolizumab and Bevacizumab in PD-L1–Positive Patients With Metastatic Kidney Cancer



The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) appears to be promising in the first-line treatment of patients with metastatic renal cell carcinoma, according to results of a phase II trial presented at the 2017 Genitourinary Cancers Symposium.1

Despite the failure of the combination to show a statistically significant difference in progression-free survival when compared with the gold standard sunitinib (Sutent), the study did demonstrate that the combination of immunotherapy plus bevacizumab reduced the risk of death or disease progression by 36% in patients enriched for expression of programmed cell death ligand 1 (PD-L1). Additionally, median progression-free survival was almost double in the PD-L1–positive group treated with the combination vs sunitinib: 14.7 months vs 7.8 months, respectively.


A subgroup analysis of progression-free survival further demonstrated the importance of PD-L1 as a biomarker of response, with enriched response for the combination [atezolizumab and bevacizumab] in PD-L1–positive patients.
— Thomas Powles, MBBS, MRCP, MD

“This study is important because it taught us what we need to do in the future and helped us evolve our thinking about how to design and conduct our clinical trials,” announced Thomas Powles, MBBS, MRCP, MD, of Barts Cancer Institute and Queen Mary University of London, United Kingdom.

“This trial showing a trend for the benefit of atezolizumab plus bevacizumab in the PD-L1–positive patients is different from what we saw with nivolumab (Opdivo) and shows the importance of the biomarker in patients treated with atezolizumab. The combination of atezolizumab plus bevacizumab looks attractive in PD-L1–positive patients,” declared Dr. Powles. “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,” he continued.

Study Details

Dr. Powles pointed out that this was the first study of frontline immunotherapy against the benchmark (ie, sunitinib) and the first study of front-line targeted therapy against the benchmark. “Bevacizumab plays a role in the immune cycle and is associated with T-cell infiltration. We think the combination may be synergistic,” Dr. Powles told listeners.

Combination Therapy for Metastatic Kidney Cancer

  • The first phase II study to evaluate the combination of an anti–PD-L1 immunotherapy plus a VEGF-targeted therapy in metastatic kidney cancer failed to show that the combination significantly improved progression-free survival in the overall study population.
  • However, the combination had more robust results in PD-L1–positive patients, achieving a 36% reduction in death and the risk of disease progression and higher overall response rates compared with sunitinib.
  • The combination is being evaluated in a phase III trial, which should
    shed more light on its efficacy and whether PD-L1 is a useful biomarker
    in this setting.

The hypothesis-generating phase II study enrolled and randomized 305 patients with metastatic renal cell carcinoma in a 1:1:1 ratio to receive standard-of-care sunitinib vs atezolizumab monotherapy vs atezolizumab plus bevacizumab. Crossover to the combination therapy arm was allowed at disease progression. Both atezolizumab-containing arms were compared with sunitinib.

The coprimary endpoints of the trial were progression-free-survival in the intent-to-treat population and in PD-L1–positive patients (ie, 1% or greater PD-L1 expression on immunochemistry).

Biomarker of Response

In the overall study, the intent-to-treat analysis showed no significant difference in progression-free survival for atezolizumab vs sunitinib or atezolizumab plus bevacizumab vs sunitinib. Median progression-free survival was 6.1 months for atezolizumab alone, 8.4 months with sunitinib, and 11.7 months for the combination of atezolizumab plus bevacizumab.

A striking difference was observed in PD-L1–positive patients, with a 36% reduction in the risk of death or disease progression favoring the combination. In PD-L1–positive patients, median progression-free survival was 5.5 months for atezolizumab, 7.8 months for sunitinib, and 14.7 months for the combination.

“A subgroup analysis of progression-free survival further demonstrated the importance of PD-L1 as a biomarker of response, with enriched response for the combination in PD-L1–positive patients. This is different from what we see with nivolumab, showing this [immunotherapy biomarkers] is a complicated area,” Dr. Powles revealed.

Responses were ongoing in 75% of patients in the immunotherapy arms. The highest overall response rate was 46% in PD-L1–positive patients in the combination arm and 28% in this subgroup with atezolizumab alone.

“In the immunotherapy era, we are interested in long-term survival. We also saw a high overall response rate to immunotherapy in unselected patients [for PD-L1 expression],” he added.

Toxicity

Tolerability was improved in the immunotherapy-containing arms compared with sunitinib. The rate of grade 3/4 adverse events was 69% with sunitinib, 63% with the combination, and 40% with atezolizumab alone. There were fewer all-cause adverse events in the combination arm vs sunitinib but more immune-related adverse events. “Quality of life is important for these patients with limited life expectancy. The toxicity profile of immunotherapy is attractive,” Dr. Powles stated.

He continued: “These data corroborate the clinical activity of atezolizumab in the first-line treatment of metastatic renal cell carcinoma. The safety of the combination is similar to previous safety data on each drug alone.”

After disease 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.

A phase III trial called IMmotion151 (ClinicalTrials.gov identifier: NCT02420821) is currently evaluating the clinical benefit of the combination of atezolizumab plus bevacizumab in the front-line treatment of metastatic renal cell carcinoma in PD-L1–positive patients. “This trial had an impact on the phase III trial. We hope this will change the way we treat metastatic renal cell carcinoma,” Dr. Powles concluded. ■

Disclosure: The study was sponsored by F. Hoffmann-LaRoche. Dr. Powles has served as a consultant or advisor to AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, and Novartis and has received research funding from AstraZeneca/MedImmune and Roche/Genentech.

Reference

1. McDermott DF, Atkins MB, Motzer RJ, et al: A phase II study of atezolizumab with or without bevacizumab versus sunitinib in untreated metastatic renal cell carcinoma patients. 2017 Genitourinary Cancers Symposium. Abstract 431. Presented February 18, 2017.


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Expert Point of View: Eric Jonasch, MD


These data are hypothesis-generating and will be confirmed in the phase III study. A positive result will usher in the first predictive biomarker for patients with advanced renal cell carcinoma….
— Eric Jonasch, MD

Eric Jonasch, MD, Professor in the Department of...


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