THE TYROSINE KINASE inhibitor sunitinib (Sutent) has been the mainstay of treatment for first-line treatment of advanced renal cell carcinoma for about a decade. The IMmotion151 study reported at the 2018 Genitourinary Cancers Symposium found that the combination of the immune checkpoint inhibitor atezolizumab (Tecentriq) plus the antiangiogenic agent bevacizumab (Avastin) improved progression-free survival compared to standard sunitinib as first-line treatment of advanced renal cell carcinoma.1
Several combination therapies are being studied in this setting, including nivolumab (Opdivo)/ipilimumab (Yervoy), an all-immunotherapy combination. IMmotion151 is the first phase III trial of a programmed cell death ligand 1 (PD-L1) inhibitor combined with an anti–vascular endothelial growth factor agent in the first-line treatment of metastatic renal cell carcinoma.
The results of IMmotion151 showed that atezolizumab plus bevacizumab delayed cancer progression by 3.5 months compared with standard sunitinib in patients with previously untreated metastatic renal cell carcinoma, and those with PD-L1–positive tumors derived a greater benefit from the combination vs sunitinib. Further, side effects were less frequent and less severe with atezolizumab plus bevacizumab compared with sunitinib.
Robert J. Motzer, MD
“Because the side effects were decidedly less harsh and the progression-free survival was better, this relatively easy-to-administer combination should be considered a first-line option for advanced renal cell carcinoma,” said lead author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.
Although a 3.5-month gain in progression-free survival is relatively modest, Dr. Motzer deemed it clinically relevant. “For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5-month longer progression-free survival, given the tolerability of this new combination treatment regimen, is an important development.”
Dr. Motzer provided a rationale for combining atezolizumab with bevacizumab. “With the introduction of checkpoint inhibitors, clinicians started looking at combinations of these medicines with antiangiogenic medicines like bevacizumab. Bevacizumab may affect the local immune response in the tumor and help prime the response of tumor and immune cells to immune-system activators like atezolizumab,” he noted.
IMMOTION151 ENROLLED 915 patients with untreated metastatic renal cell carcinoma and randomized them 1:1 to treatment with atezolizumab plus bevacizumab vs standard-of-care sunitinib. No dose reductions were allowed for atezolizumab plus bevacizumab. Patients were stratified for PD-L1 expression based on immunohistochemistry staining on tumor-infiltrating immune cells (< 1% vs ≥ 1%). Of the 915 patients, 362 (40%) were PD-L1–positive.
Patients with clear cell or sarcomatoid disease were enrolled. Baseline characteristics were comparable between the two treatment arms among the PD-L1–positive patients and for the entire study population. There were more sarcomatoid tumors in the PD-L1–positive group than in the total (intent-to-treat) population.
“For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5-month longer progression-free survival, given the tolerability of this new combination treatment regimen, is an important development.”— Robert J. Motzer, MD
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THE STUDY MET its primary endpoint of investigator-assessed progression-free survival. For PD-L1–positive patients, the median progression-free survival was 11.2 months with atezolizumab plus bevacizumab vs 7.7 months on standard sunitinib, for a 26% reduction in the likelihood of disease progression (P = .02).
For the secondary endpoint of investigator-assessed progression-free survival in the intent-to-treat population of patients with all levels of PD-L1 expression, median progression-free survival was 11.2 months for the combination vs 8.4 months for standard sunitinib—a 17% reduction in the likelihood of disease progression associated with the combination therapy (P = .02). Thus, results for the secondary endpoint supported those of the primary endpoint.
In PD-L1–positive patients, the objective response rate was 43% for the combination vs 35% for sunitinib, and the duration of response was not reached for the combination vs 12.9 months for sunitinib. In the intent-to-treat population, objective response rates were 37% for the combination and 33% for sunitinib, and the median duration of response was 16.6 vs 14.2 months, respectively.
Among PD-L1–positive patients, complete response rates were 9% for the combination vs 5% for sunitinib. In the intent-to-treat analysis, complete response rates were 5% vs 2%, respectively.
FOR THE intent-to-treat analysis, the assessment of progression-free survival and objective response rate was generally consistent between the investigator assessment and that of the independent radiology committee, but results were not in close agreement in the PD-L1–positive population. Dr. Motzer said he and his coauthors were looking into this, and so far, the explanation remains undetermined.
In PD-L1–positive patients, median overall survival was not reached for the combination vs 23.3 months for sunitinib. In the intent-to-treat analysis, median overall survival was not reached in either group.
“Survival is immature, but the hazard ratio of 0.68 favors the combination. We await the final survival analysis,” Dr. Motzer said.
“One of the main benefits of the combination is its safety profile, with low steroid use to treat immune-related side effects and delayed symptom interference,” Dr. Motzer commented.
Treatment-related grade 3 and 4 adverse events were seen in 40% of those treated with atezolizumab plus bevacizumab vs 54% of those in the sunitinib group. Only 16% of those treated with the combination required steroids for immune-related side effects. Of patients treated with sunitinib, 37% required a dose modification, but no dose modifications were allowed in the combination arm. ■
DISCLOSURE: The study was sponsored by F. Hoffmann-La Roche Ltd., Basel, Switzerland. Dr. Motzer has had a consulting or advisory role for Eisai, Exelixis, Merck, Novartis, and Pfizer and has received research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer.
1. Motzer RJ, Powles T, Atkins MB, et al: IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma. 2018 Genitourinary Cancers Symposium. Abstract 578. Presented February 10, 2018.
Sumanta K. Pal, MD
ASCO EXPERT Sumanta K. Pal, MD, of City of Hope, Duarte, California, commented, “IMmotion 151 is a positive trial and represents an important breakthrough. We have debated combination treatment strategies for advanced kidney cancer. This study looks at the combination of ...!-->!-->