The phase III CheckMate 025 trial conducted in patients with advanced renal cell carcinoma (RCC) that progressed following prior antiangiogenic therapy previously met its primary endpoint by demonstrating a survival advantage with nivolumab versus everolimus. Other outcomes included a marked improvement in overall response rate (ORR), fewer severe treatment-related adverse events, and improved quality of life, collectively ushering in nivolumab approval in advanced RCC in the United States in November 2015.
Dr. Robert J. Motzer
In this randomized, open-label phase III trial of 821 patients with advanced RCC whose disease progressed following prior antiangiogenic therapy, median overall survival (OS) within the intent-to-treat population reached 25.0 months among patients treated with single-agent nivolumab, as compared with 19.6 months among patients treated with single-agent everolimus (hazard ratio [HR] 0.73, 98.5% CI [0.57, 0.93]; p = 0.0018). Moreover, the ORR reached 25% with nivolumab versus only 5% with everolimus (odds ratio 5.98, 95% CI [3.68, 9.72]; p < 0.0001).
A prespecified analysis of OS and ORR by subgroup revealed that nivolumab confers its benefits across prognostic risk categories, the number and sites of metastases, and prior therapies, consistent with the benefit observed in the overall population of CheckMate 025.
For example, in patients with poor-risk disease according to Memorial Sloan Kettering Cancer Center criteria, median OS reached 15.3 months with nivolumab as compared with 7.9 months with everolimus (HR 0.48, 95% CI [0.32, 0.70]). “The relatively high benefit for nivolumab in the patients [with poor-risk disease] is particularly noteworthy,” Dr. Motzer said.
Nivolumab also proved efficacious in others subgroups typically associated with a poor prognosis. For example, in patients with bone metastasis, median OS was 18.5 months with nivolumab versus 13.8 months with everolimus (HR 0.72, 95% CI [0.47, 1.09]). Similarly, in patients with liver metastasis, median OS was 18.3 months with nivolumab versus 16.0 months with everolimus (HR 0.81, 95% CI [0.55, 1.18]).
The data according to the type of prior antiangiogenic therapy hold particular interest to begin to understand how to sequences therapies in mRCC. For patients who received prior sunitinib, median OS reached 23.6 months with nivolumab versus 19.8 months with everolimus (HR 0.81, 95% CI [0.64, 1.04]), and for those who received prior pazopanib, median OS is not yet estimable for patients who received nivolumab versus 17.6 months for those who received everolimus (HR 0.60, 95% CI [0.42, 0.84]).
“In both instances, for patients treated with prior pazopanib and prior sunitinib, there was a benefit for nivolumab over everolimus,” Dr. Motzer said. He emphasized that the percentage of patients alive at 18 months following nivolumab therapy was nearly identical for the prior-pazopanib and the prior-sunitinib subgroups (63% and 61%, respectively).
Of interest to many clinicians, nivolumab edged out everolimus for survival improvement among the subgroup of patients who received one prior antiangiogenic therapy. Median OS reached 23.6 months with nivolumab as compared with 19.9 months with everolimus (HR 0.79, 95% CI [0.63, 0.99]). Based on this observation, Dr. Motzer said that nivolumab should be considered as a second-line regimen following antiangiogenic therapy.
“This is based on the survival benefit we’ve established in this trial, it’s favorable safety profile, and the improvement in quality of life compared to everolimus, which has always been regarded as a very well-tolerated and safe drug,” Dr. Motzer said. “The novel mechanism of action as a checkpoint inhibitor modulator and the long-standing responses observed in a subset of patients make this drug very attractive as well as a second-line choice.”
As noted during the question-and-answer session following this and the METEOR presentation, several agents now constitute effective options in the second-line setting. Regarding which agent to use, “it’s really going to be an individual decision. It’s going to be a patient decision; it’s going to be a physician decision. Nivolumab, cabozantinib, axitinib would all be reasonable choices,” Dr. Motzer said.
As noted by others, the weight of evidence currently appears to support use of nivolumab over cabozantinib as second-line therapy in the absence of a head-to-head trial of these agents, given the established survival benefit documented with nivolumab. This may change in the future if and when a survival benefit with cabozantinib is established.