Nivolumab 5-Year OS Rate Passes 30% in Advanced RCC

David F. McDermott, MD

About one third of patients with advanced renal cell carcinoma (aRCC) who were treated with single-agent nivolumab (Opdivo) in the second-line setting or later were still alive at 4 and 5 years in long-term follow-up data from phase I and phase II clinical trials. The analysis was presented at the 2016 ASCO Annual Meeting, and represents the longest follow-up with an anti-PD-1 agent to date in the treatment of RCC.¹

In the phase I study, the 5-year overall survival (OS) rate was 34%. In the phase II study, 29% of patients remained alive at 4 years. Moreover, subgroup analyses showed that responses were consistent across patients groups, and follow-up data from the pivotal phase III CheckMate-025 study, which led to FDA approval, demonstrated improvements in health-related quality of life with nivolumab versus everolimus (Afinitor).

“Long-term survival [with nivolumab treatment] is achievable regardless of risk group, performance status, or best overall response,” said David McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, Boston.

In the pivotal phase III CheckMate-025 study, nivolumab was significantly superior to everolimus in OS in patients with aRCC who had received prior anti-angiogenic therapy, with a minimum follow-up of 14 months (25.0 vs 19.6 months, P = .002). This study led to the approval of nivolumab in the United States and Europe for the treatment of patients with aRCC following prior therapy.

The open-label phase I study enrolled 34 patients with ECOG performance status ≤2 who had received 1 to 5 prior systemic treatment regimens, who were treated with nivolumab, 1 or 10 mg/kg, every 2 weeks for a maximum of 96 weeks. The phase II study included 168 patients with Karnofsky performance status ≥70% who had received 1 to 3 prior treatment regimens in the metastatic setting; they were treated with nivolumab at 0.3, 2, or 10 mg/kg every 3 weeks continuously until disease progression.

“The median OS was greater than 22 months for patients on both the phase I and phase II trials,” said McDermott. “With follow-up now over 48 months, approximately one third of patients are alive at 4 years on both the phase I and phase II studies, and 34% of patients are alive at 5 years on the phase I trial. We look forward to examining whether nivolumab produces similar long-term survival in the phase III trial.”

Long-term OS was explored by baseline and response characteristics. In the phase II trial, encouraging long-term survival outcomes were observed in both the favorable-risk and unfavorable-risk subgroups, including good-, intermediate-, and poor-risk patients by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria.

Long-term survival was also seen in patients with excellent or reduced Karnofsky performance status (median OS: 27.2 months and 14.6 months, respectively) in the phase II trial.

“In patients with objective response, stable disease, or progressive disease as their best response, these data suggest that long-term survival is achievable in all subgroups,” he said. Median OS was not reached in patients with complete or partial response. Median OS was 22.9 months in those with stable disease, and was 9 months in those with progressive disease.

Of the 48 patients in the phase II trial who were alive at 4 years, 15 required no subsequent therapy. “Interestingly, stable disease and progressive disease was the best response for more than 50% of the patients who achieved long-term survival in this trial,” said McDermott.

An OS advantage to nivolumab over everolimus was also apparent in the phase III trial in all risk groups, including traditionally unfavorable risk groups, such as MSKCC poor-risk patients, those with reduced Karnofsky performance status, and patients whose best response was progressive disease, he noted. “It will be interesting to see if these survival benefits are maintained with longer follow-up,” he said.

Long-term safety of nivolumab was also assessed. With more than 4 years of follow-up, grade 3 toxicity occurred in <20% of nivolumab-treated patients, and treatment-related adverse events leading to discontinuation were observed in <10%. “These results are notable because they remain similar to the safety outcomes in the larger phase III study, even with an additional 3 years of follow-up,” he said.

Most side effects in the phase I and II trials were reversible. The highest percentage of adverse events in patients at risk occurred within the first 6 months of treatment; no endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin adverse events occurred after 30 months of starting nivolumab, and similar trends were seen in the emergence of all reported treatment-related adverse events.

While most side effects were well managed with immune-modulating therapy, “not all side effects resolved completely,” said McDermott. For example, while all grade 3 and 4 endocrine toxicities resolved with treatment, half of the patients with grade 1 and 2 toxicity required ongoing hormonal replacement therapy.

In the phase II trial, the median time to response was 2.8 months and the median duration of response was 23.0 months.

McDermott DF, Motzer RJ, Atkins MB, et al. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. Presented at: ASCO 2016; June 3-7, 2016; Chicago. Abstract 4507.

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