FDA Grants Priority Review to Nivolumab for Renal Cell Carcinoma

Michael Giordano, MD

The FDA has assigned a priority review designation to the PD-1 inhibitor nivolumab (Opdivo) as a treatment for patients with advanced renal cell carcinoma (RCC) following prior antiangiogenic therapy, based on an extension in overall survival (OS) in the CheckMate-025 trial.

In the pivotal phase III study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median OS. Grade 3/4 adverse events (AEs) were also lower with the PD-1 inhibitor compared with everolimus, according to data published in The New England Journal of Medicine (NEJM).

The priority review follows a breakthrough therapy designation for nivolumab, which was granted by the FDA in September 2015. A final approval decision for the supplemental biologics license application (sBLA) will be made by March 16, 2016.

“There remains a significant unmet medical need for advanced renal cell carcinoma patients who have received prior therapy and are often repeatedly treated with agents that are similar in mechanism," Michael Giordano, MD, senior vice president, head of Oncology Development, Bristol-Myers Squibb, said in a statement. "We are pleased the FDA has accepted our sBLA for Opdivo in RCC, and we will continue to work with urgency to bring Opdivo to patients with this cancer.”

In the open-label CheckMate-025 trial, 821 pretreated patients with advanced or metastatic clear-cell RCC were randomized in a 1:1 ratio to nivolumab or everolimus. Of randomized patients, 803 received treatment. Nivolumab was administered intravenously at 3 mg/kg every 2 weeks (n = 406) and everolimus was given orally at 10 mg daily (n = 397).

The median patient age was 62 years. Seventy-two percent of patients had received one angiogenesis inhibitor and 28% had received two. OS was the primary endpoint, with secondary outcome measures including objective response rate (ORR) and progression-free survival (PFS).

At a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .002). The OS benefit was observed across patient subgroups, with the greatest improvement with nivolumab seen for those with a poor MSKCC prognostic score (HR, 0.47; 95% CI, 0.30-0.73).

Median PFS was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; P = .11). In an ad hoc sensitivity analysis of patients who had not progressed at 6 months, the median PFS was 15.6 months with nivolumab versus 11.7 months with everolimus (HR, 0.64; 95% CI, 0.47-0.88). This analysis was meant to take pseudoprogression into consideration.

ORR was 25% in the nivolumab arm versus 5% in the everolimus group (odds ratio, 5.98; 95% CI, 3.68-9.72; P <.001). The median duration of response was 12.0 months for both arms, and the median time to response was 3.5 and 3.7 months in the nivolumab and everolimus arms, respectively.

PD-L1 expression was not found to significantly impact the efficacy of nivolumab. Among patients with PD-L1 expression ≥1%, median OS was 21.8 versus 18.8 months for nivolumab and everolimus, respectively. In patients with PD-L1 expression ≤1%, median OS was 27.4 and 21.2 months in the two arms, respectively. Similar outcomes were observed when using a 5% threshold for PD-L1 expression status, although only a small number of patients were evaluable by this criterion.

All-grade AE rates occurred in 79% of patients treated with nivolumab versus 88% in the everolimus group. Fatigue (33%), nausea (14%), and pruritus (14%) were the most frequently reported AEs with nivolumab. The most common AEs in the everolimus arm were fatigue (34%), stomatitis (29%), and anemia (24%).

The rate of grade 3/4 toxicities was lower with nivolumab (19%) versus everolimus (37%). The most common grade 3/4 adverse events were fatigue (2%) in the nivolumab arm and anemia (8%) in the everolimus arm. Two treatment-related deaths were reported for the everolimus group and none for the nivolumab cohort.

“Nivolumab showed a favorable toxicity profile, with fewer grade 3 or 4 adverse events compared to everolimus,” lead author of the NEJM article Robert J. Motzer, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, told OncLive. “One of the previous standouts for everolimus as a popular treatment in kidney cancer was its favorable safety profile, so showing an improvement in the safety profile compared to everolimus is really remarkable.”

Nivolumab was initially approved in December 2014 for patients with unresectable or metastatic melanoma following treatment with ipilimumab (Yervoy) or a BRAF inhibitor. Since this initially approval, the agent has gained a number of other indications. Recently, the FDA approved the PD-1 inhibitor as a treatment for patients with pretreated advanced non—small cell lung cancer across all histologies. Additionally, nivolumab has been approved in combination with ipilimumab for advanced melanoma.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. 2015;373:1803-1813.