FDA Approves Nivolumab for Metastatic Renal Cell Carcinoma

Richard Pazdur, MD

The FDA has approved nivolumab (Opdivo) as a treatment for patients with metastatic renal cell carcinoma (RCC) following prior anti-angiogenic 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. The approval for nivolumab follows a breakthrough therapy designation and was granted nearly 4 months ahead of schedule.

“Opdivo provides an important therapy option for patients with renal cell carcinoma,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease.”

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 focused on objective response rate (ORR), progression-free survival (PFS), and safety.

According to data published in The New England Journal of Medicine after 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.

The ORR with nivolumab was 21.5% compared with 3.9% for those receiving everolimus. The duration of response in the nivolumab arm was 23.0 months compared with 13.7 months with everolimus, according to the FDA.

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 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.

“Opdivo’s extended indication, from melanoma and non—small cell lung cancer to renal cell cancer, demonstrates how immune therapies can benefit patients across a wide range of tumors,” said Pazdur.

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.