Nivolumab Approved for Metastatic Renal Cell Carcinoma by FDA

The FDA has approved nivolumab (Opdivo) as a treatment for patients with metastatic renal cell carcinoma following prior treatment with an anti-angiogenic therapy.

Richard Pazdur, MD

The FDA has approved nivolumab (Opdivo) as a treatment for patients with metastatic renal cell carcinoma (RCC) following prior treatment with an anti-angiogenic therapy. The approval is based on results from the CheckMate-025 trial, which showed an extension in overall survival (OS).

The approval follows a breakthrough therapy designation for the drug and comes 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 CheckMate-025, a phase III open-label study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor). This represents 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. In trial, 821 pretreated patients with advanced or metastatic clear-cell RCC were randomized in a 1:1 ratio to nivolumab or everolimus.

Of the patients, 803 received treatment with Nivolumab being administered intravenously at 3 mg/kg every 2 weeks (n = 406) and everolimus was given orally at 10 mg daily (n = 397), with 72% of patients having received one angiogenesis inhibitor and 28% had received two.

OS was the primary endpoint for the study, with secondary outcome measures including objective response rate (ORR) and progression-free survival (PFS). The median patient age was 62 years.

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 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,” continued Pazdur.


  1. 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.