The approval was based on an extension in overall survival (OS) in the CheckMate-025 trial.
The FDA has approved Opdivo (nivolumab) as a treatment for patients with metastatic renal cell carcinoma (RCC) following prior treatment with an anti-angiogenic therapy, based on an extension in overall survival (OS) in the CheckMate-025 trial.
In the pivotal phase 3 study, Opdivo reduced the risk of death by 27 percent versus Afinitor (everolimus), 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 Afinitor. The approval for Opdivo 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 Opdivo or Afinitor. Of randomized patients, 803 received treatment. Opdivo was administered intravenously at 3 mg/kg every 2 weeks (406 patients) and Afinitor was given orally at 10 mg daily (397 patients).
The median patient age was 62 years. Seventy-two percent of patients had received one angiogenesis inhibitor and 28 percent had received two. OS was the primary endpoint, with secondary outcome measures including 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 Opdivo versus 19.6 months with Afinitor. The OS benefit was observed across patient subgroups, with the greatest improvement with Opdivo seen for those with a poor MSKCC prognostic score.
Median PFS was 4.6 and 4.4 months in the Opdivo and Afinitor arms, respectively. In an ad hoc sensitivity analysis of patients who had not progressed at 6 months, the median PFS was 15.6 months with Opdivo versus 11.7 months with Afinitor. This analysis was meant to take pseudoprogression into consideration.
The ORR with nivolumab was 21.5 percent compared with 3.9 percent 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 Opdivo. Among patients with PD-L1 expression at least 1 percent, median OS was 21.8 versus 18.8 months for Opdivo and Afinitor, respectively. In patients with PD-L1 expression less than or equal to 1 percent, median OS was 27.4 and 21.2 months in the two arms, respectively. Similar outcomes were observed when using a 5 percent 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 percent of patients treated with Opdivo versus 88 percent in the Afinitor group. Fatigue (33 percent), nausea (14 percent), and pruritus (14 percent) were the most frequently reported AEs with Opdivo. The most common AEs in the Afinitor arm were fatigue (34 percent), stomatitis (29 percent) and anemia (24 percent).
The rate of grade 3/4 toxicities was lower with Opdivo (19 percent) versus Afinitor (37 percent). The most common grade 3/4 adverse events were fatigue (2 percent) in the Opdivo arm and anemia (8 percent) in the Afinitor arm. Two treatment-related deaths were reported for the Afinitor group and none for the Opdivo cohort.
Opdivo was initially approved in December 2014 for patients with unresectable or metastatic melanoma following treatment with Yervoy (ipilimumab) 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, Opdivo has been approved in combination with Yervoy 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.