Nivolumab/Ipilimumab Combo Gets FDA Approval for BRAF Wild-Type Melanoma

Tim Turnham

Tim Turnham

The FDA has approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma

FDA’s approval was based on findings from the phase II CheckMate-069 study which found that the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab reduced the risk of progression or death by 60% compared with ipilimumab. With the combination, the objective response rate (ORR) was 60% compared with 11% with ipilimumab alone in patients with BRAF wild-type melanoma.

The accelerated approval marks the first for an immunotherapy combination for patients with cancer, and an application for full approval is pending with the FDA. The full approval submission is based on the phase III CheckMate-067 study, which showed a 59% reduction in the risk of progression or death with the combination versus ipilimumab alone. The FDA is scheduled to make a decision on this application by January 23, 2016.

“We are currently witnessing a turning point in cancer history, based on the significant impact immuno-oncology is making in the lives of patients with metastatic melanoma,” Tim Turnham, executive director, Melanoma Research Foundation, said in a statement. “Today’s approval of the first regimen of two immuno-oncology agents, Opdivo and Yervoy, is an exciting moment for our community because it reinforces we are on a positive path forward, providing new approaches which translate into meaningful results for patients.

In the CheckMate-069 trial, 142 treatment-naïve patients with stage III/IV melanoma were randomized in a 2:1 ratio to 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for four doses, followed by nivolumab at the same dose or placebo every 2 weeks until disease progression or unacceptable toxicity. Median patient age was 65 years, two-thirds of patients were male, and all but two patients had an ECOG performance status of 0 or 1.

Among patients with BRAF wild-type tumors (N = 109), median progression-free survival (PFS) was 8.9 months in the nivolumab/ipilimumab group (n = 72) versus 4.7 months in the ipilimumab arm (n = 37). In the study, similar PFS data were observed among patients with BRAF-positive melanoma (n = 33), at 8.5 months versus 2.7 months in the combination (n = 23) and control (n = 10) arms.

The complete response rate with the combination was 17% versus none with monotherapy for patients with BRAF wild-type melanoma. Moreover, ORR with the combination was found to be independent of PD-L1 status. In PD-L1—positive and –negative tumors, respectively, ORR was 58% and 55% with nivolumab/ipilimumab. In BRAF-positive patients, ORR was 52% versus 10% with the two-drug regimen versus monotherapy.

At 6 months, 79% of patients in the combination arm continued to respond to treatment. Of these patients, the median duration of response was <9 months for 14 and >9 months for 20. The remaining 9 patients had a duration of response ranging from 3 to 7 months.

Rates of all-grade adverse events (AEs) were similar between the combination and monotherapy arms at 91% and 93%, respectively. Serious AEs occurred in 62% of patients treated with the combination versus 39% with single-agent ipilimumab. AEs leading to discontinuation were more common with the combination (43% vs 11%). Grade 3/4 AEs occurred in 69% of patients with the combination and in 43% for the monotherapy.

The most frequently observed AEs with the combination versus the single-agent were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0). The most common AEs with the combination versus the single-agent, respectively, were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

“Historically, metastatic melanoma has been a difficult disease to treat. Now, a new treatment option based on the combination of two valued immuno-oncology agents demonstrates significant efficacy versus ipilimumab in metastatic melanoma,” Jedd D. Wolchok, MD, PhD, chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center, said in a statement. “Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”

Nivolumab and ipilimumab are each FDA-approved as single-agents for the treatment of patients with unresectable or metastatic melanoma. In addition to melanoma, the FDA approved nivolumab in March 2015 as a treatment for patients with metastatic squamous non-small cell lung cancer following a platinum-based chemotherapy.

Hodi FS, Postow MA, Chesney J, et al. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 4214.