FDA Approves Nivolumab/Ipilimumab Combination for BRAF Wild-Type Melanoma

Jedd D. Wolchok, MD, PhD

The FDA has granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma, based on findings from the phase II CheckMate-069 study.

In the double-blind study, the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab reduced the risk of progression or death by 60% compared with ipilimumab alone (HR, 0.40; 95% CI, 0.22-0.71; P <.002). 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, with an application for full approval pending with the FDA. The full approval submission was 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 (HR, 0.41; 95% CI, 0.32-0.53). The FDA is scheduled to make a decision on this application by January 23, 2016.

“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.”

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 males, and all but two patients had an ECOG performance status of 0 or 1.

Among patients with BRAF wild-type tumors (N = 109), median 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 versus 2.7 months in the combination (n = 23) and control (n = 10) arms, respectively (HR, 0.38; 95% CI, 0.15-1.00).

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%).

“Today’s approval of the Opdivo plus Yervoy Regimen marks another first for our research in immuno-oncology and represents our unwavering commitment to continually redefine cancer care, and offer patients new treatment options with the goal of improved outcomes,” Giovanni Caforio, chief executive officer, Bristol-Myers Squibb, the company developing the drugs, said in a statement.

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.

“Targeting the immune system in the treatment of cancer has been of interest to the oncology community for decades, and our first immuno-oncology agent, Yervoy, was approved in 2011 for metastatic melanoma,” said Caforio. “Opdivo reinforced the power of the immune system in the fight against cancer, and is quickly becoming a foundational component in how the oncology community treats this devastating disease.”

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.