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

Jedd D. Wolchok, MD, PhD

Jedd D. Wolchok, MD, PhD

The combination of nivolumab and ipilimumab has received accelerated FDA approval as a treatment for patients withBRAF V600wild-type (WT) unresectable or metastatic melanoma, based on findings from the phase II CheckMate-069 study.

“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,” said Jedd D. Wolchok, MD, PhD, chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center, in a statement. “Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”

In the phase II study, the programmed cell death-1 (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). The combination demonstrated an objective response rate (ORR) of 60% compared with 11% for ipilimumab monotherapy in patients with&nbsp;BRAF&nbsp;WT melanoma. Additionally, the complete response rate with the combination was 17% versus none with monotherapy.

The accelerated approval marks the first for an immunotherapy combination for patients with cancer; the application for full approval is pending with the FDA. This application was based on the phase III CheckMate-067 study, which showed a 69% 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.

In the double-blind CheckMate-069 trial, 142 treatment-na&iuml;ve patients with stage III/IV melanoma were randomized 2:1 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&nbsp;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&nbsp;BRAF-positive melanoma (n = 33), with 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).

ORR with the combination in patients with BRAF&nbsp;WT tumors was independent of PD-L1 status; however, response rates with ipilimumab alone were higher in patients with PD-L1—positive tumors (18% vs 4%). In&nbsp;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 nine 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% of patients who recieved 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%).

&ldquo;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. 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,&rdquo; Giovanni Caforio, chief executive officer, Bristol-Myers Squibb, the company developing the drugs, said in a statement. &ldquo;Today&rsquo;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.&rdquo;

Nivolumab and ipilimumab are each FDA approved as single agents for the treatment of patients with unresectable or metastatic melanoma in different settings. 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.