FDA approves Opdivo plus Yervoy for BRAF V600 wild-type melanoma

The FDA approved the combination of nivolumab plus ipilimumab for treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma, according to a press release issued by the agents’ manufacturer.

Nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) are immune-checkpoint inhibitors that target separate but complementary checkpoint pathways.

Ipilimumab’s blockade of CTLA-4 augments T-cell activation and proliferation, while nivolumab — a PD-1 inhibitor — helps to restore active T-cell response directed at the tumor.

This is the first time the FDA approved a regimen that includes two immuno-oncology agents for cancer treatment.

Jedd D. Wolchok

“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 … in metastatic melanoma,” Jedd D. Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, said in a press release. “[This] approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”

The FDA based the approval on results of the CheckMate 069 trial, a randomized, double blind phase 2 study in which researchers randomly assigned 140 treatment-naive patients with unresectable or metastatic melanoma to nivolumab plus ipilimumab or ipilimumab alone.

Objective response rate in patients with BRAF wild-type tumors served as the study’s primary endpoint.

Results showed the combination conferred a statistically significant increase in confirmed objective response rate among patients with BRAF wild-type melanoma (60% vs. 11%; P < .001). Among the 43 patients who responded to the combination regimen, 34 had a response duration of at least 6 months and 20 had a response duration of at least 9 months.

The combination also was associated with a reduced risk for progression (HR = 0.4; 95% CI, P < .002) and longer median PFS (8.9 months vs. 4.7 months) compared with ipilimumab alone.

A higher percentage of patients assigned the combination regimen experienced severe adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delays (47% vs. 22%), and grade 3 or grade 4 adverse reactions (69% vs. 43%).

The most common adverse reactions associated with the combination regimen were rash (67% for combination vs. 57% for ipilimumab alone), pruritus (37% vs. 26%), headache (24% vs. 20%), vomiting (23% vs. 15%) and colitis (22% vs. 11%).

The most frequent serious adverse events associated with the combination regimen were colitis (17% for combination vs. 9% for ipilimumab alone), diarrhea (9% vs. 7%), pyrexia (6% vs. 7%) and pneumonitis (5% vs. 0%).

“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 of the Melanoma Research Foundation, said in the press release. “[This] 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.”