Immunotherapy Combo for Melanoma Approved by FDA

Nick Mulcahy


October 01, 2015

The US Food and Drug Administration (FDA) approved nivolumab (Opdivo, Bristol-Myers Squibb) in combination with ipilimumab (Yervoy, Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma, the company announced today. The combination is limited to use in patients with BRAF V600 wild-type disease.

This is the first FDA approval of an immunotherapy combination for a cancer.

"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, PhD, executive director of the Melanoma Research Foundation, said in a company press statement.

Both of these drugs are already approved as monotherapies in this setting. Various experts have heralded combination therapy as the future of immuno-oncology, but others have expressed concerns about affordability and increased toxicity with two drugs.

For example, at the American Society of Clinical Oncology (ASCO) annual meeting in June, as reported by Medscape Medical News, observers cautioned that the nivolumabipilimumab combination could be very expensive — nearly $300,000.

"We need to carefully define who will benefit from the combination and from nivolumab as a single agent because, as a society, we cannot afford to treat everyone with the combination," Frances Collichio, MD, from the University of North Carolina in Chapel Hill, said at that time.

Figuring out who is an optimal candidate for potent combination therapy is "the heart of the issue," said immunotherapy researcher Jedd Wolchok, MD, PhD, from the Memorial Sloan Kettering Cancer Center in New York City, at the ASCO meeting.

The accelerated approval of the nivolumab–ipilimumab combination relied on tumor response rate and durability of response as evidence of efficacy.

The approval is based on results from the 140-patient pivotal phase 2 CheckMate-069 study, which compared the combination with ipilimumab monotherapy in the treatment of advanced melanoma.

The primary end point was the objective response rate (ORR) in patients with BRAF wild-type tumors; however, the trial also involved patients with BRAF-mutation-positive melanoma.

In patients with BRAF wild-type melanoma, the ORR was higher with the combination than with ipilimumab monotherapy (60% vs 11%; P < .001). There were also more complete responses with the combination than with monotherapy (17% vs 0%), and more partial responses (43% vs 11%).

The risk for progression was 60% lower with the combination than with monotherapy (hazard ratio [HR], 0.40; P < .002). And median progression-free survival was 8.9 months with the combination (95% confidence interval [CI], 7.0 - NA) and 4.7 months with ipilimumab alone (95% CI, 2.8 - 5.3).

"This trial provides clinical rationale for targeting the immune system with two immuno-oncology agents in metastatic melanoma," according to a company press statement.

In the pivotal trial, patients in the combination group received nivolumab1 mg/kg plus ipilimumab3 mg/kg every 3 weeks for four doses during the combination phase, which was followed by nivolumab 3 mg/kg every 2 weeks during the monotherapy phase. Patients in the monotherapy group received ipilimumab3 mg/kg every 3 weeks for four doses plus matched placebo.

The combination was more toxic. The following all occurred more frequently with the combination than with monotherapy: serious adverse reactions (62% vs 39%), adverse reactions leading to permanent discontinuation (43% vs 11%) or dose delays (47% vs 22%), and grade 3 or 4 adverse reactions (69% vs 43%).

In addition, 25 of 94 patients (27%) in the combination group did not complete all four cycles of the regimen. The first occurrence of a grade 3 or 4 adverse reaction was during administration of the combination in 56 patients (59%) and during administration of nivolumab alone in nine patients (10%).

The most common adverse reactions leading to the discontinuation of nivolumab, compared with ipilimumab alone, were colitis (16% vs 2%), diarrhea not treated with corticosteroids (4% vs 4%), increased alanine aminotransferase (ALT) levels (4% vs 0%), pneumonitis (3% vs 0%), and increased aspartate aminotransferase (AST) levels (3% vs 0%).

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

The most common adverse reactions reported in at least 20% of patients receiving the combination, compared with ipilimumab alone, were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).

Nivolumab monotherapy is associated with immune-mediated adverse events, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, and rash, as well as infusion reactions and embryofetal toxicity.


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