FDA Okays First-line Nivolumab Alone in Melanoma

Nick Mulcahy

November 24, 2015

The US Food and Drug Administration (FDA) has expanded the indication for nivolumab (Opdivo, Bristol-Myers Squibb) to include its use as a single agent in the first-line treatment of unresectable or metastatic melanoma, the company announced today.

The approval is limited to use in patients who have BRAF V600wild-type melanoma.

In the first-line treatment of this type of patient, clinicians can now use nivolumab as a monotherapy or in combination with the immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb). The combination was approved in October.

"This important news means that we now have another option to offer patients with BRAF wild-type metastatic melanoma," Jeffrey Weber, MD, PhD, from the Laura and Isaac Perlmutter Cancer Center at New York University in New York City, said in a company press statement.

Nivolumab was first approved in 2014 for use in the second-line treatment of advance melanoma. That indication is for patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab and, for patients whose tumors are positive for the BRAF V600 mutation, after treatment with a BRAF inhibitor.

Nivolumab Bests Dacarbazine

The new approval is based on data from the randomized phase 3 CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma.

In an interim analysis, nivolumabdemonstrated superior overall survival, which was the primary outcome.

Median overall survival was not reached for nivolumab, but was 10.8 months (95% confidence interval [CI], 9.3 - 12.1) with dacarbazine (hazard ratio [HR], 0.42; P < .0001).

The CheckMate-066 trial was stopped early because of this survival benefit and after a recommendation by the independent Data Monitoring Committee, as reported by Medscape Medical News.

Median progression-free survival was better with nivolumab than with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < .0001).

Table. Response Rates

Response Nivolumab Group, % Dacarbazine Group, %
Overall 34 9
Complete 4 1
Partial 30 8


At the time of the interim analysis, 63 of 72 (88%) nivolumab-treated patients had ongoing responses, and 43 of these ongoing responses lasted at least 6 months.

Dacarbazine was selected as the comparator instead of ipilimumab monotherapy in CheckMate-066 because when the study protocol was designed, dacarbazine was "the standard of care in many regions outside of the United States where [ipilimumab] had not yet been approved for first-line use," according to a company press statement.

Grade 3 and 4 adverse reactions occurred in 41% of patients in the nivolumab group. The most frequent grade 3 and 4 adverse reactions (in at least 2% of patients) were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). Adverse reactions led to the permanent discontinuation of nivolumabin 7% of patients and a dose interruption in 26% of patients. The most common adverse reactions occurred more frequently in the nivolumabthan in the dacarbazine group, including fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%).

Nivolumabis associated with a variety of immune-mediated adverse events, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, and encephalitis. It is also associated with embryofetal toxicity.


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