FDA Approves Nivolumab as a Single Agent for Previously Untreated BRAF Wild-Type Advanced Melanoma

First and only PD-1 immune checkpoint inhibitor approved as a single agent for first-line use in advanced BRAF wild-type melanoma

On 24 November 2015 Bristol-Myers Squibb announced that the US Food and Drug Administration (FDA) has approved nivolumab (Opdivo) for intravenous use as a single agent for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. The approval is based on data from the phase III trial, CheckMate 066, which demonstrated superior overall survival vs. dacarbazine in first-line treatment of patients with BRAF wild-type advanced melanoma. This approval marks the sixth FDA approval for Opdivo in the past 12 months.

A supplemental Biologics License Application for Opdivo in BRAF V600 mutation positive unresectable or metastatic melanoma, which was filed subsequent to data from CheckMate 066, is still under review with the FDA.

CheckMate 066 is a phase III, randomised, double-blind study of treatment-naive patients with unresectable or metastatic BRAF wild-type melanoma. Patients were randomised to receive Opdivo or dacarbazine. The primary efficacy endpoint of the trial was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR).

In the trial, Opdivo demonstrated superior OS versus chemotherapy drug dacarbazine in the first-line setting. Results were based on the interim analysis conducted on 47% of the total planned events for OS (50 for the Opdivo arm; 96 for the dacarbazine arm). The median OS was not reached for Opdivo and was 10.8 months in the dacarbazine arm (HR=0.42; p < 0.0001).

Median PFS more than doubled with Opdivo (5.1 months vs. 2.2 months) than for patients treated with dacarbazine (HR=0.43; p < 0.0001).

The ORR with Opdivo was 34% (4% complete response rate, 30% partial response rate) compared to 9% with dacarbazine (1% complete response rate, 8% partial response rate). At the time of analysis, 88% of Opdivo-treated patients had ongoing responses, which included 43 patients with ongoing responses of six months or longer.

Last year, the CheckMate 066 trial was stopped early following a recommendation by the independent Data Monitoring Committee based on their analysis which showed evidence of superior OS in patients receiving Opdivo compared to the control arm. As a result, patients in the trial were unblinded and patients who had received dacarbazine were allowed to receive Opdivo. Dacarbazine was selected as the comparator in this study because, at the time the study protocol was designed, it represented the standard of care in many regions outside of the US where ipilimumab had not yet been approved for first-line use.

In the trial, serious adverse reactions occurred in 36% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving Opdivo. The most frequent grade 3 and 4 adverse reactions reported in ≥2% of patients receiving Opdivo were gamma-glutamyltransferase increase (3.9%) and diarrhoea (3.4%). Adverse reactions led to permanent discontinuation of Opdivo in 7% of patients and dose interruption in 26% of patients. The most common adverse reactions in CheckMate 066 (>20%) reported with Opdivo versus dacarbazine were fatigue (49% vs. 39%), musculoskeletal pain (32% vs. 25%), rash (28% vs. 12%), and pruritus (23% vs. 12%).