The treatment options for patients with advanced melanoma that have progressed on approved agents are limited. Nivolumab is a fully human monoclonal antibody that is directed toward the immune checkpoint receptor programmed death-1 (PD-1), which has demonstrated durable antimelanoma activity in early clinical trials in pretreated patients with advanced disease. CA209-037 is a randomized, open-label, phase 3 clinical trial that is evaluating nivolumab versus investigator’s choice of chemotherapy (ICC) in 405 patients with advanced melanoma who have progressed with previous therapies directed against CTLA-4 (cytotoxic T-lymphocyte antigen-4) therapy or BRAF mutation (Weber J, et al. ESMO 2014: Abstract LBA_PR). In this trial, eligible patients were randomized to receive nivolumab 3 mg/kg intravenously every 2 weeks or ICC (dacarbazine 1000 mg/m2 every 3 weeks, or carboplatin AUC 6 plus paclitaxel 175 mg/m2 every 3 weeks) until disease progression or unacceptable toxicity. To be eligible for inclusion, patients with BRAF wild-type must have progressed after ipilimumab, whereas patients with BRAF V600 mutation must have progressed while receiving ipilimumab and a BRAF inhibitor. Patients were stratified by PD-1 ligand expression, BRAF mutation status, and best overall response to previous ipilimumab. Coprimary end points were objective response rate (ORR) and overall survival. A planned efficacy analysis of ORR was assessed as planned in the first 120 patients receiving nivolumab and 47 patients receiving ICC, with a follow-up of ?6 months. The interim efficacy analysis by central review showed that patients who received nivolumab therapy achieved a higher ORR compared with those who received ICC (32% vs 11%), including 3 complete responses. The median time to response was 2.1 and 3.5 months in the nivolumab and ICC groups, respectively, and the median duration of response was not reached with nivolumab and was 3.6 months with ICC. Of the 38 responses achieved with nivolumab therapy, 36 are ongoing, with a minimum follow-up of 24 weeks. Reduction of ?50% in target-lesion burden occurred in 82% (31/38) of nivolumab responders and 60% (3/5) of ICC responders. Among the 120 patients who received nivolumab, an additional 10 (8.3%) patients had immune-related response patterns and experienced a ?30% reduction in target lesion tumor burden. Including the patients with immune-related responses, a total of 37 patients continued treatment beyond RECIST 1.1–defined disease progression. Grade 3 or 4 treatment-related adverse events were reported in 9% and 31% of patients treated with nivolumab and ICC, respectively. Treatment discontinuations as a result of any grade treatment-related adverse events occurred in 2.2% and 7.8% of patients, respectively. The safety profile of nivolumab was consistent with that described previously. Common toxicities (any grade) included skin (29%), gastrointestinal (12%), endocrine (8%), and hepatic (5%) toxicities; grade 3 or 4 toxicities occurred in <1% of patients in each of these categories. These results indicate that nivolumab monotherapy was associated with a higher response rate compared with control, and was well tolerated in patients with advanced melanoma who had failed previous therapy with ipilimumab and BRAF inhibitors.
