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Nivolumab in Previously Untreated Melanoma without BRAF Mutation

Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D., Et al

N Engl J Med 2014, E-pub November 16, 2014,

Editor's comments: Prof Paolo A. Ascierto
Nivolumab is a fully human IgG4 anti PD-1 antibody that selectively blocks the interaction of the PD-1 receptor with its two ligands, PD-L1 and PD-L2, disrupting the negative signal which regulates T-cell activation and proliferation. In a phase I study nivolumab was associated with promising antitumor activity in patients with solid tumors, including advanced melanoma. In this manuscript were reported data of a randomized phase 3 double-blind study where nivolumab was compared to dacarbazine to verify whether it’s able to improve overall survival of previously untreated patients with advanced melanoma BRAF wild type. The study was largely positive showing a significant improvement of ORR (40 % vs 13.9%), PFS (5.1 vs 22 months) and 1-year OS (72.95 vs 42.1%) for the group of patients treated with nivolumab respect to those treated with dacarbazine. In addition to an high response rate, it was also found a long duration of responses (median DOR in the patients treated with nivolumab was not found yet), and a rapid time to response (2.1 months) with a good toxicity profile. Nivolumab treated patients had improved ORR as compared with dacarbazine treated patients both in PD-L1 positive and PD-L1 negative groups. In the subgroup with PD-L1 positive, the ORR was 52.7% in the nivolumab group versus 10.8% in the dacarbazine group. In the subgroup with PD-L1 negative, the ORR was 33.1% in the nivolumab group versus 15.7% in the dacarbazine group. The 1-year OS rate for the nivolumab PD-L1 positive, nivolumab PD-L1 negative, dacarbazine PD-L1 positive, and dacarbazine PD-L1 negative was of 82.1%, 67.8, 52.7, and 37.4 respectively. These data evidenced that PD-L1 positive status is related with a better survival but also PD-L1 negative patients had an higher OS respect to the control arm.

When this study was planning ipilimumab wasn't still approved as first-line of treatment. Currently is ongoing a three-arms phase III study which is evaluating the combination of ipilimumab and nivolumab with nivolumab and ipilimumab monotherapy in previously untreated advanced melanoma patients.

BACKGROUND
Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.

METHODS
We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.

RESULTS
At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.

CONCLUSIONS
Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number,NCT01721772.)