Nivolumab Improves Overall and Progression-Free Survival vs Dacarbazine in Previously Untreated Advanced Melanoma Without BRAF Mutation
In a phase III trial reported in The New England Journal of Medicine, Robert et al found that the PD-1 immune-checkpoint–inhibitor antibody nivolumab significantly increased overall survival, progression-free survival, and objective response rate compared with dacarbazine in patients with previously untreated metastatic melanoma without BRAF mutation.
Study Details
In this double-blind trial, 418 patients from 80 centers in Europe, Israel, Australia, Canada, and South America with previously untreated stage III or IV melanoma without BRAF mutation were randomly assigned between January 2013 and February 2014 to receive nivolumab at 3 mg/kg every 3 weeks plus dacarbazine-placebo every 2 weeks (n = 210) or dacarbazine at 1,000 mg/m2 every 3 weeks plus nivolumab-placebo every 2 weeks (n = 208). Patients had to have availability of tumor tissue from a metastatic or unresectable site for programmed death ligand-1 (PD-L1) biomarker analysis. Patients could have received prior adjuvant therapy. Treatment was continued until disease progression or unacceptable toxicity; treatment after progression was permitted in patients with clinical benefit and no substantial adverse events form study treatment. The primary endpoint was overall survival.
The nivolumab and dacarbazine groups were generally balanced for age (median, 64 and 66 years), sex (58% and 60% male), geographic region (Europe or Canada for 69% and 70%; Israel, Australia, or South America for 31% and 30%), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 70% and 58%, 1 in 29% and 40%), metastasis stage (M1c in 61% in both; M0, M1a, or M1b in 39% in both), lactate dehydrogenase (LDH) level (> upper limit of normal [ULN] in 38% and 36%, > 2 times ULN in 10% and 11%), history of brain metastases (3% and 4%), positive PD-L1 status (35% and 36%), and prior systemic therapy (adjuvant in 15% and 17%, neoadjuvant in 0.5% in both).
Follow-up and Subsequent Treatment
All randomized patients were followed for up to 16.7 months at the time of database lock, which occurred at 5.2 months after the first visit of the last randomized patient. After discontinuation of study treatment, 63 patients in the nivolumab group (30%) and 114 in the dacarbazine group (55%) received systemic therapy, including ipilimumab (Yervoy) in 45 (21% of all patients) and 79 (38% of all patients).
Overall Survival
Median overall survival was not reached in the nivolumab group vs 10.8 months (95% confidence interval [CI] = 9.3–12.1 months) in the dacarbazine group, and overall survival at 1 year was 72.9% (95% CI = 65.5%–78.9%) vs 42.1% (95% CI = 33.0%–50.9%), yielding a hazard ratio (HR) of 0.42 (99.79% CI = 0.25–0.73, P < .001).
Overall survival was significantly improved with nivolumab among both patients with positive PD-L1 status (median not reached vs 12.4 months, unadjusted HR = 0.30, 95% CI = 0.15–0.60) and those with negative or indeterminate status (median not reached vs 10.2 months, unadjusted HR = 0.48, (95% CI = 0.32–0.71). The survival benefit with nivolumab was also observed across subgroups for age, sex, metastasis stage, ECOG performance status, history of brain metastases, baseline LDH, and geographic region.
Progression-Free Survival and Response Rates
Median progression-free survival was 5.1 vs 2.2 months (HR = 0.43, P < .001). Objective response rate was 40.0% vs 13.9% (odds ratio [OR] = 4.06, P < .001), including 52.7% vs 10.8% in patients with positive PD-L1 status and 33.1% vs 15.7% in patients with negative or indeterminate status. Complete response was observed in 7.6% vs 1.0% of patients. Among patients with response, median duration of response was not reached vs 6.0 months. Median time to response was 2.1 months in both groups.
Reduction of ≥ 30% in tumor burden in the target lesion was achieved or maintained in 17 (31%) of 54 nivolumab patients treated beyond progression, compared with 8 (16%) of 49 dacarbazine patients treated beyond progression.
Adverse Events
The most common treatment-related adverse events of any grade in the nivolumab and dacarbazine groups were nausea (16.5% vs 41.5%), fatigue (19.9% vs 14.6%), pruritus (17.0% vs 5.4%), and diarrhea (16.0% vs 15.6%). Treatment-related grade 3 or 4 adverse events occurred in 11.7% vs 17.6%, with the most common being diarrhea in the nivolumab group (1% vs 0.5%) and thrombocytopenia (0% vs 4.9%) and neutropenia (0% vs 4.4%) in the dacarbazine group. Treatment-related serious adverse events occurred in 5.8% vs 5.9% and adverse events led to discontinuation of study treatment in 6.8% vs 11.7%. No deaths were attributed to study drug toxicity
The investigators concluded: “[N]ivolumab was associated with a significant improvement in overall survival and progression-free survival, as compared with dacarbazine. Nivolumab was associated with a low risk of high-grade toxic effects.”
Caroline Robert, MD, PhD, of Gustave Roussy, Villejuif Cedex, France, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
