MEK INHIBITORS FOR NRAS MUTATED MELANOMA

In the phase III NEMO trial reported in The Lancet Oncology, Dummer et al found that treatment with the MEK inhibitor binimetinib improved progression-free survival vs dacarbazine in patients with advanced NRAS-mutant melanoma.

Study Details

In the open-label trial, 402 patients from 118 sites in 26 countries were randomized 2:1 between August 2013 and April 2015 to receive oral binimetinib at 45 mg twice daily (n = 269) or intravenous dacarbazine at 1,000 mg/m2 every 3 weeks (n = 133). Patients had advanced unresectable stage IIIC or IV disease and were previously untreated or had disease progression on or after previous immunotherapy.

Randomization was stratified by stage, Eastern Cooperative Oncology Group performance status, and previous immunotherapy. The primary endpoint was progression-free survival on blinded central review in the intention-to-treat population.

Progression-Free Survival

Median follow-up was 1.7 months. Median progression-free survival was 2.8 months (95% confidence interval [CI] = 2.8–3.6 months) in the binimetinib group vs 1.5 months (95% CI = 1.5–1.7 months) in the dacarbazine group (hazard ratio [HR] = 0.62, P < .001).

With regard to stratification groups, median progression-free survival was 3.8 vs 2.8 months among patients with stage IIIC to IVM1a,b disease, 2.8 vs 1.5 months in those with stage IVM1c disease, 3.0 vs 1.5 months and 2.8 vs 1.5 months for those with performance status of 0 and 1, and 5.5 vs 1.6 months among the 21% of patients with previous immunotherapy (HR = 0.46, 95% CI = 0.26–0.81). Confirmed overall response rates were 15% vs 7% (P = .015).

Immunotherapy (ipilimumab [Yervoy], nivolumab [Opdivo], or pembrolizumab [Keytruda]) was given after study drug discontinuation to 46% of the binimetinib group and 44% of the dacarbazine group. At the time of analysis, median follow-up for overall survival was 9.2 months, and median overall survival was 11.0 vs 10.1 months (HR = 1.00, P = .50). The trial is ongoing.

Adverse Events

The most common grade 3 or 4 adverse events occurring in ≥ 5% of either group were increased creatine phosphokinase (19% vs 0%), hypertension (7% vs 2%), anemia (2% vs 5%), and neutropenia (1% vs 9%). Serious adverse events occurred in 34% vs 22%.

Adverse events led to dose reduction in 61% vs 16%, dose interruption in 58% vs 29%, and discontinuation of treatment in 25% vs 8%. The most common adverse events leading to discontinuation of treatment in the binimetinib group were decreased ejection fraction (4%), increased creatine phosphokinase (2%), retinal vein occlusion (2%), and retinal detachment (1%).

The investigators concluded: “Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy.”

The study was funded by Array BioPharma and Novartis Pharmaceuticals Corporation.

Reinhard Dummer, MD, of the University Hospital Zürich Skin Cancer Center, is the corresponding author of The Lancet Oncology article.