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Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label,
Reinhard Dummer1, Dirk Schadendorf2, Paolo A Ascierto3
1Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland.
Background:
There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma.
Methods:
NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51.
Findings:
Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group.
Interpretation:
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.
Funding:
Array BioPharma and Novartis Pharmaceuticals Corporation.
Insights
Binimetinib improved progression-free survival in patients with NRAS-mutant melanoma compared to dacarbazine. This MEK inhibitor offers a tolerable new option for advanced melanoma, especially after immunotherapy failure.
Area of Science:
- Oncology
- Melanoma Research
- Pharmacology
Background:
- NRAS-mutant melanoma lacks specific therapies beyond immunotherapy.
- The study addresses the need for effective treatments in advanced NRAS-mutant melanoma.
Purpose of the Study:
- To evaluate the efficacy and safety of binimetinib versus dacarbazine in advanced NRAS-mutant melanoma.
- To compare progression-free survival and adverse events between the two treatment arms.
Main Methods:
- A randomized, open-label, phase 3 trial (NEMO study) involving 402 patients.
- Patients received either binimetinib (MEK inhibitor) or dacarbazine, stratified by disease stage and prior immunotherapy.
- Primary endpoint was progression-free survival assessed by blinded central review.
Main Results:
- Binimetinib demonstrated significantly improved progression-free survival (2.8 months vs 1.5 months) compared to dacarbazine.
- Increased creatine phosphokinase and hypertension were more frequent in the binimetinib group.
- Serious adverse events occurred in 34% of binimetinib patients versus 22% of dacarbazine patients.
Conclusions:
- Binimetinib improved progression-free survival and was tolerable in patients with NRAS-mutant melanoma.
- Binimetinib may offer a new treatment option for patients with advanced NRAS-mutant melanoma, particularly after immunotherapy failure.
