Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

Summary

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.

Introduction

Melanomas are a heterogeneous group of neural crest-derived malignancies characterised by distinct clinical and molecular features.1, 2 Most melanomas have genetic alterations activating the MAPK pathway, such as BRAF, NRAS, or NF1 mutations.³ Activating NRAS and BRAF mutations are present in about 20% and 35–50% of metastatic melanomas, respectively.4, 5 Direct targeting of the RAS GTPase is technically challenging.⁶ Preclinical in-vitro investigations have suggested that BRAF-mutant and NRAS-mutant melanomas are sensitive to MEK inhibition.⁷

Several kinase inhibitors, including BRAF8, 9 and MEK inhibitors¹⁰ alone or in combination11, 12 have been approved for the treatment of BRAF-mutant metastatic melanoma. In a phase 2 clinical trial,¹³ the MEK1/2 inhibitor binimetinib (MEK162) showed clinical activity with a response in 15% of patients with NRAS-mutant metastatic melanoma.

Despite the documented benefit of immunotherapy14, 15, 16 in most melanoma subtypes, there is a substantial unmet medical need for new therapeutic opportunities in metastatic NRAS-mutant disease. In the metastatic setting, patients with NRAS-mutant melanoma appear to have a more aggressive disease course than patients whose tumours harbour BRAF mutations or are wild-type for BRAF and NRAS, although these findings have not yet been confirmed.4, 17 Therefore, we developed the NRAS melanoma and MEK inhibitor (NEMO) trial to compare the efficacy of binimetinib with dacarbazine in patients (either treatment-naive or have received previous immunotherapy) with advanced unresectable or metastatic melanoma harbouring an NRAS mutation.

Research in context

Evidence before this study

Evidence was identified during the development of this manuscript via PubMed and Embase searches for articles and abstracts published between Jan 1, 2014, and Dec 20, 2016. Search terms were comprehensive (melanoma + treatment + phase [all fields]; NRAS + melanoma [all fields]). Selected abstracts were not limited to the English language, and focused on phase 3 clinical trial data. Our findings indicated that emerging immunotherapies and MEK pathway inhibitors have efficacy in melanoma. However, substantial unmet need exists, particularly for patients with NRAS-mutant melanoma. Preclinical and early clinical data suggest that the MEK inhibitor binimetinib could be a promising treatment for patients with NRAS-mutant melanoma.

Added value of this study

In this study, which represents the largest controlled study to date in patients with NRAS-mutant melanoma to our knowledge, treatment with the MEK inhibitor binimetinib improved progression-free survival and overall response compared with dacarbazine, with acceptable tolerability. The progression-free survival benefit with binimetinib was also observed in patients who failed previous immunotherapy, which is currently the guideline-recommended first-line treatment.

Implications of all the available evidence

Future treatment algorithms for metastatic melanoma might incorporate binimetinib therapy in patients with advanced NRAS-mutant melanoma, including after the failure of immunotherapy.