Treatment of NRAS-Mutant Melanoma

NRAS mutations in codons 12, 13, and 61 arise in 15-20 % of all melanomas. These alterations have been associated with aggressive clinical behavior and a poor prognosis. Until recently, there has been a paucity of promising genetically targeted therapy approaches for NRAS-mutant melanoma (and RAS-mutant malignancies in general). MEK inhibitors, particularly binimetinib, have shown activity in this cohort. Based on preclinical and early clinical studies, combining MEK inhibitors with agents inhibiting the cell cycling and the PI3K-AKT pathway appears to provide additional benefit. In particular, a strategy of MEK inhibition and CDK4/ 6 inhibition is likely to be a viable treatment option in the future, and is the most promising genetically targeted treatment strategy for NRASmutant melanoma developed to date. In addition, immune-based therapies have shown increasing activity in advanced melanoma and may be particularly effective in those with NRAS mutations. Combination strategies of immune and targeted therapies may also play a role in the future although clinical trials testing these approaches are in early stages.