UTUREAlthough significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. Especially patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy. Recently, the advent of targeted therapies and immunotherapy in metastatic melanoma has significantly changed the therapeutic landscape of this devastating disease with impressive tumor responses seen after kinase inhibitor treatment along with a small proportion of patients even achieving long-term survival of 10 years or more after immunotherapy with CTLA-4 antibodies [1][2][3][4][5][6][7]. Despite the availability and effectiveness of these novel treatments, the majority of patients with advanced melanoma still eventually face fatal progression of their disease, thus maintaining an unmet need for the development of further therapeutic agents.While immunotherapy with anti-CTLA-4 or anti-PD1-antibodies in melanoma utilizes a rather universal approach harnessing the patients' own immune system, in other words, T cells to attack and kill aberrant melanocytic tumor cells, targeted therapies, such as BRAF-or MEK-inhibitors aim to reverse the effects of distinct oncogenic mutations that confer proliferation and survival of melanoma cells. Increasing insight into the mutational landscape of cutaneous melanoma by large-scale genomic studies -published by The Cancer Genome Atlas Network and others -has led to the definition of four distinct mutational profiles based on genetic alterations impacting the MAPK pathway in cutaneous melanoma [8,9]. Being the most frequent, BRAF-mutations (predominantly the V600E hotspot mutation) occur in 40-50% of all melanomas, while NRAS-and NF1 mutations are less common, found in approximately 20 and 15% of melanomas, respectively [8][9][10][11]. Of note, BRAF and NRAS mutations are considered to be mutually exclusive despite the recent demonstration of their co-occurrence in melanoma cells, whereas loss-of-function mutations in the tumor suppressor gene NF1 can infrequently be detected both in BRAF-and NRAS-mutated melanomas, albeit being most common in BRAF Wt /NRAS Wt tumors [9,12]. Last, melanomas belonging to the so-called triple

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