Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival

Approximately 50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic®) is an orally bioavailable, potent and selective MEKi, which significantly improved response rates when combined with BRAFi vemurafenib (median overall survival: 22.3 months). The toxicity profile of cobimetinib is manageable and treatment discontinuation due to adverse events is uncommon. Present efforts are addressed to overcome resistance and improve long-term outcomes: based on the evidence of the immunomodulatory properties of BRAFi and MEKi, current clinical trials of combined targeted and immunotherapy are investigating the role of cobimetinib in the context of combination or as sequential treatments.