Targeted therapy for advanced cutaneous melanoma

Drugs targeting the mitogen-activated protein kinase (MAPK) pathway with BRAF and MEK inhibitors have significantly improved survival outcomes of patients with melanoma harboring BRAF V600 mutations. To date, three combination targeted therapies have been approved, based on the results of four randomized phase-III trials (COMBI-D, COMBI-V, CoBRIM, and COLUMBUS). In these trials, combined BRAF and MEK inhibitors demonstrated superiority as compared with BRAF inhibitor monotherapy and showed quite homogeneous data in terms of response rate (63%-70%), OS (median > 24 months), and PFS (median values ranging from 11 to 14 months). Consequently, different toxicity profiles of each combination therapy presently help with the decision-making process. Despite these successful results, treatment resistance represents an issue during both immunotherapy and targeted therapy, and there is presently no consensus on the therapeutic journey of patients with BRAF mutant melanoma to optimize their survival results. Several strategies to further increase therapeutic results of targeted therapy have been investigated, by combining and/or sequencing different treatment approaches. In this review, we will present the molecular features of cutaneous melanoma, focusing on BRAF mutation, the therapeutic rationale of targeted therapies, their efficacy, and toxicity, and give an overview of future perspectives in the treatment of this disease