Targeted Therapy in Advanced Melanoma

Molecularly targeted therapy, specifically small molecule therapeutics against particular oncogenes, has transformed the treatment landscape in melanoma and other cancers. Activating mutations in BRAFV600 produce constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, causing unrestrained growth in nearly half of all melanomas. In turn, therapeutic blockade of this pathway through BRAF inhibitors produces dramatic clinical responses and improved survival compared to traditional cytotoxic chemotherapy. The addition of downstream MAPK blockade via MEK inhibition has further improved clinical outcomes. Although initial responses are impressive in most patients, and durable responses occasionally occur, acquired resistance remains a major barrier to long-term efficacy with these agents. A number of other potential therapeutic targets have been identified among other subsets of melanoma, including those with NRAS mutations, KIT mutations, and atypical BRAF alterations. Further, combinatorial regimens targeted MAPK and other pathways (including CDK4/6 and PI3K/AKT pathways) have shown early promise. This chapter reviews the development, current clinical activity, and future development directions for targeted therapy in melanoma.