Dabrafenib in Melanoma

Approximately 40% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50%, median progression free survival of 6 to 7 months, and 5-year OS rate of 20% in patients with BRAF V600E/K mutant metastatic melanoma. BRAF blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. Most patients, however, develop resistance to BRAF inhibition. Dual inhibition of BRAF and MEK has demonstrated improved efficacy over single agent therapy with a median overall survival of 25.1 months and long-term follow-up showing 23% five-year overall survival rate. The FDA approved single agent therapy with BRAF inhibitor dabrafenib and in combination with MEK inhibitor trametinib for use in patients with BRAF V600 mutated metastatic melanoma in 2014. Now either targeted therapy or immune checkpoint inhibitors are selected for front-line treatment in the metastatic setting based on individual patient factors since there is no evidence to demonstrate a superior regimen. Sequencing of these agents is currently being explored in clinical trials. Studies are also ongoing to assess the benefit of targeted therapy with BRAF and MEK inhibitors in conjunction with immunotherapy. Additionally, oncogenic BRAF mutations have been identified in other solid tumors including papillary thyroid, colon, and non-small cell lung cancers. BRAF inhibition has been explored in these malignancies leading to FDA approval in non-small cell lung cancer and ongoing investigation of combination therapies. Methods: Pubmed and MESH databases were searched for literature published between 2010-2018 using the keywords of melanoma, dabrafenib, vemurafenib, trametinib, and BRAF.

Keywords: Adjuvant, BRAF Mutation, Central Nervous System, Dabrafenib, Immunotherapy, Ipilimumab, Keratoacanthoma, MEK Inhibition, Melanoma, Neoadjuvant, Nivolumab, Pembrolizumab, Resistance, Targeted Therapy, Trametinib, Vemurafenib.