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.
