title: Selective BRAF inhibitors make inroads in mutated metastatic melanoma.
abstract: The discovery that up to 50% of melanomas harbor mutations in the BRAF gene was made in 2002 and fueled the investigation into its mechanistic role as a driver mutation. BRAF mutations at the V600 position result in a constitutively active protein that underlies a classic "oncogene addiction." Since then, there have been extensive efforts to inhibit the mutated BRAF V600E/K as a therapeutic strategy. Initial attempts were made with either nonspecifc inhibitors of BRAF or with MEK inhibitors in studies that were not enriched for tumors with the BRAF mutation. The development of selective BRAF inhibitors that potently inhibit BRAF V600E/K and quench its downstream signaling revolutionized targeted therapy in melanoma. Vemurafenib was the first such agent and was developed in a phase 1 study that determined its maximally tolerated dose (MTD) to be 960 mg taken orally twice a day, and observed unprecedented tumor regression in more than 80% of patients. Those impressive results were confirmed in phase 2 and 3 studies (BRIM2 and BRIM3) and led to the drug's approval by the US Food and Drug Administration in 2011.
authors: Division of Hematology/Oncology, University of Pittsburgh, PA USA Email: tawbih@upmc.edu.
authors: Hussein
authors: H
authors: Tawbi