Dabrafenib and its potential for the treatment of metastatic melanoma

Abstract

Alexander M Menzies,1 Georgina V Long,1,2 Rajmohan Murali3,41Melanoma Institute Australia, Sydney, New South Wales, Australia; 2Westmead Institute for Cancer Research and Crown Princess Mary Cancer Centre Westmead, Sydney, New South Wales, Australia; 3Department of Pathology; 4Human Oncology and Pathogensis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAFmut) protein in melanomas with BRAFV600E and BRAFV600K genotypes. BRAFV600E metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAFV600K patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy.Keywords: BRAF mutation, BRAF inhibitor, clinical trial, GSK1120212, GSK2118436, vemurafenib