The MEK inhibitor trametinib for the treatment of advanced melanoma

Introduction: Melanoma is the most aggressive of the cutaneous malignancies and caused over 35,000 deaths worldwide in 2013. Treatment options have been greatly expanded by the development of effective small-molecule inhibitors which target recurrent somatic mutations in melanoma (e.g., in BRAF and NRAS). Trametinib (GSK1120212) is an inhibitor of MEK1/2 which has received regulatory approval for the treatment of advanced BRAF(V600) - mutant melanoma. Trametinib has also demonstrated preclinical and early clinical activities as a single agent and in combination with other targeted therapies for melanoma with NRAS mutations in BRAF/NRAS wild-type melanoma. Areas covered: This article reviews melanoma genetics with a focus on MAPK signaling, and the preclinical and clinical evidence for treatment of melanoma with trametinib. The focus will be on a Phase III study of trametinib in BRAF(V600) - mutant melanoma, a Phase I/II study combining this agent with dabrafenib (a BRAF inhibitor) and most recently on a Phase III placebo-controlled trial assessing this combination. Finally, we will explore the role of trametinib in other, non-BRAF mutant subsets of this disease (e.g., NRAS mutations and atypical BRAF alterations) and in other malignancies. Expert opinion: Trametinib is a promising therapy which is playing a major role in combination with a BRAF inhibitor for the treatment of advanced BRAF-mutant melanoma. Increasing evidence suggests that trametinib will also play an expanding role in other genetically defined cohorts of this disease.