Trametinib in the treatment of melanoma

Abstract

Introduction: Aberrant MAPK pathway signaling is a hallmark of melanoma. Mitogen/extracellular signal-regulated kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF^V600 mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib.

Areas covered: In this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma.

Expert opinion: Trametinib is a novel oral MEK inhibitor with clinical activity in BRAF^V600 mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway.

Keywords:

• BRAF
• GSK1120212
• mitogen/extracellular kinase inhibitor
• melanoma
• molecularly targeted therapy
• NRAS
• trametinib

Declaration of interest

DB Johnson has received funding from the NIH (K12 CA 0906525). JA Sosman serves on advisory boards for GlaxoSmithKline and Bristol Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.