Trametinib: a MEK inhibitor for management of metastatic melanoma

Abstract

This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

“…We sought to explore if inhibition of both pathways simultaneously is advantageous in the preclinical metastatic CRC setting. Trametinib, a MEK inhibitor, was chosen as the MAPK pathway modulator based on its specificity profile and extensive preclinical and clinical data availability (34). First, trametinib monotherapy was tested in this model and exhibited dose-dependent efficacy (Figure 2A).…”

“…To address whether inhibition of both pathways simultaneously yields benefit, we sought to evaluate a combination of the novel β-catenin RNAi-based inhibitor, DCR-BCAT and the MEK inhibitor (MEKi) trametinib (34) in multiple preclinical CRC models. Importantly, in addition to primary tumor models, metastasis models were included as this setting represents the source of most genetic complexity (35), mortality and medical need for this disease (36–39).…”

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

“…Enhanced MEK activity can cause abnormal activation in the RAS-RAF-MEK-ERK pathway, which has been reported to be responsible for the pathogenesis of inflammation and approximately 30% of all human malignancies [4,5]. Thus, MEK has been the target of various drug discoveries [6][7][8][9][10][11][12][13][14], and inhibition of MEK activity may be used to treat MEK pathway activation-driven cancers.…”

Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism

“…Trametinib is a highly selective inhibitor of the tyrosine kinases mitogen-activated protein kinase kinase 1 and 2 (MEK 1 and MEK 2). In combination with the BRAF inhibitor, dabrafenib, trametinib prolongs life in patients with melanoma carrying an activating mutation in codon 600 of the BRAF gene (BRAF V600) [1]. The combination of dabrafenib and trametinib also received FDA approval for the treatment of BRAF V600 mutant non-small cell lung cancer in June 2017.…”