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

Abstract

The MEK inhibitor trametinib was approved in 2013 for the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation, the most common pathogenic mutation in melanoma. Trametinib blocks activation of ERK1/2, inhibiting cell proliferation in melanoma. ERK1/2 also protects against multiple types of cardiac insult in mouse models. Trametinib improves survival in melanoma patients, but evidence of unanticipated cardiotoxicity is emerging. Here we describe the case of a patient with metastatic melanoma who developed acute systolic heart failure after trametinib treatment and present the results of the literature review prompted by this case. A patient with no cardiac history presented with a 6.5-mm skin lesion and was found to have metastatic BRAF V600E melanoma. Combination treatment with trametinib and the BRAF inhibitor, dabrafenib, was initiated. The patient's pre-treatment ejection fraction was 55-60%. His EF declined after 13 days and that was 40% 1 month after treatment. Two months after initiating trametinib, he developed dyspnea and fatigue. We conducted a chart review in the electronic medical record. We conducted a PubMed search using trametinib/adverse effects AND ("heart failure" OR "left ventricular dysfunction" OR hypertension OR cardiotoxicity OR mortality). We also queried the FDA Adverse Events Reporting System for reports of cardiomyopathy, ejection fraction decrease, and left ventricular dysfunction associated with trametinib between January 1, 2013, and July 20, 2017. The literature search retrieved 19 articles, including clinical trials and case reports. Early clinical experience with the MEK inhibitor trametinib suggests that its clinical efficacy may be compromised by cardiotoxicity. Further studies in humans and animals are required to determine the extent of this adverse effect, as well as its underlying mechanisms.

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

“…No patient was treated with the combination of encorafenib-binimetinib. The median duration of treatment was 9 months (IQR [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]). 30 patients (34.1%) had a rechallenge after progressive disease under previous treatment with BRAF and/or MEKis.…”

“…5 A new spectrum of side effects has emerged related to these treatments, including several types of cardiovascular adverse events (AEs) such as left ventricular ejection fraction decrease (LVEF-D), QT interval prolongation, hypertension, and peripheral edema. 6,7 LVEF-D induced by BRAF and MEKis, although widely reported in clinical trials, has never been thoroughly described to date and data regarding its management are limited. [8][9][10] The main objective of the study presented herein was therefore to describe the characteristics of LVEF-D in a large cohort of metastatic melanoma patients treated with BRAF and/or MEKis in a real-life setting.…”

Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors

“…A second source of damage, such as hypertension that is directly linked to the combination therapy, then could give a greater damage determining, among others, the development of ejection fraction reduction. (Banks et al, 2017;Lips et al, 2004;Naitoh et al, 2006) Besides, one of the key elements necessary for the formation of new arteries from already existing vessels or also in pathogenic events, such as restenosis, is the proliferation of smooth muscle cells. This proliferation is mainly linked to the activation of signaling pathway, which starts with the interaction of platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) with their specific receptors.…”

“…Bronte, Bronte, Novo, Pernice, et al, 2015) Unfortunately, the use of BRAFi has highlighted the problem of the onset of treatment-related resistance. For this reason, MEK inhibitors (MEKi) have been developed and studied (Banks, Crowell, Proctor, & Jensen, 2017;Flaherty, Infante, et al, 2012;Flaherty, Robert, et al, 2012), showing nevertheless better results on disease when used in combination, BRAFi plus MEKi (Banks et al, 2017;Flaherty, Infante, et al, 2012;Flaherty, Robert, et al, 2012). It has to be noted that each of these drugs showed a cardiovascular toxicity profile.…”

“…It has to be noted that each of these drugs showed a cardiovascular toxicity profile. In fact, on one hand BRAFi have mainly drawn attention to hypertension and QT interval (QT) prolongation at ECG Bronte, Bronte, Novo, Pernice, et al, 2015), on the other hand cardiovascular adverse events such as peripheral oedema, hypertension, decreased cardiac ejection fraction, have been usually linked to MEKi treatment (Banks et al, 2017). These last adverse events are more frequent using the combination therapy than the monotherapy, even though they are readily reversible when the drug is interrupted (Banks et al, 2017;Dossett, Kudchadkar, & Zager, 2015;Flaherty, Infante, et al, 2012;Flaherty, Robert, et al, 2012).…”