P683Cardiovascular adverse events associated with BRAF and MEK inhibitors

Abstract

Abstract Background Cardiovascular adverse events (CVAE) following treatment with B-Raf proto-oncogene serine/threonine kinase inhibitors and mitogen-activated protein kinase (BRAF/MEK) inhibitors in patients with melanoma remain incompletely characterized. We conducted the first detailed meta-analysis focused on BRAF/MEK inhibitor-associated CVAE. Purpose To determine the type and risk of BRAF/MEK inhibitor-associated CVAE. Methods We systematically searched Pubmed, Cochrane, and Web of Science for keywords “vemurafenib”, “dabrafenib”, “encorafenib”, “trametinib”, “binimetinib”, “cobinimetinib” through November 30, 2018. We selected randomized controlled trails (RCT) reporting on CVAE in melanoma patients under BRAF/MEK inhibitors. The selected endpoints were: decrease in left ventricular ejection fraction (LVEF), pulmonary embolism, atrial fibrillation, arterial hypertension, myocardial infarction, heart failure, pericarditis, and QTc interval prolongation. All-grade and high-grade (grade 3 or higher) CVAE were recorded. Results 9 RCTs including 4,616 patients with melanoma were selected. The treatment with BRAF/MEK inhibitors was associated with an increased risk in a decrease in LVEF, pulmonary embolism, atrial fibrillation, and arterial hypertension. The relative risks (RR) of myocardial infarction, heart failure, pericarditis, and QTc prolongation were similar between the BRAF/MEK inhibitors group and control group (Figure). These results were consistent for high-grade CVAE. The subgroup analysis showed that the combination therapy with BRAF/MEK inhibitors resulted in a higher risk of a decrease in LVEF, pulmonary embolism, and arterial hypertension, while the risk for atrial fibrillation was increased in BRAF inhibitors monotherapy group compared to controls. There was no significant difference between melanoma patients with mean age below and above 55 years old, except for the increased risk of atrial fibrillation in the older population group. The endpoints were similar between studies with mean follow-up times under and over 24 months. RR of cardiovascular adverse events Conclusions The therapy with BRAF and MEK inhibitors is associated with a higher risk of CVAE. This study increases the awareness on CVAE under these therapies and help to balance between beneficial melanoma treatment options and increased cardiovascular morbidity and mortality.