Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors

Abstract

Key Points Question What is the rate of cardiovascular adverse events among patients with melanoma treated with BRAF and MEK inhibitors compared with patients treated with BRAF inhibitor monotherapy? Findings In this systematic review and meta-analysis of 5 randomized clinical trials including 2317 patients, treatment with BRAF and MEK inhibitors was associated with a higher risk of pulmonary embolism, decrease in left ventricular ejection fraction, and arterial hypertension compared with treatment with BRAF inhibitor monotherapy. The risks of myocardial infarction, atrial fibrillation, and QTc prolongation were similar between groups. Meaning These findings demonstrate an association of cardiovascular adverse events with BRAF and MEK inhibitor therapy, which may guide clinical cardio-oncological management.

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology

“…The inhibition of the Ras-Raf MEK1-ERK1/2 pathway may result in impaired LV function, increased blood pressure and QTc prolongation. More specifically, a BRAF/MEK inhibitor combination therapy resulted in a higher incidence of LVEF reduction (8.1% versus 2% for monotherapy) and hypertension (19.5% versus 14% for monotherapy) than BRAF monotherapy [93]. In the case of cobimetinib, LVEF monitoring is recommended after 1 month and then every 3 months of therapy, and if LVEF decreases (< 40% or 40-49% and by > 10%), an interruption or discontinuation of therapy (if sustained < 40%) is indicated.…”

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio‐Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio‐Oncology Society

“… Proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) : the main CV complications of PIs and IMIDs in combination are LVD and HF, ischaemia and MI, atrial and ventricular arrhythmias, venous thromboembolism and arterial thrombosis 66,67,79 Combination RAF and MEK inhibitor treatment : the main CV complications of RAF and MEK inhibitors are LVD, HF and systemic hypertension for all combinations and QTc prolongation for one combination (vemurafenib and cobimetinib) 80,81 Androgen deprivation therapies (ADT) for prostate cancer treatment including gonadotropin release hormone (GnRH) agonists : ADT are associated with an increased risk of diabetes mellitus, hypertension and atherosclerosis (see below) 82–84 …”

Oncocardiology: new challenges, new opportunities

“…Oncocardiology care of patients receiving VEGF inhibitors focuses on optimal control of arterial hypertension to reduce the risk of major adverse events. The potential benefits of thromboprophylaxis remain controversial due to the higher bleeding risk linked to VEGF inhibitors [15].…”

“…However, both classes of drug are associated with a high risk of cardiovascular adverse events that are more commonly found when they are used as combination therapy. Adverse effects include LV dysfunction, pulmonary embolism, and arterial hypertension [15]. Currently, a combination of BRAF-/MEK-inhibitor therapy and ICI therapy targeting PD1 is under clinical evaluation [17].…”