Cardiovascular Adverse Events With BRAF and MEK Inhibitors

Study Questions:

What is the rate of cardiovascular adverse events (CVAEs) among patients with melanoma treated with BRAF and MEK inhibitors compared with patients treated with BRAF inhibitor monotherapy?

Methods:

The authors performed a meta-analysis of five clinical trials comprising a total of 2,317 patients who were randomized to the available combinations of BRAF inhibitors and MEK inhibitors (i.e., dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib) or BRAF inhibitor monotherapy. All-grade and high-grade (i.e., grade 3-5, indicating severe, life-threatening, or causing death) treatment-emergent CVAEs were abstracted. The selected endpoints were as follows: 1) pulmonary embolism, 2) a decrease in left ventricular ejection fraction (LVEF), 3) arterial hypertension, 4) myocardial infarction, 5) atrial fibrillation, and 6) QTc interval prolongation. The proportion of patients with CVAEs receiving BRAF and MEK inhibitors was compared with that of the control group in the same randomized controlled trial.

Results:

BRAF and MEK inhibitor combination compared to BRAF monotherapy was associated with a fourfold increased risk of pulmonary embolism (2.2% vs. 0.4%), threefold increased risk of LV dysfunction (8.1% vs. 2.0%), and 1.5-fold increased risk of hypertension (19.5% vs. 14.0%). The rates of myocardial infarction, atrial fibrillation, and QTc prolongation where otherwise similar between both groups. High-grade events specific to LV systolic dysfunction and hypertension, but not pulmonary embolism, were more common in the BRAF/MEK inhibitor combination group. A decrease in cardiac function occurred more commonly in those younger than age 55 years who received dual therapy.

Conclusions:

Combined use of BRAF and MEK inhibitors for treatment of melanoma was associated with a higher risk of pulmonary embolism, and decrease in LVEF and hypertension compared to treatment with BRAF inhibitor monotherapy.

Perspective:

This meta-analysis sheds light on the cardiotoxic risks of using combined BRAF and MEK inhibition in the treatment of melanoma. The mechanisms of cardiovascular injury are unclear, but thought to be a combination of renin-angiotensin system disruption, impaired nitric oxide production, and inhibition of the VEGF and MAPK pathways. The authors attributed the decrease in LV function to MEK inhibition; as rates of decreased LVEF in prior studies were higher in the MEK inhibitor monotherapy arms compared to BRAF monotherapy. Of note, incident heart failure as an endpoint could not be examined in this study. While these risks do not outweigh the benefits of treating melanoma with these agents, practitioners and patients should be aware of them, and underlying cardiovascular risk factors should be aggressively optimized until further studies delineate individualized strategies to mitigate these risks.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Cardiotoxicity, Heart Failure, Hypertension, Melanoma, Myocardial Infarction, Nitric Oxide, Primary Prevention, Pulmonary Embolism, Renin-Angiotensin System, Risk Factors, Stroke Volume


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