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Risk of Cardiovascular Adverse Events in Patients With Melanoma Treated With Combined BRAF and MEK Inhibition vs BRAF Inhibition Alone

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Key Points

  • Combined BRAF and MEK inhibitor treatment was associated with a significantly increased risk of any-grade pulmonary embolism, a decrease in left-ventricular ejection fraction, and arterial hypertension.
  • Combined treatment was associated with a significantly increased risk of grade ≥ 3 decrease in left-ventricular ejection fraction and arterial hypertension.

In a meta-analysis reported in JAMA Network Open, Mincu et al found that the risk of some types of cardiovascular adverse events was higher with combined BRAF and MEK inhibitor treatment vs BRAF inhibitor monotherapy in patients with melanoma.

The meta-analysis included 2,317 patients in five randomized trials reporting cardiovascular adverse events with BRAF and MEK inhibitor combination therapy vs BRAF inhibitor monotherapy. Cardiovascular adverse events included in the analysis were pulmonary embolism, decreased left-ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc-interval prolongation.

Risk of Cardiovascular Adverse Events

Treatment with BRAF and MEK inhibitors vs BRAF inhibitor monotherapy was associated with an increased risk of any-grade pulmonary embolism (2.2% vs 0.4%, relative risk [RR] = 4.36; P = .02), a decrease in left-ventricular ejection fraction (8.1% vs 2.0%, RR = 3.72; P < .001), and arterial hypertension (19.5% vs 14.0%, RR = 1.49; P = .005), but not myocardial infarction (RR = 4.22, P = .11), atrial fibrillation (RR = 0.76, P = .76), or QTc prolongation (RR = 0.23, P = .16).

Relative risks for grade ≥ 3 events were significantly increased for a decrease in left-ventricular ejection fraction (2.1% vs 0.7%, RR = 2.79; P = .005) and arterial hypertension (8.0% vs 5.1%, RR = 1.54; P = .005), but not for pulmonary embolism (RR = 1.46, P = .56), myocardial infarction (RR = 2.96, P = .25), atrial fibrillation (RR = 4.05, P = .13), or QTc prolongation (RR = 0.80, P = .76).

Among all patients, higher risk of a decrease in left-ventricular ejection fraction was associated with a mean age younger than 55 (RR = 26.5, P = .001), and higher risk of pulmonary embolism was associated with follow-up time longer than 15 months (RR = 7.70, P = .02).

The investigators concluded, “Therapy with BRAF and MEK inhibitors was associated with a higher risk of [cardiovascular adverse events] compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.”

Matthias Totzeck, MD, of the Department of Cardiology and Vascular Medicine, University Hospital Essen, is the corresponding author for the JAMA Network Open article.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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