Melanoma Treatment with BRAF and MEK Inhibitors Increases Cardiovascular Risks

Melanoma patients who undergo treatment with BRAF and MEK inhibitors may be more likely to sustain cardiovascular adverse events (CVAEs) compared to patients receiving BRAF inhibitor monotherapy, according to a recent systematic review and meta-analysis.

“The nature and incidence of CVAEs associated with BRAF and MEK inhibitor therapy are incompletely described. However, cardiovascular complications may affect a patient’s quality of life or may require temporary or permanent cancer therapy termination,” wrote the study authors, whose work was published in JAMA Network Open.

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The researchers queried PubMed, Cochrane, and Web of Science databases; TCTMD, Clinical Trial Results, Medscape, and CardioSource Plus websites; and annual meeting abstracts and presentations from major cardiovascular and cancer societies for studies from the inception of the database until Nov. 30, 2018. The following search terms were used: vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib. All studies were published in English. Primary outcomes were pulmonary embolism, decreased left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation.

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Final analysis included five randomized clinical trials encompassing 2,317 melanoma patients. Patients treated with BRAF and MEK inhibitors, compared to BRAF inhibitor monotherapy, had significantly greater risks for pulmonary embolism (relative risk [RR], 4.36; 95% confidence interval [CI], 1.23-15.44; P = 0.02), left ventricular ejection fraction decrease (RR, 3.72; 95% CI, 1.74-7.94; P < 0.001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = 0.005). There were no significant between-group differences in risks for myocardial infarction, atrial fibrillation, and QTc prolongation. Risks were also increased when evaluating certain high-grade CVAEs, including left ventricular ejection fraction (RR, 2.79; 95% CI, 1.36-5.73; P = 0.005; I² = 29%) and high-grade arterial hypertension (RR, 1.54; 95% CI, 1.14-2.08; P = 0.005; I² = 0%), but there were no significant between-group differences in high-grade pulmonary embolism. Left ventricular ejection fraction risk was significantly higher in patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = 0.001), while pulmonary embolism was more likely to occur in patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = 0.02).

The authors concluded that “therapy with BRAF and MEK inhibitors was associated with an increased risk of CVAEs, especially pulmonary embolism, a decrease in LVEF, and arterial hypertension, compared with BRAF inhibitor monotherapy”; they also recommended, “These adverse events should be carefully approached in cardio-oncology teams for an optimal treatment of patients with melanoma.”