Combination Therapy for Melanoma May Increase Cardiovascular Risks

A recent study published in JAMA Network Open found that patients with melanoma may have a higher risk for cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors compared to BRAF inhibitor monotherapy.

“The incidence of melanoma has been increasing, and it now accounts for 55 500 cancer deaths annually worldwide. The most frequent mutations in melanoma occur at the level of BRAF with a subsequent upregulation of the canonical MAPK pathway responsible for tumor growth and proliferation,” the researchers wrote, adding, “The combination of BRAF and MEK inhibitor therapy has emerged as an optimal treatment of metastatic BRAF-mutated melanoma, with improved survival rates compared with monotherapy.”

The researchers therefore conducted a meta-analysis, querying the PubMed, Cochrane, and Web of Science databases using the keywords vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib. Eligible studies were randomized clinical trials published from database inception through Nov. 30, 2018, that evaluated CVAEs in melanoma patients being treated with BRAF and MEK inhibitors compared to BRAF inhibitor monotherapy. The primary outcomes were pulmonary embolism, decreased left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation.

The final analysis included five randomized clinical trials encompassing 2,317 total melanoma patients. According to the researchers, “Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism ([relative risk] RR, 4.36; 95% CI, 1.23-15.44; P = .02), a decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94; P < .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = .005) compared with BRAF inhibitor monotherapy.” There were no significant between-group differences in RRs for myocardial infarction, atrial fibrillation, and QTc prolongation. When looking specifically at high-grade CVAEs, the outcomes were similar for high-grade left ventricular ejection fraction (RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%) and high-grade arterial hypertension (RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%); however, there were no significant between-group differences in RRs for high-grade pulmonary embolism. Younger age (< 55 years) was associated with decreased left ventricular ejection fraction (RR, 26.50; 95% CI, 3.58-196.10; P = .001). Patients with follow-up longer than 15 months had a higher associated risk for pulmonary embolism (RR, 7.70; 95% CI, 1.40-42.12; P = .02).

The study authors concluded that “therapy with BRAF and MEK inhibitors was associated with an increased risk of CVAEs, especially pulmonary embolism, a decrease in [left ventricular ejection fraction], and arterial hypertension, compared with BRAF inhibitor monotherapy. … These adverse events should be carefully approached in cardio-oncology teams for an optimal treatment of patients with melanoma.”