Risks of high-grade arterial hypertension and high-grade reduction in left ventricular ejection fraction (LVEF) are increased for patients with advanced melanoma treated with a combination of BRAF and MEK inhibitors compared with those treated with BRAF inhibitor alone, according to study results published in JAMA Open Network.

Mutations in BRAF are common in melanoma, and are associated with increased tumor growth and proliferation through upregulation of the mitogen-activating protein kinase (MAPK) signaling pathway.

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Results of randomized clinical trials of patients with advanced melanoma have demonstrated that dual targeting of the MAPK pathway with the combination of a BRAF inhibitor and a MEK inhibitor (eg, dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) improved survival rates more effectively than did BRAF inhibitor therapy alone. Although increased risks of cardiovascular adverse events (CVAEs) with BRAF/MEK inhibitor combination therapy have been previously reported, these investigators stated that “the nature and incidence of CVAEs associated with BRAF and MEK inhibitor therapy are incompletely described.”

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For this meta-analysis, a systematic review of the literature identified 5 randomized clinical trials comparing BRAF/MEK inhibitor combination therapy with BRAF inhibitor monotherapy in adult patients with advanced melanoma as meeting study inclusion criteria. Data were from a total of 2317 patients.

With 2.2% of patients receiving combination therapy and 0.4% of those treated with a single-agent BRAF inhibitor experiencing all-grade pulmonary embolism, the relative risk of this CVAE was 4.36 (95% CI, 1.23-15.44; P =.02) for those in the former group compared with the latter. However, there was no significant difference in the risk of high-grade pulmonary embolism between the 2 groups.

The relative risk of a decrease in LVEF was 3.72 (95% CI, 1.74-7.95; P <.001) for those receiving combination therapy vs monotherapy, with 8.1% and 2.0% of patients, respectively, experiencing this CVAE. In addition, risk of a high-grade decrease was greater for those receiving combination vs monotherapy (relative risk [RR], 2.79; 95% CI, 1.36-5.73; P = .005). Interestingly, patients younger than 55 years were more likely to experience a high-grade decrease in LVEF compared with older patients (RR, 26.50; 95% CI, 3.58-196.10; P = .001).

All-grade arterial hypertension was reported in 19.5% of patients receiving a BRAF/MEK combination and 14.0% of patients receiving a BRAF inhibitor alone, with a relative risk of 1.49 (95% CI, 1.12-1.98; P = .005) for those in the combination group compared with the monotherapy group. When only high-grade arterial hypertension was considered, the risk remained higher for those receiving combination therapy (RR, 1.54; 95%CI, 1.14-2.08; P = .005).

In contrast, the risks of myocardial infarction, atrial fibrillation, and QTc interval prolongation were not significantly different between the combination therapy group and the monotherapy group.

“Our findings increase the awareness of CVAEs in patients with melanoma treated with BRAF and MEK inhibitors and may help to determine the appropriate clinical cardio-oncology management,” the investigators concluded.


Mincu RI, Mahabadi AA, Michel L, et al. Cardiovascular adverse events associated with BRAF and MEK inhibitors: A systematic review and meta-analysis. JAMA Netw Open. 2019;2(8):e198890.