Abstract
Cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized. To determine the association of BRAF and MEK inhibitor treatment with CVAEs in patients with melanoma compared with BRAF inhibitor monotherapy. PubMed, Cochrane, and Web of Science were systematically searched for keywords vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib from database inception through November 30, 2018. Randomized clinical trials reporting on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors compared with patients with melanoma being treated with BRAF inhibitor monotherapy were selected. Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Pooled relative risks (RRs) and 95% CIs were determined using random-effects and fixed-effects analyses. Subgroup analyses were conducted to assess study-level characteristics associated with CVAEs. The selected end points were pulmonary embolism, a decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation. All-grade and high-grade (≥3) CVAEs were recorded. Overall, 5 randomized clinical trials including 2317 patients with melanoma were selected. Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (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. The RRs for myocardial infarction, atrial fibrillation, and QTc prolongation were similar between the groups. These results were consistent when assessing high-grade CVAEs (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%), but RRs for high-grade pulmonary embolism were similar between groups. A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02). Therapy with BRAF and MEK inhibitors was associated with a higher risk of CVAEs compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.
Highlights
The incidence of melanoma has been increasing, and it accounts for 55 500 cancer deaths annually worldwide.1 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.2,3 The identification of BRAF mutations prompted the development of a new class of targeted cancer drugs: BRAF inhibitors
Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (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
A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02)
Summary
The incidence of melanoma has been increasing, and it 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 identification of BRAF mutations prompted the development of a new class of targeted cancer drugs: BRAF inhibitors. The identification of BRAF mutations prompted the development of a new class of targeted cancer drugs: BRAF inhibitors. Subsequent research showed that treatment with BRAF inhibitors alone causes resistance through a paradoxical signaling cascade mediated by MEK, leading to the development of MEK inhibitor therapies.. 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.. A 2018 study found that the first BRAF and MEK inhibitor combination showed significant improvement in relapse-free survival in treating adjuvant stage III melanoma, which led to global approval. 3 BRAF inhibitors (dabrafenib, vemurafenib, and encorafenib7) and 3 MEK inhibitors (trametinib, cobinimetinib, and binimetinib16) have received US Food and Drug Administration and European Medicines Agency approval. Common combination therapies are dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib.
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