Combo Tx for Melanoma Ups CV Risk

Dual BRAF and MEK inhibition therapy for melanoma may carry certain cardiovascular harms, according to a meta-analysis.

Across five randomized trials with a total of 2,317 patients, the addition of MEK inhibition to a BRAF inhibitor, in comparison with BRAF inhibitor monotherapy, was associated with certain cardiovascular adverse events:

• Pulmonary embolism: RR 4.36 (95% CI 1.23-15.44)

• Decreased left ventricular ejection fraction (LVEF): RR 3.72 (95% CI 1.74-7.94)

• Arterial hypertension: RR 1.49 (95% CI 1.12-1.97)

When it came to high-grade events, patients on dual therapy had significantly more severe or life-threatening drops in LVEF (RR 2.79, 95% CI 1.36-5.73) and arterial hypertension (RR 1.54, 95% CI 1.14-2.08) -- whereas the difference in pulmonary embolism was not applicable to that degree of severity, reported investigators Matthias Totzeck, MD, of University Hospital Essen, Germany, and colleagues in JAMA Network Open.

"These adverse events should be carefully approached in cardio-oncology teams for an optimal treatment of patients with melanoma," the team concluded.

Groups who took BRAF with or without MEK inhibition experienced similar rates of myocardial infarction, atrial fibrillation, and QTc interval prolongation in the meta-analysis.

"The authors are to be congratulated for providing the most thoroughgoing evaluation of the potential cardiovascular toxicities of combined BRAF and MEK inhibition to date," commented Brian Jensen, MD, of UNC School of Medicine in Chapel Hill, who was not involved with the study.

"Regardless, these findings should not dampen enthusiasm for the use of these very effective agents, but do suggest that thoughtful periodic cardiovascular monitoring of patients receiving combined BRAF and MEK inhibition might be warranted," Jensen told MedPage Today.

Indeed, dual therapy is currently seen as the "optimal treatment" of metastatic BRAF-mutated melanoma, according to Totzeck's group.

Three BRAF inhibitors -- dabrafenib (Tafinlar), vemurafenib (Zelboraf), and encorafenib (Braftovi) -- have been approved by the FDA and the European Medicines Agency. As have three MEK inhibitors -- trametinib (Mekinist), cobimetinib (Cotellic), and binimetinib (Mektovi).

But the downside is that BRAF and MEK inhibition negatively interferes with cardiovascular MAPK signaling, the authors said. "This generates oxidative stress and apoptosis of myocytes and impairs angiogenesis, leading to significant cardiovascular diseases."

The exact mechanisms for cardiotoxicity are incompletely understood.

For example, it is unclear if combination BRAF and MEK inhibition triggers arterial hypertension through a perturbation in renin-angiotensin system regulation or by the reduced bioavailability of nitric oxide (due to an impaired vascular endothelial growth factor pathway normally mediated through the MAPK pathway).

"It is interesting to note that these adverse effects include such potentially pathophysiologically disparate processes: hypertension, pulmonary embolism, and left ventricular contractile dysfunction," said Jensen. "Defining underlying mechanisms of injury seems timely and potentially important."

Totzeck and colleagues cautioned that the adverse events in their meta-analysis had been reported according to oncology, rather than cardiology, definitions. The researchers also had to exclude many studies that did not report on cardiovascular events, and the ones they did include evaluated different treatment regimens among them.

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