Passing this study along so you can talk with your providers about your individual concerns as a care provider. Peace,
Missy
Targeting BRAF/MEK in Melanoma Raises CV Risks
-CV harms emerge with dual BRAF/MEK inhibition not seen with BRAF monotherapy
Study Authors: Raluca I. Mincu, Amir A. Mahabadi, et al.
Target Audience and Goal Statement:
Oncologists, cardiologists, dermatologists, cardio-oncologists, internists
The goal of this systematic review and meta-analysis was to determine the association of dual BRAF/MEK inhibition with cardiovascular adverse events (CVAEs) in melanoma patients in comparison with BRAF inhibitor monotherapy.
Questions Addressed:
Are melanoma patients who are treated with dual BRAF/MEK inhibitors at higher risk for CVAEs compared with patients treated only with BRAF inhibitors?
What are the specific cardiovascular risks regarding pulmonary embolism, decrease in left ventricular ejection fraction (LVEF), arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation with dual versus monotherapy?
What is currently understood about the mechanisms by which dual BRAF/MEK inhibition increases certain CVAEs?
Action Points
Study Synopsis and Perspective:
Treatment of melanoma patients with dual BRAF and MEK inhibitor therapy appears to increase cardiovascular risks compared with BRAF inhibitor monotherapy, according to a systematic review and meta-analysis of five randomized controlled studies.
In a total of 2,317 melanoma patients, adding a MEK inhibitor to a BRAF inhibitor, in comparison with BRAF inhibitor monotherapy, was associated with a higher risk of certain CVAEs:
Pulmonary embolism: RR 4.36 (95% CI 1.23-15.44)
Decreased LVEF: RR 3.72 (95% CI 1.74-7.94)
Arterial hypertension: RR 1.49 (95% CI 1.12-1.97)
Regarding high-grade events in particular, 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) -- while the difference in pulmonary embolism was not applicable to that degree of severity, reported Matthias Totzeck, MD, of University Hospital Essen, Germany, and colleagues in JAMA Network Open.
"A higher risk of a decrease in LVEF was associated with patients with a mean age younger than 55 years ... and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months," the researchers wrote.
Patients who took BRAF inhibitors with and without MEK inhibitors experienced similar rates of myocardial infarction, atrial fibrillation, and QTc interval prolongation.
"These adverse events should be carefully approached in cardio-oncology teams for an optimal treatment of patients with melanoma," the team said.
Dual therapy is currently seen as the optimal treatment of metastatic BRAF-mutated melanoma due to resistance seen with BRAF inhibitor monotherapy. Three BRAF inhibitors -- dabrafenib, vemurafenib, and encorafenib -- are now approved by the FDA and the European Medicines Agency, as are three MEK inhibitors -- trametinib, cobimetinib, and binimetinib.
However, 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 Brian Jensen, MD, of UNC School of Medicine in Chapel Hill, who was not involved with the study. "Defining underlying mechanisms of injury seems timely and potentially important."
Totzeck and colleagues cautioned that the adverse events noted in their meta-analysis had been reported according to oncology, rather than cardiology, definitions. Another study limitation is that they had to exclude many studies that did not report on cardiovascular events, and the ones they did include evaluated different treatment regimens among them.
"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," Jensen said.
"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.
Source Reference: JAMA Network Open 2019; DOI: 10.1001/jamanetworkopen.2019.8890
Study Highlights: Explanation of Findings
With the available combinations of the three approved BRAF inhibitors and three approved MEK inhibitors for melanoma, the researchers found that dual BRAF/MEK inhibition raised the risk of pulmonary embolism, a decrease in LVEF, and arterial hypertension compared with BRAF inhibitor monotherapy.
Specifically, 2.2% of patients in the combination therapy group developed a pulmonary embolism versus 0.4% in the BRAF inhibitor-alone group. The dual therapy was associated with more than a threefold increase in the risk of decrease in LVEF and a 1.4-fold increase in the risk of arterial hypertension. Overall, 8.1% of patients in the dual inhibitor treatment group had a decrease in LVEF compared with 2.0% of those in the monotherapy group; 19.5% of patients receiving both inhibitors developed arterial hypertension, compared with 14% in the BRAF inhibitor-alone group.
Other clinical data indicated that 5% to 11% of patients undergoing dual BRAF/MEK inhibition experienced a reduction in LVEF, and 10% to 15% of patients are diagnosed with arterial hypertension. Some studies reported QTc interval prolongation, while others did not, the authors noted, leaving this question still unanswered.
Regarding the efficacy of dual versus monotherapy, a number of studies have demonstrated that "effective inhibition of the MAPK pathway through a combination of BRAF and MEK inhibitor therapy resulted in better clinical outcomes, and it is known to ameliorate BRAF inhibition-related adverse events caused by MEK hyperproduction, like squamous skin cancer and other skin-related toxicities," the authors wrote. Although, the various combinations with available BRAF and MEK inhibitors indicate mostly overlapping adverse events, pyrexia has been seen with dabrafenib and trametinib, and photosensitivity with vemurafenib and cobimetinib, though both of these adverse effects were less frequent with encorafenib and binimetinib.
Finally, the authors noted that it is unclear whether the increased risks of reduced LVEF and arterial hypertension seen with the combination treatment is a MEK-mediated phenomenon or related to a more efficient inhibition of the MAPK pathway, since earlier studies as well as the current study present evidence for both possibilities.
The bottom line is that in the case of stage 2 hypertension, defined as systolic blood pressure over 160 mm Hg or diastolic blood pressure over 100 mm Hg, dual treatment should be stopped. Arterial hypertension should be treated according to current guidelines; therapy should be reintroduced at a lower dose after the reduction of arterial hypertension to stage 1 or lower. For an asymptomatic LVEF decrease of 10% or more from baseline, BRAF therapy should be continued at the current dose, but MEK therapy should be discontinued.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
Primary Source
JAMA Network Open
Source Reference: Mincu RI, et al "Cardiovascular adverse events associated with BRAF and MEK inhibitors: a systematic review and meta-analysis" JAMA Netw Open 2019; DOI: 10.1001/jamanetworkopen.2019.8890.
Source Reference: Lou N "Combo Tx for Melanoma Ups CV Risk" 2019.
