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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross-sectional and longitudinal
Avirup Guha1, Prantesh Jain2, Michael G Fradley3
1Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
Insights
Combination BRAF/MEK inhibitors increase cardiovascular risks like heart failure and hypertension compared to BRAF inhibitors alone. This finding highlights potential safety concerns with combination therapy in melanoma treatment.
Area of Science:
- Oncology
- Cardiology
- Pharmacology
Background:
- Cardiovascular adverse events (CVAEs) from BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.
- Melanoma treatment often involves targeted therapies like BRAF and MEK inhibitors.
- Understanding CVAE profiles is crucial for patient safety and treatment optimization.
Purpose of the Study:
- To compare the incidence and risk of CVAEs between BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy.
- To identify specific types of CVAEs associated with each treatment regimen.
- To provide real-world evidence on the cardiovascular safety of these targeted therapies.
Main Methods:
- Utilized FDA's Adverse Events Reporting System (FAERS) and IBM MarketScan database (2011-2018).
- Included adult patients receiving BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or BRAF/MEK inhibitor combinations.
- Analyzed CVAEs including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE) using adjusted regression techniques.
Main Results:
- In FAERS, combination therapy showed increased odds for HF (ROR=1.62), hypertension (ROR=1.75), and VTE (ROR=1.80) versus monotherapy.
- MarketScan data revealed 26.2% CVAEs within 6 months for combination therapy vs. 16.7% for monotherapy.
- Combination therapy was associated with a higher risk of CVAEs (aHR=1.56) compared to monotherapy.
Conclusions:
- Combination BRAF/MEK inhibitors are associated with a significantly increased risk of CVAEs compared to BRAF inhibitor monotherapy.
- Heart failure and hypertension are key CVAEs elevated with combination therapy.
- These findings underscore the importance of cardiovascular monitoring in patients receiving combination BRAF/MEK inhibitor therapy.
Background:
Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.
Methods:
This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.
Results:
In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).
Conclusions And Relevance:
In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.
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