Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross-sectional and longitudinal analysis using two large national registries.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ adverse effects
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Azetidines
/ adverse effects
Benzimidazoles
/ adverse effects
Carbamates
/ adverse effects
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cardiotoxicity
/ etiology
Cardiovascular Diseases
/ chemically induced
Colonic Neoplasms
/ drug therapy
Cross-Sectional Studies
Female
Heart Failure
/ chemically induced
Humans
Hypertension
/ chemically induced
Imidazoles
/ adverse effects
Lung Neoplasms
/ drug therapy
Male
Melanoma
/ drug therapy
Middle Aged
Mitogen-Activated Protein Kinase Kinases
/ antagonists & inhibitors
Oximes
/ adverse effects
Piperidines
/ adverse effects
Protein Kinase Inhibitors
/ adverse effects
Proto-Oncogene Proteins B-raf
/ antagonists & inhibitors
Pyridones
/ adverse effects
Pyrimidinones
/ adverse effects
Registries
Regression Analysis
Skin Neoplasms
/ drug therapy
Sulfonamides
/ adverse effects
Vemurafenib
/ adverse effects
Venous Thromboembolism
/ chemically induced
Young Adult
BRAF inhibitors
BRAF/MEK inhibitors
FAERS
Marketscan
cardiotoxicity
cardiovascular adverse events
pharmacoepidemiology
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
04
04
2021
received:
13
12
2020
accepted:
05
04
2021
pubmed:
14
5
2021
medline:
25
12
2021
entrez:
13
5
2021
Statut:
ppublish
Résumé
Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood. 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. 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). In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.
Sections du résumé
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.
Identifiants
pubmed: 33982883
doi: 10.1002/cam4.3938
pmc: PMC8209554
doi:
Substances chimiques
Antineoplastic Agents
0
Azetidines
0
Benzimidazoles
0
Carbamates
0
Imidazoles
0
Oximes
0
Piperidines
0
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
Sulfonamides
0
binimetinib
181R97MR71
Vemurafenib
207SMY3FQT
trametinib
33E86K87QN
encorafenib
8L7891MRB6
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
cobimetinib
ER29L26N1X
dabrafenib
QGP4HA4G1B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3862-3872Informations de copyright
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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