Emerging cardiovascular toxicity associated with CDK4/6 inhibitors: real-world insights from the FDA adverse event
Wensheng Liu1,2, Feifei Gao1,2, Xue Song3
1Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.
Background:
Despite the unprecedented advancement of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in the treatment paradigm for hormone-dependent breast cancer, reports of cardiovascular adverse events (CVAEs) in both pivotal trials and real-world settings have garnered concerns.
Objectives:
we aim to profile the incidence, clinical characteristics and risk factors of CVAEs associated CDK4/6i to provide a vigilant reference for cancer management.
Methods:
The global disproportionality study was conducted by utilizing safety reports submitted to the FDA adverse event reporting system (FAERS) during the period from January 2015 to September 2024. Reporting odds ratio (ROR) was employed to identify and evaluate emerging CVAEs related to CDK4/6i. Multivariable logistic regression analysis was utilized to explore factors associated with CVAEs following CDK4/6i treatment. Parametric and cumulative distribution was used for the reported time-to-onset analysis.
Results:
A total of 4,709 reports of CVAEs were identified with CDK4/6i, of which 4264 (90.5%) were classified as serious and 12.0% were fatal situation. The median onset time of CVAEs with CDK4/6i was 102 days (interquartile range [IQR], 25-374 days). Disproportionality analysis revealed that Abemaciclib was significantly increased signal of venous thromboembolism (ROR = 2.57 [2.24-2.96]), whereas cardiac arrhythmia (ROR = 2.51 [2.13-2.96]) and torsade de pointes/QT prolongation (ROR = 5.7 [5-6.5]) were showed significantly disproportionate for ribociclib. Meanwhile, cerebrovascular accident and thrombosis were showed significant associated with Abemaciclib ribociclib or palbociclib treatment. Some emerging potential CVAEs, such as myocardial infarction and pulmonary edema, were found to be significantly associated with ribociclib and palbociclib. Additionally, age exceeding 65 years and types of CDK4/6i were significant risk factors for the incidence of CDK4/6i-related CVAEs.
Conclusion:
CVAEs might occur with a greater frequency in the context of CDK4/6i than had been previously acknowledged. Our study provide an overview of the incidence, characteristics and risk factors of CDK4/6i-related CVAEs, and also uncovered potential CVAEs that were not identified in the clinical trials.
Insights
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are linked to cardiovascular adverse events (CVAEs), including serious and fatal cases. Older age and specific CDK4/6i types increase the risk of these events.
Area of Science:
- Cardiology
- Oncology
- Pharmacovigilance
Background:
- Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are crucial in treating hormone-dependent breast cancer.
- Cardiovascular adverse events (CVAEs) have been reported with CDK4/6i, raising concerns in clinical practice.
- Real-world data suggests a need to further investigate CVAEs associated with CDK4/6i therapy.
Purpose of the Study:
- To profile the incidence and clinical characteristics of CVAEs in patients receiving CDK4/6i.
- To identify risk factors associated with CVAEs during CDK4/6i treatment.
- To provide a reference for vigilant cancer management regarding CDK4/6i-related CVAEs.
Main Methods:
- A global disproportionality study using FDA adverse event reporting system (FAERS) data from January 2015 to September 2024.
- Reporting odds ratio (ROR) was used to detect emerging CVAEs related to CDK4/6i.
- Multivariable logistic regression and time-to-onset analyses were employed to identify risk factors and patterns.
Main Results:
- 4,709 CVAEs reports associated with CDK4/6i were identified; 90.5% were serious, and 12.0% were fatal.
- Abemaciclib showed increased risk for venous thromboembolism (ROR = 2.57), while ribociclib was linked to cardiac arrhythmia (ROR = 2.51) and QT prolongation (ROR = 5.7).
- Age over 65 and specific CDK4/6i agents were significant risk factors for CVAEs.
Conclusions:
- CVAEs may occur more frequently with CDK4/6i than previously recognized.
- This study provides a comprehensive overview of CDK4/6i-related CVAEs, including incidence, characteristics, and risk factors.
- Potential CVAEs not identified in clinical trials were uncovered, highlighting the importance of ongoing pharmacovigilance.
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