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Sex Differences in Cardiotoxicity of Anaplastic Lymphoma Kinase Inhibitors: An Analysis of the FDA Adverse Event
Hiroki Asano1, Yoshihiro Noguchi2,3, Rikuto Masuda4
1Department of Pharmacy, Ogaki Municipal Hospital, Gifu, Japan, hiro6imp@yahoo.co.jp.
Introduction:
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have transformed the management of ALK-rearranged non-small-cell lung cancer (NSCLC), yet their cardiotoxicity profile remains incompletely characterized, particularly with respect to sex differences. Given the high prevalence of cardiovascular disease in patients with NSCLC, understanding potential sex-specific risks is critical.
Methods:
We conducted a pharmacovigilance analysis using the US FDA Adverse Event Reporting System (FAERS) database (Q1 2004-Q3 2021) to examine cardiotoxicity signals associated with five ALK-TKIs (alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib). Adverse events were classified using the MedDRA hierarchy, focusing on cardiac disorders. Disproportionality analysis was performed via the Bayesian Confidence Propagation Neural Network (BCPNN) method, calculating Information Component (IC) scores. Sex differences were assessed by computing the IC delta and its 95% confidence interval.
Results:
Cardiotoxicity signals, particularly heart failure and pericardial disorders, were detected for alectinib, ceritinib, crizotinib, and lorlatinib but not brigatinib. Notably, significant female-specific signals emerged for left ventricular failure with alectinib; pericardial disorders with ceritinib and crizotinib; and heart failure not elsewhere classified (the MedDRA category used for heart failure cases that do not fall into specific classifications) with crizotinib.
Conclusion:
This is the first study to identify sex differences in ALK-TKI-associated cardiotoxicity, highlighting a consistent female predominance in reported adverse events. In particular, considering its widespread use and the clinical importance of left ventricular failure, the pronounced disproportionality signal of cardiotoxicity in females associated with alectinib is thought to have substantial clinical impact. These results underscore the need for heightened clinical vigilance and further research into sex-specific risk stratification and preventive strategies for cardiotoxicity in patients receiving ALK-TKIs.
Insights
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) show cardiotoxicity, with alectinib posing risks for female patients. Further research is needed for sex-specific prevention strategies in non-small-cell lung cancer (NSCLC) treatment.
Area of Science:
- Pharmacovigilance and Oncology
- Cardiovascular Risk Assessment
- Sex-Based Medicine
Background:
- Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have improved ALK-rearranged non-small-cell lung cancer (NSCLC) treatment.
- The cardiotoxicity of ALK-TKIs is not fully understood, especially regarding sex-specific differences.
- Cardiovascular disease is common in NSCLC patients, necessitating an understanding of sex-specific risks.
Purpose of the Study:
- To investigate cardiotoxicity signals of five ALK-TKIs.
- To identify potential sex differences in ALK-TKI-associated cardiotoxicity.
Main Methods:
- Pharmacovigilance analysis of the US FDA Adverse Event Reporting System (FAERS) database (Q1 2004-Q3 2021).
- Examined cardiotoxicity signals for alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib.
- Used Bayesian Confidence Propagation Neural Network (BCPNN) for disproportionality analysis and assessed sex differences via IC delta.
Main Results:
- Cardiotoxicity signals (heart failure, pericardial disorders) were found for alectinib, ceritinib, crizotinib, and lorlatinib.
- Brigatinib did not show significant cardiotoxicity signals.
- Significant female-specific signals included left ventricular failure (alectinib), pericardial disorders (ceritinib, crizotinib), and unspecified heart failure (crizotinib).
Conclusions:
- This study is the first to report sex differences in ALK-TKI cardiotoxicity, with a female predominance.
- Alectinib showed a notable cardiotoxicity signal in females, particularly left ventricular failure, requiring clinical attention.
- Results emphasize the need for vigilance, sex-specific risk stratification, and preventive strategies for ALK-TKI cardiotoxicity.
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