Sex differences in cardiotoxicity of anaplastic lymphoma kinase inhibitors: An analysis of the FDA Adverse Event Reporting System

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 U.S. 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.