Heterogeneity of thromboembolic risk across ALK inhibitors: a retrospective real-world study identifying crizotinib-specific signals and high-risk subpopulations.

BACKGROUND: Patients with anaplastic lymphoma kinase (ALK)-positive malignancies increasingly rely on ALK inhibitors (ALKis) as first-line therapy, yet thromboembolism (TE) across the ALKi family and its impact on patients' safety remain incompletely characterized, particularly in the real-world populations. OBJECTIVE: The aim of this study was to evaluate the real-world TE risks associated with ALKis using pharmacovigilance data mining and to identify and characterize the high-risk contributors to TE. METHODS: We extracted 52,808 adverse event (AE) reports from the FDA Adverse Event Reporting System (2013-2024), including 17,124 ALKi-treated patients. TE signal strength was calculated via disproportionality analysis and presented by the lower limit of reporting odds ratio (ROR025) and information component (IC025). Multivariate logistic regression and time-to-onset (TTO) analyses were conducted to characterize the risk factors. RESULTS: Among ALKi users, 251 TE cases were identified. Crizotinib exhibited significant TE safety signals for embolism (ROR025 = 2.66; IC025 = 1.19), pulmonary artery thrombosis (ROR025 = 4.94; IC025 = 1.01), pulmonary thrombosis (ROR025 = 1.29; IC025 = 0.13), and venous thrombosis limb (ROR025 = 1.66; IC025 = 0.08). Older age (OR = 1.006, P = 2.40e-06), male sex (OR = 1.47, P = 2.00e-16), and crizotinib use (OR = 2.79, P = 1.59e-05) independently predicted fatal TE outcomes. Female patients <65 years experienced earlier TE onset (median 14 vs. 44-53 days; P = 0.006). CONCLUSION: This study validates the elevated TE safety signal strength of crizotinib in the real-world settings, while no disproportionate TE signals were detected for other ALKi in the FAERS database. Clinicians could prioritize agent-specific risks, especially in older male patients and during early treatment phases.