文献类型：期刊文献

英文题名：Safety recommendations for ALK tyrosine kinase inhibitors in non-small cell lung cancer: evidence from FAERS and CVARDD real-world databases

作者：Zhang, Yuanyuan[1];Zhang, Tuanzhuang[1,2];Yang, Yuping[1];Zhang, Wenhui[1];Ma, Qiangping[1];Li, Juan[1];Li, Jintian[1];Yang, Xuan[1];Gong, Jirong[1];Wang, Xinyi[1];Liang, Jianqing[1]

第一作者：张彦彦;张芸燕;张延英

通信作者：Li, JT[1];Liang, JQ[1]

机构：[1]Gansu Univ Chinese Med, Clin Coll Tradit Chinese Med, Lanzhou, Peoples R China;[2]Gansu Prov Tradit Chinese Med Hosp, Orthoped & Traumatol, Lanzhou, Peoples R China

第一机构：甘肃中医药大学中医临床学院

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Clin Coll Tradit Chinese Med, Lanzhou, Peoples R China.|[10735ccd4a8840d96ab71]甘肃中医药大学中医临床学院;[10735]甘肃中医药大学;

年份：2026

卷号：16

外文期刊名：FRONTIERS IN ONCOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001735103700001)】；

基金：The author(s) declared that financial support was received for this work and/or its publication. The work was supported by National Natural Science Foundation of China in 2025 (82560964); 2021 Gansu Province "Double First Class" Scientific Research Key Project (GSSYLXM-05); 2021 National Natural Science Foundation of China (82160872); Major Cultivation Project for Research and Innovation Platforms in Universities in 2024 (2024CXPT-08); The "Qihuang Talents" Mentor Special Fund Doctoral Program for the First Class Discipline of Traditional Chinese Medicine in 2024 (ZYXKBD-202418); Open Project of Dunhuang Medical and Translational Key Laboratory of the Ministry of Education in 2022 (DHYX22-06).

语种：英文

外文关键词：ALK tyrosine kinase inhibitors; hepatotoxicity; non-small cell lung cancer; pharmacovigilance; pleural effusion; sex differences

摘要：Background Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer mortality worldwide. The development of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) has significantly improved survival among patients with ALK-positive NSCLC. However, prolonged treatment and wider clinical use have led to increasing reports of adverse events (AEs). Existing studies have primarily explored individual drugs, with limited comparative evidence across different ALK-TKIs regarding sex-specific safety differences and time-to-onset patterns. Methods This real-world pharmacovigilance study analyzed data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS, Q1 2004-Q2 2025) and the Canadian Vigilance Adverse Reaction Database (CVARDD). Disproportionality analyses were performed using four algorithms-Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS)-to detect adverse event signals for crizotinib, alectinib, and brigatinib. Sex-stratified risk analyses, cross-database validation, and Weibull time-to-onset modeling were further conducted to assess robustness and temporal patterns of AE occurrence. Results A total of 18-683 AE reports were identified (crizotinib = 9 030; alectinib = 8 486; brigatinib = 1 167). Distinct toxicity spectra were observed among the three ALK-TKIs. Brigatinib exhibited the strongest hepatotoxic and pulmonary signals, notably hepatic function abnormal (ROR = 13.95) and pleural effusion (ROR = 11.03), indicating a high risk of early liver and respiratory toxicity. Alectinib showed pronounced metabolic and edema-related AEs (oedema, ROR = 9.47; hepatic function abnormal, ROR = 9.21), suggesting a tendency toward fluid retention and hepatobiliary dysfunction. Crizotinib demonstrated a more balanced safety profile but still presented notable risks for pleural effusion (ROR = 8.88) and hepatic function abnormal (ROR = 7.92), both showing early-onset patterns (median TTO = 34.5 days and 14.5 days, respectively). Sex-stratified analyses revealed that males were more prone to renal, cardiac, and respiratory toxicities, whereas females were more likely to develop hepatic and hematologic events. Weibull modeling indicated an "early failure" pattern (beta< 1) for all agents, meaning AEs predominantly occurred within the first 12 weeks of therapy. Cross-database validation confirmed consistent risk signal direction and strong reproducibility between FAERS and CVARDD datasets. Conclusions All three ALK-TKIs demonstrate distinct, generation-dependent safety profiles characterized by early-onset hepatobiliary and pulmonary toxicities, with evident sex-specific differences in organ susceptibility. Intensive safety monitoring during the initial 12 weeks of therapy is essential for preventing severe outcomes.