SYSTEMATIC REVIEW article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1644034
Toxicity profiles of ROS1 tyrosine kinase inhibitors in advanced non-small cell lung cancer: a systematic review and proportional meta-analysis
Provisionally accepted
- Department of Pharmacology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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ROS1 tyrosine kinase inhibitors (TKIs) have shown significant efficacy in advanced ROS1-rearranged non-small cell lung cancer (NSCLC). However, no systematic investigation has been conducted on the toxicity profiles of these TKIs, which are critical for clinical decision-making and patient management. We conducted a systematic search across PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov to identify studies that reported on the safety profiles of ROS1-TKIs in patients with advanced NSCLC. Eligible studies were those published between January 1, 2013 and February 28, 2025 in English language. A proportional meta-analysis was performed. Primary outcomes included the incidence rates of systemic all-grade adverse events (AEs; grades 1-5) and serious adverse events (SAEs; grades 3-5) for each ROS1-TKI, while secondary outcomes focused on incidence rates of specific AEs and SAEs. This systematic review and proportional meta-analysis included 26 studies involving 5,273 patients. ROS1-TKIs demonstrated high incidences of systemic all-grade AEs, ranging from 90% to 99%. Systemic SAEs exhibited greater variability across agents, ranging from 29% to 47%: crizotinib, 43% (95% CI, 36-49%); ceritinib, 41% (95% CI, 37-45%); lorlatinib, 39% (95% CI, 25-55%); entrectinib, 32% (95% CI, 28-36%); repotrectinib, 29% (95% CI, 24-33%); iruplinalkib, 44% (95% CI, 38-50%); and unecritinib, 47% (95% CI, 38-56%). This indicated that repotrectinib might be more tolerable, while unecitinib might have a lower safety profile. Additionally, specific AE profiles varied across ROS1-TKIs: repotrectinib exhibited higher rates of dizziness, entrectinib demonstrated frequent fatigue, and lorlatinib showed an increased incidence of edema. Taletrectinib and unecritinib were notably associated with hepatotoxicity. This study presents the first comprehensive evaluation of ROS1-TKIs' toxicity profiles in NSCLC patients. These findings will guide drug selection and safety monitoring, emphasizing the necessity of considering patients' health status, potential risk factors, and the characteristics of ROS1-TKI-related adverse reactions.
Keywords: ROS1, tyrosine kinase inhibitors, Toxicity, Non-small cell lung cancer, proportional meta-analysis
Received: 09 Jun 2025; Accepted: 04 Aug 2025.
Copyright: © 2025 Jiang, Zeng, Yan and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Li-Yan Zhao, Department of Pharmacology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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