Jiang Bo-Xuan, Zeng Jia-Wei, Yan Jia-Jia, Zhao Li-Yan
Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Front Pharmacol. 2025 Aug 29;16:1644034. doi: 10.3389/fphar.2025.1644034. eCollection 2025.
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 1 January 2013 and 28 February 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.
https://www.crd.york.ac.uk/PROSPERO/view/CRD42024551353, identifier CRD42024551353.
ROS1酪氨酸激酶抑制剂（TKIs）在晚期ROS1重排的非小细胞肺癌（NSCLC）中已显示出显著疗效。然而，尚未对这些TKIs的毒性特征进行系统研究，而这些特征对于临床决策和患者管理至关重要。我们在PubMed、Embase、Cochrane图书馆和ClinicalTrials.gov上进行了系统检索，以识别报告晚期NSCLC患者中ROS1-TKIs安全性特征的研究。符合条件的研究是2013年1月1日至2025年2月28日期间以英文发表的研究。进行了比例荟萃分析。主要结局包括每种ROS1-TKI的全身性所有级别不良事件（AEs；1-5级）和严重不良事件（SAEs；3-5级）的发生率，而次要结局则侧重于特定AEs和SAEs的发生率。这项系统评价和比例荟萃分析纳入了26项研究，涉及5273名患者。ROS1-TKIs显示全身性所有级别AEs的发生率很高，范围从90%到99%。全身性SAEs在不同药物之间表现出更大的变异性，范围从29%到47%：克唑替尼，43%（95%CI，36%-49%）；色瑞替尼，41%（95%CI，37%-45%）；洛拉替尼，39%（95%CI，25%-55%）；恩曲替尼，32%（95%CI，28%-36%）；瑞波替尼，29%（95%CI，24%-33%）；伊鲁普拉纳基布，44%（95%CI，38%-50%）；和乌尼替尼，47%（95%CI，38%-56%）。这表明瑞波替尼可能更耐受，而乌尼替尼的安全性可能较低。此外，特定的AE特征在不同的ROS1-TKIs之间有所不同：瑞波替尼头晕发生率较高，恩曲替尼经常出现疲劳，洛拉替尼水肿发生率增加。他雷替尼和乌尼替尼与肝毒性显著相关。本研究首次对NSCLC患者中ROS1-TKIs的毒性特征进行了全面评估。这些发现将指导药物选择和安全监测，强调考虑患者健康状况、潜在风险因素以及ROS1-TKI相关不良反应特征的必要性。
https://www.crd.york.ac.uk/PROSPERO/view/CRD42024551353，标识符CRD42024551353。
