基于美国FAERS数据库对免疫检查点抑制剂相关神经毒性的分析研究

Analysis of neurological toxicities associated with immune checkpoint inhibitor based on the FDA adverse event reporting system

目的:基于美国不良事件报告系统(FAERS)对免疫检查点抑制剂(ICI)相关神经系统相关不良事件(nAEs)进行挖掘,为临床安全用药提供参考。方法:利用FAERS平台,收集2004年第1季度-2021年第4季度中ICI(包括纳武利尤单抗、帕博利珠单抗、Cemiplimab-rwlc、阿替利珠单抗、阿维单抗、度伐利尤单抗、伊匹木单抗和Tremelimumab)相关nAEs的报告,采用报告比值比法计算不同ICI药物及联用方式相关的神经毒性事件信号、发生时间及死亡率。结果:共收集10704份ICI单药治疗相关nAEs的报告,涉及93个风险信号,联合治疗2876份,检测出50个风险信号。ICI相关nAEs报告例数最多的是重症肌无力,帕博利珠单抗致该不良事件信号最强(ROR_(025)=25.81),伊匹木单抗/纳武利尤单抗次之(ROR_(025)=22.64)。ICI联合用药相关重症肌无力的死亡率为33.60%,前十位高发的nAEs中位发生时间为28 d。结论:不同ICI药物和联用方式所致神经毒性的风险有所差异,多发生于治疗早期。临床在应用ICI时应警惕神经系统不良反应。

Objective:To mine the neurological adverse events(nAEs)associated with the immune checkpoint inhibitor(ICI)based on the FDA adverse event reporting system(FAERS),in order to provide references for clinical safety drug use.Methods:The nAEs associated with ICIs(including nivolumab,pembrolizumab,cemiplimab-rwlc,atezolizumab,avelumab,durvalumab,ipilimumab,tremelimumab)from the first quarter in 2004 to the fourth quarter in 2021 were extracted from FAERS to explore the signals,the onset time and the fatality rate of nAEs related with different ICIs and the combination use of ICIs by reporting odds ratio(ROR)method.Results:A total of 10704 reports of ICI monotherapy-related nAEs with 93 signals and 2876 nAEs induced by combination ICI therapy with 50 signals were collected in this study.Myasthenia gravis was the most common nAE associated with ICIs.Pembrolizumab showed a higher risk of myasthenia gravis than other ICIs(ROR_(025)=25.81),and ipilimumab/nivolumab showed a higher risk than other combination regimens(ROR_(025)=22.64).The mortality rate of myasthenia gravis caused by combination therapy of ICIs was 33.60%.The median onset time of the top 10 nAEs induced by ICIs was 28 days.Conclusion:The risk of nAEs associated with ICIs was different in different ICIs and combination use of ICIs,most of which occurred in the early stage of the treatment.Clinicians should be vigilant about nAEs associated with ICI therapy.