ICIs治疗NSCLC致免疫相关不良反应与疗效相关性的Meta分析

Meta-analysis of the correlation between immune-related adverse events and efficacy of immune checkpoint inhibitors in the treatment of non-small cell lung cancer

目的系统评价免疫检查点抑制剂(ICIs)治疗非小细胞肺癌(NSCLC)致免疫相关不良反应(irAEs)与疗效的相关性,为ICIs的临床应用及安全性评估提供循证参考。方法计算机检索PubMed、Embase、Cochrane图书馆、Web of Science、中国知网、万方数据、维普网、中国生物医学文献服务系统,收集ICIs治疗NSCLC致irAEs与疗效相关性的前瞻性或回顾性队列研究,检索时限均为各数据库建库起至2021年6月30日。筛选文献、提取资料后,采用纽卡斯尔-渥太华量表对纳入文献质量进行评价;采用RevMan 5.3软件进行Meta分析及发表偏倚分析;采用Stata 15.0软件进行敏感性分析。结果共纳入31项研究,共计7957例患者。Meta分析结果显示,irAEs组患者的客观反应率(ORR)[RR=2.34,95%CI(1.98,2.76),P<0.00001]、无进展生存期(PFS)[HR=0.49,95%CI(0.44,0.55),P<0.00001]、总生存期(OS)[HR=0.45,95%CI(0.39,0.53),P<0.00001],以及该组第6周时的ORR[RR=1.88,95%CI(1.57,2.25),P<0.00001]、PFS[HR=0.59,95%CI(0.50,0.69),P<0.00001]、OS[HR=0.58,95%CI(0.48,0.70),P<0.00001]均显著高于或长于非irAEs组。按irAEs器官特异性、irAEs严重程度及数量进行的亚组分析结果显示,皮肤、胃肠道、内分泌系统、轻度(1~2级)及发生1种或≥2种irAEs与患者PFS、OS的改善相关(P<0.05),肝、肺和重度(≥3级)irAEs与患者PFS、OS的改善无相关性(P>0.05)。敏感性分析结果显示,所得结果较稳健。发表偏倚分析结果显示,本研究可能存在一定的发表偏倚。结论对于接受ICIs治疗的NSCLC患者,irAEs的发生可能与其更好的预后有关;irAEs可能是ICIs疗效的预测因子。

OBJECTIVE To systematically evaluate the relationship between immune-related adverse events(irAEs)and efficacy of immune checkpoint inhibitors(ICIs)in the treatment of non-small cell lung cancer(NSCLC),and to provide evidence-based reference for clinical application of ICIs and safety evaluation.METHODS PubMed,Embase,Cochrane Library,Web of Science,CNKI,Wanfang database,VIP and CBM were searched to collect prospective or retrospective cohort studies on the correlation between irAEs and efficacy of ICIs in the treatment of NSCLC.The retrieval time was from the inception to June30th,2021.After literature screening and data extraction,Newcastle-Ottawa scale was used to evaluate the quality of included literatures.Meta-analysis and publication bias analysis were performed by using RevMan 5.3 software;Stata 15.0 software was used for sensitivity analysis.RESULTS A total of 7957 patients were included in 31 studies.Meta-analysis showed that the objective response rate(ORR)[RR=2.34,95%CI(1.98,2.76),P<0.00001],progression-free survival(PFS)[HR=0.49,95%CI(0.44,0.55),P<0.00001]and overall survival(OS)[HR=0.45,95%CI(0.39,0.53),P<0.00001]of irAEs group as well as ORR[RR=1.88,95%CI(1.57,2.25),P<0.00001],PFS[HR=0.59,95%CI(0.50,0.69),P<0.00001]and OS[HR=0.58,95%CI(0.48,0.70),P<0.00001]of this group at 6th week were all significantly higher or longer than non irAEs group.According to organ specificity,severity and quantity of irAEs,subgroup analysis showed that skin,gastrointestinal and endocrine system,mild irAEs(grade 1-2)and one or more than 2 kinds of irAEs were significantly correlated with the improvement of PFS and OS(P<0.05),while liver and lung,severe irAEs(≥grade 3)were not significantly correlated with the improvement of PFS and OS(P>0.05).Sensitivity analysis results showed that the results of the above-mentioned meta-analysis were relatively robust.The results of publication bias showed that there was may be some possibility of publication bias in this study.CONCLUSIONS For NSCLC patients treated with ICIS,the occurrence of ir AEs may be related to their good prognosis.The ir AEs may be a predictor of the efficacy of ICIs.