DataSheet_1_A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer.docx

BackgroundImmune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune–related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI–based regimens in patients with advanced lung cancer.
MethodsWe systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment–related AEs and irAEs, including grade 1–5 and grade 3–5. The secondary outcomes were grade 1–5 and grade 3–5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node–splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non–small cell lung cancer.
ResultsOverall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment–related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1–5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3–5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI–based options provided irAE profiles based on specific organ/system and severity.
ConclusionsIn consideration of overall immune–related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI–based treatments for advanced lung cancer. The safety profiles of ICI–based treatments are various by specific irAEs and their severity.
Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42021268650

背景
免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为晚期肺癌的标准治疗方案之一。然而，此类药物引发的不良事件（adverse events, AEs），尤其是免疫相关不良事件（immune-related AEs, irAEs），已引发公众广泛关注。本项网络Meta分析（network meta-analysis, NMA）旨在对比晚期肺癌患者接受不同免疫检查点抑制剂联合治疗方案时的不良事件发生风险。

方法
本研究系统检索了PubMed、EMBASE及Cochrane Library数据库（建库至2021年4月19日），纳入对比两种及以上治疗方案、且至少有一种方案包含免疫检查点抑制剂的晚期肺癌患者随机对照试验（randomized controlled trials, RCTs）。本研究的主要结局指标为治疗相关不良事件及免疫相关不良事件，涵盖1~5级与3~5级不良事件；次要结局指标为特定器官发生的1~5级及3~5级免疫相关不良事件。针对化疗、免疫检查点抑制剂单药治疗、免疫检查点抑制剂单药联合化疗、双免疫检查点抑制剂治疗以及双免疫检查点抑制剂联合化疗这五类方案的所有安全性结局，本研究均开展了配对Meta分析及网络Meta分析。同时通过节点拆分分析检验网络分析的不一致性，并通过限定纳入Ⅲ期随机对照试验以及纳入非小细胞肺癌患者的研究，完成敏感性分析。

结果
最终共纳入38项随机对照试验，涉及22178例晚期肺癌患者。合并发生率及网络Meta分析结果显示，相较于不含化疗的免疫检查点抑制剂治疗方案，含化疗的治疗方案的治疗相关不良事件风险更高。在1~5级免疫相关不良事件方面，双免疫检查点抑制剂联合化疗的免疫相关不良事件发生风险最高（排名首位的概率为50.5%），其次为双免疫检查点抑制剂治疗（排名第二的概率为47.2%）、免疫检查点抑制剂单药治疗（排名第三的概率为80.0%）、免疫检查点抑制剂单药联合化疗（排名第四的概率为98.0%），最后为单纯化疗（排名第五的概率为100.0%）。在3~5级免疫相关不良事件方面，仅存在细微差异：按安全性从低到高排序，依次为双免疫检查点抑制剂治疗（60.4%）、双免疫检查点抑制剂联合化疗（42.5%）、免疫检查点抑制剂单药治疗（76.3%）、免疫检查点抑制剂单药联合化疗（95.0%）以及单纯化疗（100.0%）。此外，本研究针对不同免疫检查点抑制剂治疗方案开展了详细对比，明确了特定器官/系统免疫相关不良事件的发生特征及严重程度分层。

结论
综合免疫相关安全性特征来看，在晚期肺癌的免疫检查点抑制剂治疗方案中，免疫检查点抑制剂单药联合化疗或许是更优选择。不同免疫检查点抑制剂治疗方案的安全性特征因特定免疫相关不良事件类型及严重程度而异。

系统评价注册信息
注册网址：https://www.crd.york.ac.uk/prospero，识别号：CRD42021268650