免疫检查点抑制剂在晚期肺癌中的安全性特征网络比较。

BACKGROUND: Immune 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. METHODS: We 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. RESULTS: Overall, 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. CONCLUSIONS: In 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 REGISTRATION: https://www.crd.york.ac.uk/prospero, identifier CRD42021268650.

背景：免疫检查点抑制剂（ICIs）已成为晚期肺癌的标准治疗选择之一。然而，这些药物引起的不良反应（AEs），特别是免疫相关不良反应（irAEs），引起了公众的关注。本项网络荟萃分析（NMA）旨在比较不同基于 ICI 的方案治疗晚期肺癌患者的不良反应风险。

方法：我们系统地检索了 PubMed、EMBASE 和 Cochrane 图书馆数据库（从成立到 2021 年 4 月 19 日），以获取比较两种或多种治疗方法的相关随机对照试验（RCT），其中至少有一种 ICI 用于治疗晚期肺癌患者。主要结局是治疗相关不良反应和 irAEs，包括 1-5 级和 3-5 级。次要结局是特定器官的 1-5 级和 3-5 级 irAEs。对于所有安全性结局，我们均进行了化疗、ICI 单药治疗、ICI 单药联合化疗、双 ICI 治疗和双 ICI 联合化疗的两两和网络荟萃分析。进行节点分割分析以检验网络的不一致性。通过限制 III 期 RCT 和纳入非小细胞肺癌患者的研究进行敏感性分析。

结果：总共纳入了 38 项涉及 22178 例晚期肺癌患者的 RCT。汇总发生率和 NMA 均表明，与不包含化疗的 ICI 方案相比，含化疗的治疗方法增加了治疗相关不良反应的风险。对于 1-5 级 irAEs，双 ICI+化疗与 irAEs 风险最高相关（排名第一的概率：50.5%），其次是双 ICI 治疗（排名第二的概率：47.2%）、ICI 单药治疗（排名第三的概率：80.0%）、ICI 单药联合化疗（排名第四的概率：98.0%），最后是化疗（排名第五的概率：100.0%）。在 3-5 级 irAEs 中，观察到细微差异；安全性从低到高的排序趋势为双 ICI 治疗（60.4%）、双 ICI+化疗（42.5%）、ICI 单药治疗（76.3%）、ICI 单药联合化疗（95.0%）和化疗（100.0%）。此外，基于特定器官/系统和严重程度对 ICI 治疗方案之间进行详细比较，提供了 irAE 特征。

结论：考虑到总体免疫相关安全性特征，ICI 单药联合化疗可能是晚期肺癌中基于 ICI 的治疗的更好选择。基于特定 irAEs 及其严重程度，ICI 治疗方案的安全性特征各不相同。

系统评价注册：https://www.crd.york.ac.uk/prospero，标识符 CRD42021268650。