Table_1_Comparative Safety of PD-1/PD-L1 Inhibitors for Cancer Patients: Systematic Review and Network Meta-Analysis.DOCX

Background: Comprehensive evidence comparing treatment-related adverse events (trAEs) among PD-1/PD-L1 inhibitors is unavailable.Methods: A systematic review and network meta-analysis (NMA) was conducted. Randomized controlled trials in cancer patients treated with PD1/PD-L1 inhibitors or their combinations with chemotherapy/placebo and compared with PD1/PD-L1 inhibitors/chemotherapy/placebo were identified through comprehensive searches of multiple databases. Bayesian NMA was performed using random-effects model. Relative ranking of treatments was assessed with surface under the cumulative ranking (SUCRA) probabilities. Incidences and odds ratios of trAEs and immune-related adverse events (irAEs) of all-grade (Grade 1–5) and high-grade (Grade 3–5) were estimated.Results: Twenty-three RCTs (14,204 patients) comparing six different strategies were included. The incidence of trAEs was lowest for PD-L1 inhibitors (all-grade: pooled incidence = 60.4%, SUCRA = 77.2%; high-grade: 6.4, 73.8%). PD-L1 inhibitors plus chemotherapy had the highest incidence of all-grade trAEs (88.6, 10.1%), while PD-1 inhibitors plus chemotherapy had the highest incidence of high-grade trAEs (8.2, 9.3%). The use of PD-1/PD-L1 inhibitors alone was associated with significant reductions on high-grade trAEs, compared with PD-1/PD-L1 inhibitors plus chemotherapy. PD-1 inhibitors had the highest incidence of irAEs (all-grade: 15.1, 9.5%; high-grade: 3.5, 16.8%). Compared with PD-L1 inhibitors, PD-1 inhibitors neither increased trAEs nor irAEs significantly. Results from sensitivity analyses were consistent.Conclusions: Current data showed that PD-L1 inhibitors had the best safety on both trAEs and irAEs. Awareness of the comparative safety could promote further appropriate utilization of PD-1/PD-L1 inhibitors in clinical practice.

背景：关于比较PD-1/PD-L1抑制剂相关治疗性不良事件（trAEs）的全面证据尚不充分。
方法：本研究进行了系统评价和网络荟萃分析（NMA）。通过全面检索多个数据库，确定了在癌症患者中使用PD1/PD-L1抑制剂或其与化疗/安慰剂的联合治疗，并与PD1/PD-L1抑制剂/化疗/安慰剂进行比较的随机对照试验。采用贝叶斯NMA，并使用随机效应模型进行。通过累积排名曲线下面积（SUCRA）概率评估治疗的相对排名。对所有等级（1-5级）和高等级（3-5级）trAEs和免疫相关不良事件（irAEs）的发生率和比值比进行了估计。
结果：纳入了23项RCT（14,204名患者），比较了六种不同的策略。trAEs的发生率在PD-L1抑制剂中最低（所有等级：合并发生率=60.4%，SUCRA=77.2%；高等级：6.4，73.8%）。PD-L1抑制剂联合化疗的全等级trAEs发生率最高（88.6，10.1%），而PD-1抑制剂联合化疗的高等级trAEs发生率最高（8.2，9.3%）。与PD-1/PD-L1抑制剂联合化疗相比，单独使用PD-1/PD-L1抑制剂显著降低了高等级trAEs。PD-1抑制剂的高等级irAEs发生率最高（所有等级：15.1，9.5%；高等级：3.5，16.8%）。与PD-L1抑制剂相比，PD-1抑制剂并未显著增加trAEs或irAEs。敏感性分析的结果一致。
结论：现有数据显示，PD-L1抑制剂在trAEs和irAEs方面的安全性最佳。对比较安全性的认识可以促进在临床实践中进一步合理使用PD-1/PD-L1抑制剂。