PD-1/PD-L1与CTLA-4联合治疗实体瘤患者有效性和安全性的Meta分析

目的: 系统评价PD-1/PD-L1与CTLA-4联合治疗对比PD-1/PD-L1单药治疗实体瘤患者的有效性和安全性,旨在为临床用药提供循证参考。方法: 计算机检索PubMed、Embase、Cochrane Library、中国知网、CBM、维普和万方数据,检索时限均为各数据库建库至2021年11月。根据纳入与排除标准筛选文献后,采用Cochrane 系统评价员手册 5.1.0 推荐的偏倚风险评估工具对纳入文献质量进行评价;采用Rev Man 5.4软件进行Meta分析;采用倒漏斗图进行发表偏倚分析。结果: 共纳入22项研究,共计8 535例患者。Meta分析结果显示,从生存指标方面分析,PD-1/PD-L1与CTLA-4联合治疗显著改善实体瘤患者的客观反应率(ORR)、疾病控制率(DCR)和无进展生存期(PFS),但总生存期(OS)改善无统计学差异。亚组分析结果显示,PD-1/PD-L1与CTLA-4联合治疗能显著改善黑色素瘤患者的ORR和PFS,而OS改善无统计学差异;能显著改善肺癌患者的PFS,而ORR和OS改善无统计学差异;显著改善其他实体瘤患者的ORR和DCR,而PFS和OS改善无统计学差异。从安全指标方面分析,PD-1/PD-L1与CTLA-4联合治疗显著增加实体瘤患者的所有级别和3~4级不良反应发生率、死亡率以及中止治疗率。亚组分析结果显示,PD-1/PD-L1与CTLA-4联合治疗能显著增加黑色素瘤和其他实体瘤患者的3~4级不良反应发生率和中止治疗率,显著增加肺癌患者所有级别和3~4级不良反应发生率、死亡率以及中止治疗率。结论: PD-1/PD-L1和CTLA-4联合治疗与PD-1/PD-L1单药治疗相比,能显著改善实体瘤患者的PFS、DCR和ORR,但是也显著增加实体瘤患者治疗相关不良反应发生率。

Meta-analysis on the efficacy and safety of PD-1/PD-L1 and CTLA-4 combination therapy in the treatment of solid tumor patients

OBJECTIVE To systematically evaluate the efficacy and safety of PD-1/PD-L1 and CTLA-4 combination therapy in the treatment of solid tumor patients, so as to provide evidence based reference for clinical medication.METHODS The related literature were searched from PubMed, Embase, Cochrane Library, CNKI, CBM, VIP and Wanfang by computer, and the search time ranged from the establishment date of each database to November 2021. After screening the literature according to the inclusion and exclusion criteria, the bias risk assessment tool recommended by Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 was used to evaluate the quality of the included literature. Rev Man 5.4 software was used for Meta-analysis, and the inverted funnel plot was used to analyze the publication bias.RESULTS A total of 22 studies with 8 535 patients were included. Meta-analysis showed that PD-1/PD-L1 and CTLA-4 combination therapy significantly improved the objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) of patients with solid tumors, but there was no statistical difference in the improvement of overall survival (OS). The results of subgroup analysis showed that PD-1/PD-L1 and CTLA-4 combination therapy could significantly improve ORR and PFS of melanoma patients, but there was no statistical difference in OS improvement. PD-1/PD-L1 and CTLA-4 combination therapy could significantly improve PFS of lung cancer patients, but there were no statistical differences in ORR and OS improvement. In addition, PD-1/PD-L1 and CTLA-4 combination therapy could significantly improve ORR and DCR of other solid tumor patients, but there were no statistical differences in PFS and OS improvement. In terms of safety indicators, PD-1/PD-L1 and CTLA-4 combination therapy could significantly increase the incidence of adverse reactions at all grades and grade 3-4, mortality and treatment discontinuation rate in solid tumor patients. The results of subgroup analysis showed that PD-1/PD-L1 and CTLA-4 combination therapy could significantly increase the incidence of adverse reactions at grade 3-4 and discontinuation rate of treatment in patients with melanoma and other solid tumors, as well as the incidence of adverse reactions at all grades and grade 3-4, mortality and discontinuation rate of treatment in patients with lung cancer.CONCLUSION Compared with PD-1/PD-L1 alone, PD-1/PD-L1 and CTLA-4 combination therapy can significantly improve PFS, DCR and ORR in patients with solid tumor, but also significantly increase the incidence of treatment-related adverse reactions in patients with solid tumor.