抗PD-1/PD-L1治疗在胃癌或胃食管结合部腺癌中的疗效荟萃分析

Meta-Analysis of Efficacy of PD-1/PD-L1 Monoclonal Antibody in Gastric Cancer or Adeno-carcinoma of the Gastroesophageal Junction

目的:系统评价抗程序性死亡蛋白-1(programmed death-1,PD-1)/程序性死亡蛋白配体-1(programmed death ligand-1,PD-L1)治疗在胃癌或胃食管结合部腺癌中的疗效。方法:由2名研究人员分别对Pub Med、Embase和the Cochrane Library等数据库,以及近3年内的美国临床肿瘤学会(American society of clinical oncology,ASCO)、2020年欧洲肿瘤内科学会(European society for medical oncology,ESMO)会议摘要进行了系统搜索,纳入前瞻性研究、Ⅱ期及Ⅲ期临床研究(研究组患者采用抗PD-1/PD-L1药物单药或联合化疗,对照组患者采用化疗或安慰剂),检索截止日期为2020年9月26日。通过亚组分析,评估不同的治疗方案(抗PD-1/PD-L1治疗组与化疗组比较,抗PD-1/PD-L1治疗+化疗组与化疗组比较,抗PD-1/PD-L1治疗组与安慰剂组比较)的疗效,森林图的绘制通过Stata SE 12软件完成。结果:最终纳入7项临床研究,包括3篇原始文献、2篇ASCO会议摘要和2篇ESMO会议摘要。荟萃分析结果显示,(1)单纯抗PD-1/PD-L1治疗组与化疗组患者的总生存期(overall survival,OS)(HR=0.96,95%CI=0.87~1.07,P=0.451)、客观缓解率(objective response rate,ORR)(RR=0.65,95%CI=0.39~1.09,P=0.102)的差异均无统计学意义,但两组患者无进展生存期(progress free survival,PFS)的差异有显著统计学意义(HR=1.45,95%CI=1.17~1.81,P=0.001);(2)抗PD-1/PD-L1治疗联合化疗组与化疗组患者的OS(HR=0.84,95%CI=0.76~0.94,P=0.001)、PFS(HR=0.78,95%CI=0.70~0.86,P=0.000)和ORR(RR=1.24,95%CI=1.10~1.39,P=0.000)比较,差异均有显著统计学意义;(3)抗PD-1/PD-L1治疗组与安慰剂组患者的OS(HR=0.63,95%CI=0.51~0.78,P=0.000)、PFS(HR=0.60,95%CI=0.49~0.75,P=0.000)和ORR(RR=29.93,95%CI=1.84~485.72,P=0.017)比较,差异均有显著统计学意义。结论:本研究结果表明,抗PD-1/PD-L1治疗联合化疗可使晚期胃癌或胃食管结合部腺癌患者获益;与安慰剂比较,单纯抗PD-1/PD-L1治疗同样可以使晚期胃癌或胃食管结合部腺癌患者获益;但是,相比于化疗,单纯抗PD-1/PD-L1治疗对于晚期胃癌或胃食管结合部腺癌患者并没有明显优势,上述结论还需更多的证据来证实。

OBJECTIVE: To systematically evaluate the efficacy of programmed death-1/programmed death ligand-1( PD-1/PD-L1) monoclonal antibody in gastric cancer or adenocarcinoma of the gastroesophageal junction.METHODS: PubMed,Embase,the Cochrane Library database and abstracts of American society of clinical oncology( ASCO) conferences in the past three years,and European society for medical oncology( ESMO) conferences in 2020 were retrieved to collect the prospective studies,phase Ⅱ and phase Ⅲ clinical trials( the study group was treated with PD-1/PD-L1 monoclonal antibody alone or in combination with chemotherapy,while the control group received chemotherapy or placebo. The retrieval deadline was Sept. 26 th,2020. The efficacy of different treatment regimens( PD-1/PD-L1 monoclonal antibody treatment group compared with chemotherapy group,PD-1/PD-L1 monoclonal antibody treatment + chemotherapy group compared with chemotherapy group,and PD-1/PD-L1 monoclonal antibody treatment group compared with placebo group) was assessed by subgroup analysis,and forest plotting was performed by Stata SE 12 software. RESULTS: Seven clinical trials were ultimately enrolled,including three original papers,two abstracts of ASCO conferences and two abstracts of ESMO conferences.( 1) The differences in overall survival( OS)( HR = 0. 96,95% CI = 0. 87-1. 07,P = 0. 451) and objective response rate( ORR)( RR = 0. 65,95% CI = 0. 39-1. 09,P = 0. 102) between the PD-1/PD-L1 monoclonal antibody treatment group alone and the chemotherapy group were not statistically significant,yet the difference in progression free survival( PFS) between two groups was statistically significant( HR = 1. 45,95% CI = 1. 17-1. 81,P = 0. 001).( 2) The differences of OS( HR = 0. 84,95% CI = 0. 76-0. 94,P = 0. 001),PFS( HR = 0. 78,95% CI = 0. 70-0. 86,P = 0. 000) and ORR( RR = 1. 24,95% CI = 1. 10-1. 39,P = 0. 000) between the PD-1/PD-L1 monoclonal antibody treatment + chemotherapy group and the chemotherapy group were statistically significant.( 3) The differences of OS( HR = 0. 63,95% CI = 0. 51-0. 78,P = 0. 000),PFS( HR = 0. 60,95% CI = 0. 49-0. 75,P = 0. 000) and ORR( RR = 29. 93,95% CI = 1. 84-485. 72,P = 0. 017)between the PD-1/PD-L1 monoclonal antibody treatment group and the placebo group were statistically significant.CONCLUSIONS: The results of this study suggest that PD-1/PD-L1 monoclonal antibody combined with chemotherapy may benefit patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction.Compared with placebo,PD-1/PD-L1 monoclonal antibody alone also benefits patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction. However,compared with chemotherapy,patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction may not get a more significant treatment effect from PD-1/PD-L1 monoclonal antibody,and more evidence is needed to confirm these findings.