Efficacy And Safety Of PD-1 Inhibitors Plus Chemotherapy As The First-line Treatment For Advanced Esophageal Squamous Cell Carcinoma:A Systematic Review And Network Meta-analysis

Esophageal cancer is the eighth most common malignancy and the seventh leading cause of cancer-related mortality worldwide.Esophageal squamous cell carcinoma(ESCC)is the most common type of esophageal cancer,accounting for approximately 85% of all esophageal cancer cases.Most esophageal cancers are diagnosed at a late stage and conventional chemotherapy has limited efficacy.A series of randomized controlled trials(RCTs)have investigated different first-line programmed death-1(PD-1)inhibitors plus chemotherapy for patients with advanced ESCC.The results of RCTs suggested that PD-1 inhibitors in combination with chemotherapy showed effective antitumor activity in the first-line treatment of advanced ESCC.However,the differences in efficacy and safety between different treatment regimens have not been clarified,and the selection of the best treatment option is a major challenge for clinicians.Objective: This study compared the efficacy and safety of different PD-1 inhibitors combined with chemotherapy in the first-line treatment of advanced ESCC using principles of network meta-analysis,with the aim of selecting the better first-line treatment regimen for clinicians.Methods: The Pub Med,Embase,Web of science,and Cochrane library databases,as well as other channels that included Clinical Trials.gov,European Society of Medical Oncology(ESMO),American Society of Clinical Oncology(ASCO),American Association for Cancer Research(AACR)and Chinese Society of Clinical Oncology(CSCO)were searched for retrieving articles which concentrated on PD-1 inhibitors plus chemotherapy as the first-line treatment for advanced ESCC.The retrieval period was from inception until November 9,2022.The primary outcomes were overall survival(OS)and progression-free survival(PFS),and the secondary outcomes were objective response rate(ORR),treatment-related adverse events(tr AEs)with grade≥3 and immune-related adverse events(ir AEs)with grade≥3.OS and PFS data from RCTs were analyzed using hazard ratio(HR)and 95% confidence interval(CI).ORR,tr AEs,and ir AEs were analyzed using odds ratio(OR)and 95% CI.The Cochrane risk bias assessment tool in Review Manager5.3 was used to evaluate the quality.Network meta-analysis were performed using Stata17 and R4.1.3 software.Effect size analysis,heterogeneity test,sensitivity analysis,publication bias test and subgroup analysis of main outcome indicators were performed using Stata17 software.Network diagrams,league diagrams and surface under the cumulative ranking curve(SUCRA)diagrams were performed using R4.1.3software.Efficacy and safety were ranked according to SUCRA,and its model was tested for convergence and consistency to confirm the stability and reliability of the results.Results: A total of seven phase-III RCTs involving 4,162 patients met the inclusion criteria.The results of network meta-analysis were mainly divided into the following aspects:1.PD-1 inhibitors in combination with chemotherapy group significantly improved OS(HR=0.68;95%CI,0.62,0.74),PFS(HR=0.62;95%CI,0.57,0.67)and ORR(OR=2.08;95%CI,1.81,2.39)compared with chemotherapy group.There was no statistically significant difference in the incidence of tr AEs with grade≥3 in the PD-1 inhibitor in combination with chemotherapy group compared to the chemotherapy group(OR=1.16;95%CI,1.00,1.35).However,PD-1 inhibitors in combination with chemotherapy group increased the incidence of ir AEs with grade≥3(OR=3.70;95%CI,2.46,5.57)compared with chemotherapy group.2.The available evidence suggested that in terms of clinical efficacy,SUCRA showed that Toripalimab plus chemotherapy provided better OS,Sintilimab plus chemotherapy and Camrelizumab plus chemotherapy provided better PFS,and Nivolumab plus chemotherapy provided better ORR.In terms of safety,SUCRA showed that Nivolumab plus chemotherapy was more likely to have tr AEs of grade≥3.Tislelizumab plus chemotherapy was more likely to have ir AEs of grade≥3.3.Subgroup analysis suggested that female(HR=0.78;95%CI,0.60,1.02)patients and patients with programmed death-ligand 1(PD-L1)combined positive score(CPS)<1(HR=0.92;95%CI,0.61,1.38)did not have a statistically significant benefit in OS and patients with PD-L1 CPS<1(HR=0.71;95%CI,0.46,1.08)did not have a statistically significant benefit in PFS.Conclusions:1.In advanced ESCC,PD-1 inhibitors plus chemotherapy as first-line therapy had better survival outcomes than chemotherapy with greater but manageable toxicity.2.The available evidence suggested that Toripalimab plus chemotherapy was better at prolonging OS,Sintilimab and Camrelizumab plus chemotherapy were better at prolonging PFS and Nivolumab plus chemotherapy was better at imroving ORR.Nivolumab plus chemotherapy was more likely to have tr AEs of grade≥3 and Tislelizumab plus chemotherapy was more likely to have ir AEs of grade≥3.3.Subgroup analysis suggested that female patients and patients with PD-L1 CPS<1 did not have a statistically significant benefit in OS and patients with PD-L1 CPS<1 did not have a statistically significant benefit in PFS.