SHR-1316,an Anti-PD-L1 Antibody,plus Chemotherapy As The First-line Treatment For Advanced Esophageal Squamous Cell Carcinoma:a Multi-centre,phase 2 Study

Background:In recent years,results of several prospective clinical trials have shown that the monoclonal antibodies against programmed cell death protein-1(PD-1)are effective in the treatment of the patients with advanced esophageal squamous cell carcinoma(ESCC).The results of anti-programmed cell death-ligand 1(PD-L1)monoclonal antibodies in combination with chemotherapy for patients with other malignancies have been reported.However,results of anti-PD-L1 antibodies combined with chemotherapy in patients with unresectable locally advanced or distant metastatic ESCC have never been reported.This multicentre,open-label,single arm and phase 2 prospective clinical trial evaluated the efficacy and safety of anti-PD-L1 antibody SHR-1316 plus liposomal irinotecan and 5-fluorouracil as the first-line treatment for patients with unresectable locally advanced or distant metastatic ESCC.Methods:Eligible patients received SHR-1316(10 mg/kg,intravenous drip,day 1 of the treatment cycle),liposomal irinotecan(60 mg/m2 for the first cycle;patients who were tolerated well after first cycle would receive liposomal irinotecan 80 mg/m2 from second cycle,intravenous drip,day 1 of the treatment cycle)and 5-fluorouracil(2400 mg/m2,continuous infusion for 46 hours from day 1 of the treatment cycle)every 14 days until disease progression,intolerable toxicity or withdrawal of consent.The primary endpoint was progression-free survival(PFS).Secondary endpoints were objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety.The exploratory endpoint of the study was the investigation of the correlation between the different PD-L1 expression level in tumour samples and the achieved ORR and DCR in the study.We used SPSS(version 22)for statistical analyses.The Kaplan-Meier method was used to estimate time-to-event variables.The differences in rate were compared using Fisher's exact test.Results:Twenty-three eligible patients with unresectable locally advanced or distant metastatic ESCC were enrolled between March 11,2019 and May 31,2019 in the present study.The median follow-up duration was 15.2 months(95%confidence interval(CI):14.2-16.2)as of the data cut-off date(July 31,2020).The median PFS was 8.5 months(95%CI:1.2-15.8),ORR and DCR were 52.2%(95%CI:30.1-74.3)and 73.9%(95%CI:54.5-93.3),respectively.The median OS was 11.6 months(95%CI:6.7-16.6).The most common treatment-related grade 3-4 adverse events(AEs)were neutropenia(4/23,17.4%),nausea(3/23,13.0%),anorexia(3/23,13.0%)and leukopenia(2/23,8.7%).Treatment-related serious adverse events(SAEs)occurred in total two patients,including one patient(4.3%)with grade 1 fever,one patient(4.3%)with grade 3 diarrhoea and grade 2 fever,both the two patients were suspended from study treatment due to SAEs.AEs that were immune-related,occurred in five patients(21.7%)in the present study,including hyperthyroidism(4/23,17.4%),hypothyroidism(1/23,4.3%),pruritus(1/23,4.3%),and rash(1/23,4.3%),all of the immune-related AEs were grade 1-2,and no grade?3 immune-related AEs occurred.No treatment-related deaths occurred.Conclusions:SHR-1316 plus liposomal irinotecan and 5-fluorouracil as the first-line treatment regimen for patients with unresectable locally advanced or distant metastatic ESCC has an encouraging efficacy and manageable safety profile.Thus,SHR-1316 plus liposomal irinotecan and 5-fluorouracil could be a new first-line treatment approach for patients with unresectable locally advanced or distant metastatic ESCC.Clinical trial registration:NCT03732508(Clinicaltrials.gov).