Exploring The Efficacy And Potential Biomarkers Of Immunotherapy Plus Chemotherapy For Advanced Esophageal Squamous Cell Carcinoma

Objectives:The ASTRUM-007 study is a randomized,controlled,phase III,multicenter clinical study comparing the efficacy and safety of surplulimab or placebo plus chemotherapy(cisplatin and 5-FU)in the first-line treatment of PD-L1-positive locally advanced/metastatic esophageal squamous cell carcinoma(ESCC),and the results of the study have been reported.This study analyzed the efficacy and safety of 85 patients enrolled in a single center at the Cancer Hospital of the Chinese Academy of Medical Sciences.And the efficacy of patients who received subsequent nab-paclitaxel-based regimens as second or later-line treatment was also analyzed.We also explored the potential prognostic value of TMB in first-line immunotherapy plus chemotherapy in advanced ESCC.Methods:Patients with unresectable locally advanced/metastatic ESCC were enrolled and randomized(2:1)to receive serplulimab or placebo plus chemotherapy.Randomization was stratified by PD-L1 expression level,age,and tumor status.The median PFS,median OS,ORR,DCR,and TRAEs of patients in the surplulimab and placebo groups in our center were analyzed.We also retrospectively collected data of patients who received subsequent nab-paclitaxel-based regimens as second or later-line treatment after study discontinuation,and analyzed the ORR,DCR and the safety.Besides,baseline tumor specimens were collected to detect the frequency of different mutations and the predictive value of TMB in first-line immunotherapy plus chemotherapy in advanced ESCC.Results:A total of 114 patients were screened and 85 were enrolled and randomly assigned to serplulimab group(n=57)or placebo group(n=28).The confirmed ORR evaluated by IRRC was 61.4%and 46.4%in the serplulimab and placebo groups,respectively.And DCR evaluated by IRRC was 78.9%and 64.3%,respectively.The median follow-up was 26.91 months,median PFS assessed by IRRC was 5.78 months and 4.37 months,respectively(hazard ratio,0.49;p=0.0195).It showed a trend of OS benefit in the serplulimab group compared to the placebo group,median OS were 14.29 months and 13.60 months(hazard ratio,0.69;p=0.1967).TRAEs of grade 3 or higher occurred in 43.9%of patients in the serplulimab group versus 53.6%in the placebo group.A total of 37(64.9%%)patients in the serplulimab plus chemotherapy group and 21(75.0%)in the placebo plus chemotherapy group received subsequent anticancer therapy,higher than that in the multicenter cohort of 38%and 52%;18(31.6%%)in the serplulimab plus chemotherapy group and 10(35.7%)in the placebo plus chemotherapy group received subsequent immunotherapy.39 patients received albumin-paclitaxel-based regimen in the second or later-line.Overall,the ORR and DCR were 33.3%and 61.5%,respectively.With a median follow-up of 9.7 months,the median PFS and median OS were 5.0 and 7.9 months,respectively.The most common adverse events were neuropathy peripheral(30.8%),anemia(30.8%),and neutrophil count decreased(23.1%).Tumor tissues of 63 patients in ASTRUM-007 study were collected.The median TMB was 3.54 muts/Mb.Two of the 63 patients had MSI-H(3.2%).The genes with the highest mutation frequency were TP53,APOE,FGB,HPX,and GC.Median PFS of the patients in the TMB<10 muts/Mb subgroup was 7.9 months and 4.3 months in the serplulimab group compared to the placebo group,respectively(HR,0.35,p=0.0206).The median OS was 18.6 and 10.4 months in the two groups,respectively(HR,0.46,p=0.0350).There were only 3 patients with TMB≥10 muts/Mb,and subgroup survival analysis was not performed.We also found that there was a tendency for higher TMB in the PD-L1 high expression group(CPS≥10)than low expression group(1≤CPS<10).Conclusions:Serplulimab plus cisplatin and 5-fluorouracil administered every 2 weeks significantly improved ORR and PFS in patients with previously untreated,PD-L1positive advanced ESCC,with a manageable safety profile.There was no statistical difference in OS between the two groups in our single center,which differs from the results of published multicenter,probably because of the fewer sample size and the fact that a higher proportion of patients in the placebo group in our center received subsequent immunotherapy after the study discontinuation.Nab-paclitaxel-based regimen could be a safe and effective option as second or later-line treatment in patients with advanced ESCC,regardless of their previous exposure to PD-1 inhibitors.This study initially analyzed the gene mutation landscape of advanced ESCC and provided new evidence for further understanding the molecular characteristics and the predictive value of TMB in first-line immunotherapy plus chemotherapy in advanced ESCC.