Exploratory Study Of Neutrophil-to-lymphocyte Ratio And Human Leukocyte Antigen Class I Genotyping As Potential Biomarkers For Immunotherapy In Esophageal Squamous Cell Carcinoma

Background:Immune checkpoint inhibitors(ICIs)have become standard-of-care in patients with pretreated advanced esophageal squamous cell carcinoma(ESCC).However,reliable biomarkers for clinical outcomes are lacking for ICIs.The exploration of effective biomarkers is therefore needed to optimize patient benefit in the treatment of ESCC.This study is designed to evaluate the association between neutrophil-to-lymphocyte ratio(NLR)and human leukocyte antigen(HLA)class I genotyping with the clinical outcomes of patients with advanced ESCC treated with ICI,and explore the potential prognostic and predictive biomarkers or combination of biomarkers in ESCC.Methods:Patients with advanced ESCC enrolled at one center from two prospective trials were consecutively analyzed.All the patients were treated with camrelizumab monotherapy.Tumor cell PD-L1 expression was measured by a central laboratory using immunohistochemistry.NLR was dynamically collected and high-resolution HLA-Ⅰgenotyping were performed on genomic DNA.Overall response rate(ORR),progressionfree survival(PFS)and overall survival(OS)were investigated.The Kaplan-Meier(KM)method is used to analyze time-to-event data.Group comparisons of categorical data were performed by χ2 or Fisher’s Exact test.Results:A total of sixty-nine patients with advanced ESCC enrolled in our center from two prospective trials were consecutively analyzed.All patients were treated with camrelizumab monotherapy.Among the ITT patients,the ORR and DCR were 23.2%(16/69)and 46.4%(32/69),respectively.And the median PFS(mPFS)and median OS(mOS)were 1.9(95%confidence interval[CI]1.6-2.1)months and 8.9(95%CI 6.6-11.2)months,respectively.Thirty-three(47.8%)of 69 patients with baseline NLR≥4 demonstrated significantly worse clinical outcomes(ORR 9.1%vs.36.1%,p=0.018;mPFS 1.8 vs.3.2 months,hazard ratio[HR]1.79,p=0.026;mOS 7.4 vs.11.0 months,HR 2.28,p=0.008).Eleven(15.9%)patients with HLA-Ⅰ homozygosity presented poorer clinical outcomes(ORR 0 vs.27.6%,p=0.056;mPFS 1.8 vs.2.4 months,HR 3.37,p=0.010;mOS 5.6 vs.10.5 months,HR 3.97,p=0.004).Patients with baseline NLR≥4 and HLA-Ⅰhomozygosity had the worst outcome(ORR 0;mPFS 1.4 months;mOS 1.8 months)amongst all.We also explored the association of clinical outcomes with the number of favorable factors(baseline NLR<4,HLA-Ⅰ heterozygosity,PD-L1 TPS≥10%),and the results suggested that patients with more favorable factors had better response and survival.Conclusions:NLR and HLA-Ⅰ genotyping presented predictive and prognostic value in patients with advanced ESCC receiving camrelizumab,and the combination of biomarkers may help to identify more patients benefit from immunotherapy.