Efficacy And Safety Of Neoadjuvant Immunotherapy Plus Chemotherapy In Subjects With Resectable Esophageal Squamous Cell Carcinoma

Background and purposeEsophageal cancer is a major health burden worldwide.Esophageal squamous cell carcinoma(ESCC)remains the most frequent histologic subtype,especially in Asia,which accounting for about 90% of the incidence of esophageal cancer.Nearly half of the patients were locally advanced stage by first diagnosis.Neoadjuvant chemoradiotherapy(n CRT)followed by surgery is recommended as the first choice for patients with locally advanced ESCC.There are about 40-50% patients experienced tumor recurrence or metastasis after surgery,and more than 70% were metastasis.Resectable,locally advanced ESCC patients still lack effective systemic therapies.Hence,there is still an unmet need for the development of alternative new therapies.PD-1/PD-L1 antibody interferes with the binding of PD-1 and PD-L1 to relieve the immunosuppressive effect of this pathway and restore T cell anti-tumor immunity.Many PD-1 antibodies have conducted exploratory clinical studies,like Keynote028,Keynote180 and Keynote181,in advanced esophageal cancer and have achieved impressive results.The subsequent Keynote590、Checkmate648 and ESCORT-1st clinical trials confirmed the clinical and statistical survival benefits in the first-line setting.There is no study to assess the feasibility,safety,and efficacy of neoadjuvant camrelizumab plus chemotherapy in patients with resectable ESCC.The combination of PD-1 antibody and chemotherapy has achieved multiple positive results in lung cancer.We designed this study to assess the feasibility,safety,and efficacy of neoadjuvant camrelizumab plus chemotherapy in patients with resectable ESCC.We report on the results of a correlative biomarker study in patients with locally advanced ESCC,where the primary aim was to screen profitable populations and assist in diagnosis and treatment can help improve the effectiveness and safety in the process of immunotherapy.MethodsThis phase 2 study aimed to assess neoadjuvant camrelizumab plus chemotherapy in this population(NCT04225364).Patients(clinical stage II-IVA)received two cycles of neoadjuvant chemoimmunotherapy(NIC)with camrelizumab(200 mg on day 1)plus nab-paclitaxel(260 mg/m2 in total on day 1 and day 8)and cisplatin(75 mg/m2 in total on days 1 to 3)of each 21 day cycle.Surgery was performed approximately six weeks after completion of NIC.Primary endpoint was complete pathologic response(CPR)rate in primary tumor.Secondary endpoints were objective response rate(ORR)per RECIST v1.1,two-year progression-free survival(PFS)rate after surgery,PFS,overall survival(OS),and safety during NIC and perioperative period.ResultsBetween Jan 17,2020 and Dec 8,2020,56 patients were enrolled,and 51 received esophagectomy.The CPR rate in primary tumor was 35.3%(95% CI: 21.7% to 48.9%).No in-hospital mortality occurred.The most common treatment-related adverse events(TRAEs)of any grade were decreased white blood cell(20 [36%] of 56 patients),vomiting(19 [34%]),and alopecia(18 [32%]).Grade 3 TRAEs only occurred in six(11%)patients,and there were no grade 4 or 5 events.Presence of mutations in CREBBP and KMT2 D at treatment-na?ve time-point was correlated with non-response(incomplete pathologic response and stable disease)(p = 0.046 and 0.047,respectively).Among the immune populations,CD8+,CD8+PD-1+,and CD8+PD-L1+ T cells increased significantly after two doses of NIC,especially in the patients with complete or major pathologic response(p = 0.013,< 0.001,and = 0.068,respectively).The ct DNA clearance rate was significantly higher in the CPR group than that in non-CPR group,and it decreased along with the pathologic response in MPR and IPR patients.This study provided an unique value of ct DNA in predictive theraputic effect of NIC therapy of esophageal cancer.The accuracy of radiologic CR criteria in predicting pathologic CPR was 66.67%.In combining ct DNA clearance,the accuracy reached 70.57%.ConclusionCamrelizumab plus neoadjuvant chemotherapy in resectable ESCC demonstrates promising efficacy with acceptable toxicity,providing a feasible and effective option.Furthermore,lymphatic metastases seem to have better response to NIC compared with primary lesions.The number of most immune populations analyzed increased in postneoadjuvant surgical specimens than pre-neoadjuvant samples.The umor infiltrating lymphocytes increased significantly after two doses of NIC,especially in MPR andCPR.The ct DNA zero clearance rate can served as an effective tool for predicting pathologic response of NIC in locally advanced ESCC.