Efficacy And Safety Of Anti-PD-1 Antibody In Advancedesophageal Squamous Cell Carcinoma

Background and ObjectiveEsophageal carcinoma is the seventh most common cancer and the sixth leading cause of cancer-related deaths worldwide,with an estimated 400,000 deaths annually.Meanwhile,esophageal squamous cell carcinoma(ESCC)is among the most common subtype and has a poor outcome with a 5-year survival rate of only about 15%-25%.No chemotherapeutic regimens or targeted agents are approved specifically for the esophageal carcinoma indication.Metastatic ESCC has been managed primarily with chemotherapy(such as fluorouracil,cisplatin,and taxanes),is associated with substantial toxicity,and has limited survival benefit.The poor prognosis of ESCC highlights the urgent need for improved therapies,especially novel therapeutic approaches.Recently,breakthroughs in immune checkpoint blockade have offered new therapeutic options for many malignancies.Immunotherapy targeting the checkpoint programmed cell death protein 1(PD-1)or programmed death ligand 1(PD-L1)has been shown to be effective in the management of melanoma,non-small cell lung cancer,and renal cell carcinoma.There are many clinical studies abroad to explore the safety of PD-1 antibody in the treatment of advanced esophageal cancer,and its efficacy in advanced esophageal cancer has been confirmed.In addition,a number of clinical studies compared the efficacy and safety of second-line chemotherapy and the survival benefit of PD-1 antibody in immunotherapy of esophageal cancer was confirmed for the first time in KEYNOTE181 study.We analyze the safety and activity of anti-PD-1 antibody in the treatment of patients with advanced esophageal squamous cell carcinoma(ESCC)in this study.To explore the relationship between the expression of PD-L1,TMB and the efficacy of PD-1 antibody in esophageal squamous cell carcinoma.Materials and MethodsA retrospective analysis of clinical data of 52 patients with advanced ESCC after first-line chemotherapy failure in the First Affiliated Hospital of Zhengzhou University.According to the patient's treatment plan,the patients were divided into 2 groups,26 patients in the observation group received continuous treatment of anti-PD-1 antibody,26 patients in the control group received irinotecan intravenously.The primary endpoints were progression-free survival(PFS)and disease control rate(DCR);secondary endpoints were objective response rate(ORR),safety and quality of life.PD-L1 expression was measured in tumor tissues by Recombinant Rabbit Monoclonal PD-L1 Antibody(Clone: SP142).PD-L1 positivity was defined as ?5% of tumor cell membrane staining.The NGS method was used to measure TMB in the tumor tissues of 23 patients.Also we analysed the correlation between TMB and the efficacy of anti-PD-1antibody.ResultsTotal 52 patients were participated in the study from January 2016 to January 2018,and all of them could be evaluated for objective efficacy and safety.In observation group,objective efficiency(ORR)and disease control rate(DCR)were 26.9% and 46.2% respectively.In control group,objective efficiency(ORR)and disease control rate(DCR)was 23.1% and 42.3% respectively.Median progressionfree survival(PFS)was 3.1months(95%CI,1.9-5.4 months)and 3.5months(95%CI,1.3-7.9 months)in control group and in observation group respectively.The differences between the 2 groups in ORR,DCR and PFS were not statistically significant(P>0.05).In control group,25 patients(96.15%)experienced treatmentrelated adverse events and the most common adverse reactions are neutropenia(88.46%),anemia(88.46%),fatigue(69.23%)and fever(65.38%),19(73.08%)treatmentrelated grade 3 or grade 4 events were reported.No grade 5 adverse events or deaths or deaths were attributed to irinotecan.Immune-related adverse reactions occurred in 20 patients(76.92%)in the observation group and the most common adverse reaction was rash(30.77%),the next was fatigue(19.23%).Most events were grade 1 or 2.One(3.84%)treatment-related grade 3 events(pneumonitis)was reported.No grade 4 or grade 5 adverse events or deaths were attributed to anti-PD-1 antibody.In observation group,23 patients were assessed for PD-L1 expression,15(65.2%)had PD-L1-positive tumors.ORR was more common in patients with PD-L1-positive tumors(40.0%)than in those with PD-L1 negative tumors(12.5%),which was without statistical significance(all P>0.05).The TMB in the group with clinical benefit(CB)was much higher than that in without clinical benefit(NCB)(P= 0.0479).Conclusion1.Our results suggest promising efficacy and a manageable safety profile of anti-PD-1 antibody in pretreated patients with metastatic ESCC.TMB can be used to predict the efficacy of anti-PD-1 antibodies.2.PD-1 antibody can be used as a second-line treatment for advanced esophageal cancer.