Phase Ⅱ Clinical Study Of The Safety,Effectiveness And Tolerability Of KN046 Combined Chemotherapy And Radiotherapy In Recument Or Metastatic Esophageal Squamous Cell Carcinoma

PART I Phase II clinical study of the safety,effectiveness and tolerability of KN046 combined chemotherapy and radiotherapy in recurrent or metastatic esophageal squamous cell carcinoma-Interim analysisBACKGROUND:Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma(ESCC).Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts.KN046 is a recombinant humanized new bispecific antibody that can simultaneously bind PD-L1 and CTLA-4,thereby blocking the binding of PD-L1 to PD1 and CTLA-4 to CD80/CD86.Here we report the addition of KN046,a PD-L1/CTLA-4 bispecific antibody,to concurrent chemoradiation therapy(CCRT)to determine the safety and efficacy of thistherapeutic regimen(ChiCTR2000031544).OBJECTIVES&METHODS:Patiients with recurrent or metastatic ESCC,not been treated by chemoradiation or other systemic treatment within 6 months,were recruited and received palliative CCRT consisting of cisplatin(75 mg/m2 IV Q3W for 4～6 cycles),paclitaxel(135mg/m2 IV Q3W for 4-6 cycles)and radiation(Stereotactic Body Radiation Therapy,SBRT or Conventional radiatherapy)and radiation dose are determined at the investigator’s discretion according to institutional standard).The study designed two modes of administration,mode of administration 1(Cohort-1):KN046 at ascending doses of 1,3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy(RT)and concurrently with chemotherapy,followed by KN046 Q2W maintenance;mode of administration 2(Cohort-2):KN046 concurrent radiotherapy and chemotherapy,followed by KN046 Q2W maintenance after the end of adiotherapy and chemotherapy.Dose limiting toxicities(DLTs)were assessed for the first treatment cycle of KN046.Evaluating the efficacy and safety data of the two administration methods.Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year,and every 12 weeks thereafter.RESULTS:As of April,2021,a total of 30 subjects were enrolled and received KN046 treatment(administration method 1:1mg/kg,n=3;3mg/kg,n=12;5mg/kg,n=10;administration 2:3mg/kg concurrent radiotherapy and chemotherapy,n=5).The overall incidence of adverse events(TEAE)during treatment:96%for Cohort-1,60%for Grade≥3.The incidence of TEAE related to KN046,Cohort-1 is 52%.KN046-related adverse reactions include:fatigue,skin pruritus,rash,immune-related enteritis,immune-related pneumonia,infusion reactions,hypothyroidism,Immune-related hepatitis.The incidence of≥3 grade KN046-related TEAE was 16%for Cohort-1,including 2 cases of immune-related enteritis,1 case of immune-related pneumonia,1 case of immune-related hepatitis,after hormone therapy All are getting better.No immune-related adverse reactions above grade 4 were observed.No adverse reactions of grade 4 or above were observed,and no dose-limiting toxicity was observed.Adverse reactions of grade≥3 included 1 case of immune-related pneumonia,2 cases of immune-related enteritis,and 1 case of immune-related hepatitis,which improved after treatment.There were no treatment-related adverse events and deaths caused by KN046-related adverse reactions.A total of 24 patients were included in the efficacy statistics.There were 24 cases in the KN046 sequential radiotherapy and chemotherapy group.The ORR of KN046 sequential chemoradiation group was 41.7%.The DCR of the KN046 sequential chemoradiation group was 87.5%.KN046 sequential radiotherapy and chemotherapy group:1 mg/kg group PFS 5.2 months,3 mg/kg group PFS has not yet reached,5 mg/kg group PFS 5.6 months.CONCLUSION:The addition of KN046 to CCRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC.This pilot study enables further investigation of a new treatment modality of KN046 with CCRT in this detrimental disease with poor prognosis.PART Ⅱ Study of the correlation between intestinal microbial flora and its metabolites(short-chain fatty acids)and the efficacy of KN046 combined with ChemoradiationBACKGROUND:Immune checkpoint inhibitors mainly use immune checkpoint inhibitors to antagonize the immune escape of tumors,but this strategy is only effective in a small number of patients.The currently available biomarkers can not reliably select patients who can respond well to immunotherapy.The intestinal symbiotic microbiota can participate in the regulation of the host’s immune response,and can affect the immune system in two ways:bacterial components and bacterial metabolites.Some studies have found that there is a certain correlation between the intestinal microbial flora and its metabolite short-chain fatty acids and the efficacy of PD-1.OBJECTIVES&METHODS:Stool specimens of all enrolled patients at baseline were collected,and metabolomics tests were performed,including intestinal microbial flora and short-chain fatty acids,and the patients were divided into two groups according to the treatment effect:Treatment response group(PR,partial response)and non-treatment response group(SD,stable disease),the cases with too large individual differences in the distribution of the flora are eliminated.The differences in the distribution of intestinal microbial flora and the content of short-chain fatty acids between the two groups of patients were analyzed.RESULTS:The distribution of the flora between the PR group and the SD group is significantly different,and the similarity of the flora within the group is closer;the number of short-chain-producing Faecalibacterium,Coprococcus and Clostridium are high in the PR group and low in the SD group.The expression trend of short-chain-producing Bacteroides was low in the PR group and high in the SD group;the content of some short-chain fatty acids(butyric acid,acetic acid,valeric acid)in the SD group was significantly lower than that in the PR group;metabolite pathway enrichment analysis shows that bile acid metabolism,nicotinamide metabolism,and alanine metabolism pathways may be involved in immune regulation.CONCLUSION:The intestinal alanine flora and its metabolites,short-chain fatty acids,may be the regulatory factors of system immunity during the treatment of immune checkpoint inhibitors,which can be used to predict the efficacy of immunotherapy.Intestinal microbes→metabolic products provide a new detection direction for clinical immunotherapy.In the future,clinical immunotherapy may change the level of short-chain fatty acids by changing the Intestinal microbial flura to enhance the effect of immunotherapy.