Phase Ⅱ Study Of Anlotinib Plus Sintilimab As Second-line Treatment For Patients With Advanced Biliary Tract Cancers

BackgroundGlobally,biliary tract cancer(BTC)is still a healthcare challenge with a poor outcome.Such a rare group of malignancies originate from bile duct epithelial cells,including intrahepatic cholangiocarcinoma,extrahepatic cholangiocarcinoma and gallbladder.BTCs account for about 10%to 15%of primary liver tumors and 3%of gastrointestinal tumors.Surgical resection and liver transplantation are the only possible means of curing biliary tract tumors in patients without distant metastasis or vascular invasion.However,due to the invisibility of the onset of BTCs and the low specificity and sensitivity of the auxiliary diagnostic methods,most patients are diagnosed in advanced stages and miss the best time zones for surgery.Even for patients undergoing radical surgery,the 5-year survival rate was only 10%～40%.Anlotinib is a multi-target tyrosine kinase inhibitor,which can effectively inhibit VEGFR,PDGFR,FGFR,c-Kit,Met and other kinases.It has anti-tumor angiogenesis and inhibition of tumor growth.The anti-tumor efficacy of a variety of tumors has been affirmed.Sintilimab is a recombinant fully human IgG4 type monoclonal antibody.The effect of blocking the PD-1 pathway with Sintilimab has been studied in a variety of preclinical in vitro tests.The mouse tumor model has demonstrated that the murine analog of Sintilimab has anti-tumor activity.There were no reports on the efficacy and predictors of efficacy of Anlotinib combined with Sintilimab in the treatment of biliary system cancer.This article discusses the issue.Objective To evaluate the effectiveness and safety of anlotinib combined with sintilimab for patients with advanced biliary system cancers who have failed previous first-line chemotherapy.At the same time,whole exome sequencing(WES)was used to detect gene expression in tumor tissues of the biliary system and the intestinal microbial metagenomic sequencing method was used to analyze the composition of the patient’s intestinal microbes,in order to be able to early screen the patients from Patients with advanced biliary system tumors who benefit from the combination of anlotinib and sintilimab can be better guided treatment.MethodsFrom August 2019 to February 2021,we recruited 20 patients with advanced biliary system cancers who failed first-line chemotherapy and were given second-line treatment with anlotinib combined with sintilimab.Three weeks is a cycle.On the first day,200 mg of Sintilimab is administered intravenously.On days 1-14,the initial dose of anlotinib is given at a starting dose of 12 mg/day.For the degree of drug-related toxic reaction and the possible benefit of curative effect,reduce the dose of anlotinib to 10/8 mg,and adjust the dose at any time during each dosing cycle.After the dose is lowered,it must not be returned to the previous level.Subjects are allowed to adjust the dose up to 2 times,and are not allowed to continue to adjust the dose,including any increase or decrease of the dose for any reason,but the dose is still allowed to be suspended.Regular follow-ups were conducted,and the efficacy evaluation was conducted according to the Response Evaluation Criteria in Solid Tumors(RECIST)Version 1.1.According to the National Cancer Institute General Toxicity Standard(NCT-CTC 4.0),the safety(drug-related adverse reactions)of anlotinib combined with sintilimab was evaluated.The primary research endpoint is overall survival(OS),and the secondary research endpoints are objective response rate(ORR),Progression-freesurvival(PFS),disease control rate(DCR),quality of life score QoL and drug safety.Kaplan-Meier survival curve and Log-Rank test were used to analyze PFS and OS.COX proportional hazard regression model single factor and multivariate analysis of WES-related gene expression and clinicopathological characteristics on PFS and OS.The P value is a two-way test,and the test level isα=0.05.Results1.Clinical pathological information of patients:In this trial,we recruited 20 patients with advanced biliary system tumors who had failed or intolerated first-line treatment,including 11 men and 9 women,ranging in age from 43 to 69 years,with a median age of 58 years.The Eastern United States Oncology Group(ECOG)scores of the patients were all 0-1,14 patients had ECOG scores of 0,and 6 patients were scored 1.10 cases were intrahepatic cholangiocarcinoma,6 cases were gallbladder cancer and 4 cases were extrahepatic cholangiocarcinoma.The liver is the most common site of metastasis,and the rest include lymph node metastases such as lung,retroperitoneum,neck,mediastinum.The median follow-up time was 15.376 months(95%CI:13.662-17.090),the median overall survival was 12.68 months(95%CI:6.7-NA),and the median progression-free survival(PFS)was 6.44 months(95%CI:3.06-10.94),the objective response rate(ORR)was 30%,and the disease control rate(DCR)was 95%.2.Best response:According to the RICIST1.1 evaluation standard,the measurement data of 20 patients with measurable target lesions showed that none of the patients achieved CR,6 achieved PR(30%),13 achieved SD(65%),and 1 was PD(5%).Therefore,up to 95%of patients respond to the combination of Anlotinib Hydrochloride Capsules and Sintilimab Injection.3.Tolerability and safety:Among the 20 patients enrolled,the main adverse events were GGT elevation(75%,15/20),hypertension(65%,13/20),ALP elevation(65%,13/20),D-dimer elevation(65%,13/20),ALT elevation(55%,11/20),ALT elevation(55%,11/20),anemia(50%,10/20),thrombocytopenia(45%,9/20),hypothyroidism(40%,8/20),diarrhea(30%,6/20),loss of appetite(25%,5/20),fatigue(20%,4/20)20);No treatment-related grade 4 or 5 adverse events occurred.Two patients(10%)reduced the dose of anlotinib due to high blood pressure.No patient discontinued the drug due to adverse events.4.Biomarker explorations:Among the 20 subjects,we analyzed the genome profiles of 18 subjects,and 2 subjects were not sequenced due to insufficient specimens.The top five frequently mutated genes were TP53,TTN,C9orf84,MTUS2 and APOB for BTC.Only one of the 18 subjects had a tumor mutational burden(TMB)exceeding 10/Mb,but this patient did not respond to this treatment.The abundances of 14 species were significantly different.4 bacteria,including Yersinia pseudotuberculosis(P=0.027)and Vibrio cholerae(P=0.044)were enriched in the NR group,while 10 bacteria,including Lactobacillus ruminis(P=0.044),were enriched in the R group.Conclusion1.Anlotinib combined with sintilimab for second-line treatment of patients with advanced biliary system cancers is better than current treatments in terms of clinical benefit rate,PFS and OS,and the adverse reactions are mild,controllable and tolerable.2.The top five frequently mutated genes were TP53,TTN,C9orf84,MTUS2 and APOB for BTC.The treatment outcomes,including immunotherapy,in cancer patients are positively correlated with some specific types of gut microbiota,such as Lactobacillus ruminis and Clostridium sporosphaeroides.