Efficacy And Safety Of PD-1/PD-L1 Inhibitors Combined With Lenvatinib As First-line Treatment For Patients With Advanced Biliary Tract Carcinoma Who Are Intolerant To Or Refuse Chemotherapy

Background:Biliary tract carcinoma(BTC)is a malignant tumor originated from the epithelial cells lining the biliary tract.Due to insidious onset and non-specific clinical presentations,most patients are diagnosed at advanced stage with poor prognosis and limited therapeutic options.In recent years,the advent of immunotherapeutic agents such as programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1)inhibitors has brought the treatment for patients with advanced BTC into a new era.PD-1/PD-L1 inhibitors combined with chemotherapy have been recognized as the firstline standard treatment for advanced BTC patients.However,many advanced BTC patients are with biliary obstruction or infection,and in poor physical condition,resulting in intolerance to chemotherapy.In addition,some patients may refuse chemotherapy concerning about the toxicity.Therefore,there is an urgent need to develop new first-line treatments for advanced BTC patients who are unable to receive chemotherapy.Lenvatinib is a multi-target tyrosine kinase inhibitor with major targets of action including vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet derived growth factor receptor α,adhesion molecules and so on.It can play a synergistic role with PD-1/PD-L1 inhibitors by improving the immunosuppressive microenvironment.PD-1/PD-L1 inhibitors combined with lenvatinib for advanced BTC have also shown good anti-tumor effects in phase II clinical studies.There are also many clinical practices showing good efficacy of PD-1/PD-L1 inhibitors combined with lenvatinib for advanced BTC patients who are intolerant to or refuse chemotherapy.However,data on the efficacy and safety of PD-1/PD-L1 inhibitors combined with lenvatinib as first-line treatment in the real world are lack.Therefore,we conducted this retrospective study to investigate the efficacy and safety of PD-1/PD-L1 inhibitors combined with lenvatinib as the first-line treatment for patients with advanced BTC who are intolerant to or refuse chemotherapy,which may provide more treatment options for patients with advanced BTC who are intolerant to or refuse chemotherapy.Methods:We retrospectively analyzed 25 advanced BTC patients who were intolerant to or refused chemotherapy receiving PD-1/PD-L1 inhibitors combined with lenvatinib as the first-line treatment from February 2022 to September 2022 at the First Hospital of Jilin University Oncology Center(lenvatinib group).Twenty-six advanced BTC patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy at the same center during the same period were used as controls(chemotherapy group).Baseline characteristic,laboratory data,imaging files,survival and adverse events were collected.Objective efficacy evaluation was performed according to Response Evaluation Criteria in Solid Tumors(RECIST 1.1),and adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0.Immunotherapy-related adverse reactions were determined according to the 2021 CSCO guidelines for the management of toxicity associated with immune checkpoint inhibitors.The primary endpoint of our study was progression-free survival(PFS)and the secondary endpoints included overall survival(OS)rates at 6th and 9th months,objective response rate(ORR),disease control rate(DCR)and adverse events.Results:1.The baseline characteristics were virtually balanced in two groups except for ECOG PS score,presence of ascites and ALT levels.Seven patients(28.0%)in the lenvatinib group had an ECOG PS score of 2,while all patients in the chemotherapy group had an ECOG PS score of 0-1.Seven patients(28.0%)in the lenvatinib group had presences of ascites in different degree,while only one patient in the chemotherapy group(3.8%)had a small amount of ascites.2.Up to the last follow-up,the median follow-up time was 10.2 months(95% CI:9.7-10.7).The ORR in the lenvatinib group and chemotherapy group were 16.0 % and23.1%,respectively,(P=0.777);DCR was 52.0% and 46.2%,respectively,(P=0.676).The median PFS in the lenvatinib group and chemotherapy group was 9.5 months vs5.1 months,respectively,(P=0.454).The median OS in both groups was not reached.The 6-month OS rate and 9-month OS rate were 82.0% and 76.9% in the lenvatinib group,and the 6-month OS rate and 9-month OS rate were 87.4% and 71.5% in the chemotherapy group,respectively.3.Univariate Cox analysis showed that patients’ ECOG PS score and AST level may affect PFS,with ECOG PS score(HR=3.388,95% CI: 1.312-8.746,P=0.012)being an independent risk factor for PFS.Univariate Cox analysis showed that patient’ECOG PS score,Child-Pugh grade and TBil level may affect OS,with ECOG PS score(HR = 4.220,95% CI: 1.131-15.742,P=0.032)being an independent risk factor for OS.4.The adverse events rates in the lenvatinib and chemotherapy groups were 72.0%and 88.5%,respectively,(P=0.625).The adverse events of lenvatinib group were frequently presented in gastrointestinal tract such as anorexia,nausea and vomiting,constipation and diarrhea.Adverse events in the chemotherapy group were mainly fatigue,anorexia,nausea and vomiting,myelosuppression and other common chemotherapy-related side effects.There were 4 cases(16.0%)adverse events of grade3 in the lenvatinib group,including 1(4.0%)fatigue,1(4.0%)hand-foot skin reaction,1(4.0%)anorexia and 1(4.0%)dizziness.There were 4 cases(15.4%)adverse events of grade 3 in the chemotherapy group,including 1(3.8%)fatigue and 3(11.5%)myelosuppression.No grade 4 adverse event and death case associated with side effect was observed in this study.Conclusion:PD-1/PD-L1 inhibitors combined with lenvatinib have shown good efficacy and controllable adverse events as the first-line treatment for patients with advanced BTC who are intolerant to or refuse chemotherapy,which are expected to be an alternative treatment for first-line treatment of advanced BTC patients who are intolerant to or refuse chemotherapy.