Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: Update analytic results of an open-label phase II clinical study (JS001-ZS-BC001).

e16170 Background: A phase II clinical study was conducted to evaluate the safety and efficacy of toripalimab, a novel PD-1 inhibitor, combined with chemotherapy in patients with advanced biliary tract cancers (aBTCs) (NCT03796429). The preliminary results indicated the combination treatment is well tolerable and effective. Methods: Treatment naive patients with aBTCs received toripalimab (240mg intravenously every three weeks) combined with chemotherapy (gemcitabine 1000 mg/m2 d1, d8 + S-1 40-60mg bid D1-14, Q21d). The treatment continued until the disease progress or having intolerable effects. The primary endpoints of the study were progression free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), safety and treatment biomarkers. Results: At data cutoff (January 24, 2021), fifty aBTC patients were enrolled at Shanghai Zhongshan Hospital. Among these patients, 56% are males. The median age of the study participants was 62 years of age. The median follow-up time was 10 months (ranged from 4 to 19 months). The primary tumor type was intrahepatic cholangiocarcinoma (ICC) accounting for 48% of total cases, followed by gallbladder cancer (GBC) (40.0%), and extrahepatic cholangiocarcinoma (ECC) (12.0%). At the time of data collection, 48 eligible patients were included for data analysis. The median PFS was 7.0 months（95%CI, 5.5-9.1 months）and median OS was 16.0 months (95%CI, 12.1 to unreachable). The ORR was 27.1 % and disease control rate was 87.5% including 13 partial response (PR) and 29 stable disease (SD) cases. The most treatment related AEs (TRAE) were leukopenia (92.0%), anemia (86.0%) and rash (52.0%). Grade III/IV non-hematological TRAEs were seen in 12 patients (24.0%), including rash (n = 3), infection (n = 6), immune-related colitis (n = 1), immune-related pneumonitis (n = 1) and mucositis (n = 1). Grade III/IV hematological TRAEs were seen in 62% patients. 6 patients discontinued the study drug due to TRAE. Serious adverse events (SAE) were seen in 8 patients and 2 patients died of biliary obstruction complicated with infection. Forty-nine patients were included in biomarker analysis. The most mutated genes were TP53 (51%), KRAS (20%), CDKN2A (18%) and SMAD4 (16%). Patients with activated PI3K signaling pathway had significantly shorter PFS (P = 0.026). Tumor mutational burden (TMB) could not serve as a predictor for the efficacy of immunotherapy combined with chemotherapy. Conclusions: The clinical study of toripalimab combined with chemotherapy continued to show tolerance and efficacy in patients with aBTCs. Gene mutation profiling by NGS suggested mutated PI3K pathway might assocate with shorter PFS. Clinical trial information: NCT03796429.