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Background: Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs), but the overall effect needs to be further improved. This study intended to explore the safety and efficacy of toripalimab combined with chemotherapy in the first-line treatment of advanced BTCs. Methods: This single-arm, phase II clinical trial enrolled patients with advanced BTCs who had not received systemic treatment. Toripalimab combined with chemotherapy were applied as first-line treatment: toripalimab (240 mg, iv, d1), gemcitabine (1000 mg/m2, iv, d1&d8), and S-1 (40-60mg bid po, d1-14, Q21d). The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) and safety. The study explored the association between response with PD-L1 expression, tumor mutational burden (TMB) and genetic variations identified by next-generation sequencing (NGS) of peripheral blood. Results: 50 patients were enrolled from January 2019 to August 2021 with a median follow-up time of 24.0 months (4.3-31.0). The median PFS was 7.0 months (95%CI: 5.0-8.9 months); median OS was 15.0 months (95%CI: 11.6-18.4 months). Of the 49 patients who completed the evaluation for tumor response, the ORR was 30.6% (95%CI: 17.2%-44.0%), and the disease control rate was 87.8% (95%CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%) and immune-related colitis (2%).Among them, the Grade III/IV immune-related adverse events irAEs) worthy of attention included were skin rash and immune-related colitis. There was no significant difference in PFS and OS among intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder cancer. Exploratory study showed that patients with CPS≥1 had longer PFS. However, there was no significant correlation between TMB and PFS. Conclusions: Toripalimab combined with gemcitabine and S-1 (GS) has shown good safety in the first-line treatment of advanced BTCs. Although the primary endpoint did not reach the preset goal, toripalimab plus GS as first-line treatment has shown encouraging data of PFS and OS in patients with advanced BTC, which is worthy for further verification. Biomarker analysis showed that the expression level of PD-L1 could predict the curative effect. Clinical trial information: NCT03796429.