AbstractAimThis study was aimed to evaluate the safety and the efficacy of gemcitabine and oxaliplatin (GEMOX) combined with donafenib plus tislelizumab as the first‐line treatment for patients with unresectable biliary tract cancer (BTC).MethodsThis is a prospective single‐center exploratory study. Eligible patients (Stage III/IV BTC, at least one measurable disease according to RECIST v1.1, etc.) received gemcitabine 1000 mg/m2IV Q3W, oxaliplatin 100 mg/m2IV Q3W, donafenib 200 mg PO BID, and tislelizumab 200 mg IV Q3W until disease progression, unacceptable toxicity, or withdrawal of consent whichever occurred first. The primary endpoint was safety and secondary endpoints included disease control rate (DCR), objective response rate (ORR), conversion rate, and overall survival (OS).ResultsA total of 13 patients were enrolled. The median follow‐up time was 420 days (range 345–487). The median duration of treatment was four cycles (range 1–15). The incidence of ≥Grade 3 treatment‐related adverse events (TRAEs) was 53.8% and no Grade 5 TRAE. The most frequent Grade 3–4 TRAEs were rash (4/13, 30.8%), platelet count decreased (2/13, 15.4%), and fatigue (2/13, 15.4%). Tumor response was assessed in eight evaluable patients; ORR was 25.0% (95% CI, 3.2%–65.1%) and DCR 87.5% (95% CI, 47.3%–99.7%). The median PFS was 4.8 months (95% CI, 1.25‐NE). Three Stage III patients underwent subsequent surgery with a conversion rate of 23.1%. The median OS was not estimable.ConclusionsGEMOX combined with donafenib plus tislelizumab as the first‐line therapy for unresectable BTC showed manageable toxicity and encouraging efficacy especially in terms of promising conversion rate in Stage III patients.