Ivonescimab plus gemcitabine/cisplatin and stereotactic body radiotherapy as first-line treatment for advanced biliary tract cancer: A single-arm, open-label, phase II exploratory study.

e16170 Background: Although gemcitabine/cisplatin (GC) plus immunotherapy is now standard first-line treatment for advanced biliary tract cancer (BTC), efficacy remains limited with survival outcomes still failing to meet clinical needs. Ivonescimab (AK112), a novel PD-1/VEGF bispecific antibody, exerts synergistic antitumor activity by simultaneously blocking PD-1 and VEGF pathways. This study aimed to evaluate the efficacy and safety of AK112 combined with GC and stereotactic body radiotherapy (SBRT) as a first-line treatment for advanced BTC. Methods: This prospective, single-arm, open-label, phase II exploratory study enrolled patients with histologically or cytologically confirmed locally advanced or metastatic BTC deemed unresectable by both radiologic evaluation and surgical assessment, with no prior systemic therapy. Patients first received SBRT to the primary tumor (18–60 Gy in 3–8 fractions), followed within one week by ivonescimab (20 mg/kg, Q3W) combined with GC (gemcitabine 1000 mg/m², D1 and D8; cisplatin 25 mg/m², D1 and D8; Q3W) for up to 8 cycles, then ivonescimab maintenance therapy (up to 24 months). The primary endpoint was ORR per RECIST v1.1 and mRECIST. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of December 18, 2025, 22 patients were enrolled. Median age was 63 years (range: 47–72), and 68.2% (15/22) were male. Tumor types included intrahepatic cholangiocarcinoma in 15 patients (68.2%) and gallbladder cancer in 7 patients (31.8%); 86.4% (19/22) had distant metastases. Twenty patients completed at least one radiologic assessment (1 lost to follow-up, 1 still on treatment). Per RECIST v1.1, CR in 0 (0.0%), PR in 11 (55.0%), SD in 7 (35.0%), and PD in 2 (10.0%). The ORR was 55.0% (11/20) and DCR was 90.0% (18/20). Based on mRECIST, 15 patients were evaluable, with a CR rate of 0%, ORR of 60.0% (9/15), and DCR of 86.7 % (13/15). All patients (21/22, 95.5%) experienced treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 36.4% (8/22), mainly including leukopenia/neutropenia (18.2%), hyperbilirubinemia (13.6%), thrombocytopenia (9.1%), intestinal obstruction (9.1%), elevated transaminases (4.5%), and esophageal ulcer (4.5%). No treatment-related deaths occurred. Conclusions: Ivonescimab combined with GC chemotherapy and SBRT as first-line treatment for advanced BTC demonstrated encouraging antitumor activity with a manageable safety profile. This combination regimen may represent a promising new treatment option for patients with advanced BTC and warrants further validation in larger studies. Clinical trial information: ChiCTR2400088480.