Phase II trial of hepatic arterial infusion chemotherapy plus bevacizumab and toripalimab for advanced biliary tract cancers: efficacy, safety, and exploratory analysis

Background: Chemotherapy combined with immune checkpoint inhibitor have prolonged survival of patients with advanced biliary tract cancers (BTCs), and the previous studies showed the synergistic antitumor effect of chemotherapy, anti-angiogenesis therapy, and immunotherapy. Hepatic arterial infusion chemotherapy (HAIC) achieved a higher tumor response and survival benefit in previous phase II studies for advanced BTCs. Thus, we conducted this phase II trial to evaluate the efficacy and safety of HAIC combined with bevacizumab and toripalimab for advanced BTCs. Methods: Treatment-na & iuml;ve participants with advanced BTCs were recruited for this phase II trial. Combination therapy, comprising HAIC with bevacizumab (300 mg, day 1), oxaliplatin (40 mg/m2, 2 h, days 1-3), and 5-fluorouracil (800 mg/m2, 22 h, days 1-3) plus intravenous toripalimab (240 mg, day 1 before HAIC), was repeated every 4 weeks for a maximum of six consecutive cycles. Intravenous toripalimab (240 mg) and bevacizumab (300 mg) were administered every 4 weeks as maintenance treatment. The primary endpoint was objective response rate (ORR) according to Immune-Modified Response Evaluation Criteria in Solid Tumors criteria, and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Olink proximity extension assay with a Target 96 Immuno-Oncology panel was exploratory investigated. Results: Between July 2020 and January 2022, 32 participants were enrolled. The ORR was 84.38%, and the disease control rate was 96.88%. Median PFS and OS were 13.20 months [95% confidence interval (CI): 8.93-17.47] and 19.0 months (95% CI: 12.22-25.78), respectively. Grade 3 or higher adverse events (AEs) were observed in 10 participants (31.25%), and the most frequent grade 3 or higher AEs were elevated ALT/AST (4/32, 12.50%), elevated total bilirubin (3/32, 9.38%), and neutropenia (3/32, 9.38%). In exploratory analysis, Child-Pugh B [hazard ratio (HR): 22.65, 95% CI: 3.66-140.08, P=0.001] and high level of macrophage metalloproteinase-12 (HR: 5.99, 95% CI: 1.60-22.37, P=0.008) were indicated as the risk factors related to worse PFS. Conclusions: HAIC combined with bevacizumab and toripalimab may serve as an improved first-line treatment for advanced BTCs, which require a randomized control trial for verification.