Combined treatment of durvalumab, bevacizumab and tremelimumab in subjects with hepatocellular carcinoma (HCC) or biliary tract carcinoma (BTC).

4081 Background: Anti-VEGF in combination with anti-PD1/PD-L1 represents a synergistic therapeutic strategy that has demonstrated efficacy, prolonging survival in cancers like HCC, RCC, and NSCLC. This combination induces modifications in the tumor microenvironment, leading to a reduction in immunosuppressive cells, improved dendritic cell maturation, antigen presentation, downregulation of immune checkpoint molecules, and enhanced T-cell activity. Combining CTLA-4 inhibitors with anti PD-1/PD-L1 enhances T-cell mediated anti-tumor responses by leveraging distinct yet complementary mechanisms. Targeting VEGF, PD-L1, and CTLA-4 pathways simultaneously in HCC and BTC provides a novel approach that hasn’t been tested in clinical trials. Our group previously reported in vivo activity in murine BTC models and preliminary clinical results supporting this triplet combination in BTC. The aim of this study is to determine if VEGF inhibition with anti-CTLA-4 and anti-PD-LI therapy augments antitumor immunity and clinical responses in HCC and BTC patients. Methods: This was a Phase II trial conducted to evaluate efficacy of durvalumab, bevacizumab and tremelimumab in advanced HCC BCLC stage C or BTC. Participants received bevacizumab at 7.5mg/kg and durvalumab 1150mg every 3 weeks by IV infusion on Day 1 of Cycle 1 (durvalumab) and Day 1 of Cycle 2 (bevacizumab). Tremelimumab at a dose of 300mg was administered by IV infusion only once on Day 1 of Cycle 1. The combination of durvalumab and bevacizumab continued in 3-week cycles until disease progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival (PFS) and secondary endpoints were safety, overall survival (OS) and best overall response (BOR). Correlative studies assessing immune response were performed. Results: Between March 2021 and August 2024, 27 patients were enrolled (HCC: 6pts, BTC: 21pts). The median age was 66y (39-80) and 62% were male. 37% of the patients enrolled received prior ICI. As of November 4 th , 2024, with a median follow-up of 8mos, mPFS was 3.5mos and mOS 9.5mos in all 27 efficacy-evaluable pts. The estimated 6 months PFS rate was 37%. The BOR was partial response in 4 pts (18%) followed by stable disease in 9pts (40%). The most common grade 3-4 TRAEs were lymphopenia (6pts, 22%), anemia (9pts, 33%), diarrhea/colitis (7pts, 25.9%), elevated lipase (4pts, 14.8%). Treatment discontinuation related to AEs occurred in 7pts (26%). One treatment-related death occurred secondary to an upper gastrointestinal bleed. Conclusions: The combination of durvalumab, bevacizumab and tremelimumab did not meet its primary endpoint but demonstrated a clinically meaningful overall survival benefit. No new safety signals were seen. Clinical trial information: NCT03937830 .