A dual blockade of vascular endothelial growth factor (VEGF) and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) can modulate the tumor microenvironment and enhance antitumor immunity. This approach reduces immunosuppressive cells, improves dendritic cell function, lowers immune checkpoint expression, and boosts T-cell activation. This combination of mechanisms has shown synergistic efficacy and survival benefits in cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and non–small cell lung cancer. Adding CTLA-4 inhibitors further amplifies T-cell responses, supporting a multipathway immunomodulation treatment strategy. Preclinical murine biliary tract cancer (BTC) models and early clinical findings suggest that the blockade of VEGF, PD-L1, and CTLA-4 could be a promising approach for HCC and BTC, warranting further study.
This was a phase 2 trial (NCT03937830) conducted to evaluate efficacy of durvalumab, bevacizumab, and tremelimumab in advanced HCC Barcelona Clinic Liver Cancer stage C or BTC. Eligible patients received a single intravenous infusion of durvalumab 1150 mg and tremelimumab 300 mg on day 1 of cycle 1. Starting on day 1 of cycle 2, bevacizumab 7.5 mg/kg and durvalumab 1150 mg were administered every 3 weeks by intravenous infusion. Therapy continued in 3-week cycles until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS), with secondary endpoints including overall survival (OS), safety, and best overall response (BOR).
The trial enrolled 27 patients between March 2021 and August 2024, including 6 with HCC and 21 with BTC. The study results highlighted the challenges of achieving durable disease control in these difficult-to-treat cancers. After a median follow-up time of 8 months, the median PFS was 3.5 months and the 6-month PFS rate was 37%. However, the median OS was 9.5 months, demonstrating a clinically meaningful survival benefit in this patient population. In terms of BOR, 18% of patients experienced a partial response, and 40% experienced stable disease, indicating that the therapy was able to achieve disease stabilization or better in a significant portion of patients.
The most common grade 3/4 treatment-related adverse events included anemia (33%), diarrhea/colitis (25.9%), and lymphopenia (22%). Notably, 26% of patients discontinued treatment due to adverse events, and 1 treatment-related death occurred due to an upper gastrointestinal bleed.
This study represents a novel approach to treating advanced HCC and BTC by targeting 3 distinct, but complementary pathways involved in tumor progression antitumor immunity. Although the primary PFS endpoint was not met, the clinically meaningful OS and disease stabilization observed in the study suggest that this triplet therapy may hold promise for select patients. Although challenges remain, this study provides valuable insights into the potential of multipathway immunotherapy and sets the stage for further investigations in this field. Future research should focus on refining patient selection criteria, optimizing dosing schedules, and mitigating toxicity to improve outcomes further.
Awisika J, M Cecilia Monge B, Xie C, et al. Combined treatment of durvalumab, bevacizumab and tremelimumab in subjects with hepatocellular carcinoma (HCC) or biliary tract carcinoma (BTC). Presented at: 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Poster 371.
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