Sequential or upfront triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma: the MONTBLANC trial protocol (AIO-HEP-0325/ass)

Background: Immune checkpoint inhibitor (ICI)-based combination therapy has transformed the therapeutic landscape of advanced hepatocellular carcinoma (aHCC). However, durable clinical benefit remains limited to a subset of patients, highlighting the need for approaches that enhance efficacy. Objectives: The MONTBLANC study presents a novel investigational strategy utilizing triple immunotherapy through the combination of the anti-programmed cell death ligand 1 antibody durvalumab, the anti-cytotoxic T-lymphocyte-associated antigen-4 tremelimumab, and the anti-vascular endothelial growth factor bevacizumab in patients with aHCC. Methods and analysis: This randomized, open-label, phase II clinical trial examines two distinct therapeutic regimens through parallel study arms: upfront triple-agent administration or doublet therapy with durvalumab and tremelimumab, followed by the addition of bevacizumab upon disease progression or lack of objective radiological response. The primary endpoint is the overall response rate. Secondary endpoints include overall survival, progression-free survival, safety, and patient-reported outcomes. Ethics: The ethics review boards of all participating sites have approved the study protocol. The trial will be performed in accordance with the Declaration of Helsinki, Good Clinical Practice Standards, and the applicable laws and regulations. All patients must provide written informed consent. Discussion: The MONTBLANC study aims at guiding the design of future trials in aHCC by assessing efficacy signals of upfront triple or response-adapted treatment escalation with durvalumab, tremelimumab, and bevacizumab. Trial registration: The MONTBLANC clinical trial is registered at the US National Institutes of Health (ClinicalTrials.gov, NCT05844046) and the European Union Drug Regulating Authorities Clinical Trials Database (clinicaltrialsregister.eu, 2022-001201-48).