Fatty acid degradation (FAD)–guided comprehensive therapy for unresectable hepatocellular carcinoma: A prospective phase II study (FAD-HCC-01).

Abstract

TPS4256 Background: Hepatocellular carcinoma (HCC) exhibits marked molecular and metabolic heterogeneity, leading to variable therapeutic responses and limiting the effectiveness of current systemic treatments. Despite recent advances in immunotherapy and targeted agents, no validated biomarker is available to guide treatment selection in unresectable HCC. We previously established a fatty acid degradation (FAD) pathway-based molecular classification of HCC, revealing that FAD-associated transcriptional programs delineate biologically distinct HCC subtypes with heterogeneous immune microenvironments and differential responses to systemic and locoregional therapies. These findings suggest that FAD-based stratification may enable a more precise, biology-driven treatment strategy. However, the feasibility of implementing FAD-guided treatment allocation in a prospective clinical setting has not been established. FAD-HCC-01 is designed to evaluate the feasibility, safety, and preliminary efficacy of a FAD-guided comprehensive therapy in patients with unresectable HCC. Methods: FAD-HCC-01 is a prospective, multicenter, open-label phase II study enrolling patients with unresectable or non-curatively treatable HCC. Eligible patients have histologically or clinically confirmed HCC, BCLC stage B or C disease, Child–Pugh class A to B (≤7), ECOG performance status 0-1, and no prior systemic therapy. Tumors are classified into FAD subtypes (F1, F2, or F3) using transcriptomic profiling with ssGSEA-based FAD scoring; MRI-derived fat fraction may serve as a provisional surrogate when tumor tissue is unavailable. A total of 86 patients will be enrolled, with 43 patients planned for each treatment cohort. Patients are assigned to two parallel cohorts according to FAD subtype. Patients with F1 or F2 tumors receive camrelizumab (200 mg intravenously every 3 weeks) plus rivoceranib (250 mg orally once daily). Patients with F3 tumors receive transarterial chemoembolization (TACE) combined with camrelizumab and rivoceranib, with TACE performed per institutional standards and repeated as clinically indicated. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is objective response rate assessed by RECIST v1.1. Secondary endpoints include ORR by mRECIST, disease control rate, progression-free survival, overall survival, duration of response, conversion to curative treatment, and safety. Key feasibility objectives include successful FAD subtyping, adherence to FAD-guided treatment allocation, and integration of molecular or imaging-based classification into routine clinical workflows. Exploratory analyses will assess concordance between MRI fat fraction and FAD subtypes and explore molecular correlates of treatment response. Clinical trial information: NCT07314372 .