Background: Hepatocellular carcinoma (HCC) exhibits substantial biological and metabolic heterogeneity, contributing to variable therapeutic responses in unresectable disease. Although immune checkpoint inhibitors combined with anti-angiogenic agents have improved outcomes, treatment selection remains largely empirical because validated predictive biomarkers are lacking. Recent multi-omics studies have identified fatty acid degradation (FAD)-related transcriptional signatures that classify HCC into distinct metabolic subtypes with different immune microenvironment characteristics and therapeutic vulnerabilities. Retrospective analyses suggest that F1/F2 subtypes may derive greater benefit from immune checkpoint inhibitor-based systemic therapy, whereas F3 tumours may be more responsive to transarterial chemoembolisation (TACE). However, whether FAD-based metabolic stratification can prospectively inform treatment allocation remains unknown. Methods: FAD-HCC-01 is a prospective, multicentre, open-label proof-of-concept Phase II study designed to evaluate the feasibility and preliminary clinical activity of FAD-informed treatment allocation in patients with unresectable HCC. Eligible patients with Barcelona Clinic Liver Cancer stage B or C disease and no prior systemic therapy will undergo baseline tumour transcriptomic profiling to determine FAD subtype. Patients with F1/F2 tumours will receive camrelizumab plus rivoceranib, whereas patients with F3 tumours will receive TACE combined with camrelizumab and rivoceranib. Eighty-six patients will be enrolled, with 43 in each biomarker-defined cohort. The primary endpoint is objective response rate according to RECIST version 1.1. Secondary endpoints include objective response rate by mRECIST, disease control rate, progression-free survival, overall survival, duration of response, conversion to curative treatment, and safety. Exploratory analyses will assess concordance between MRI-derived proton density fat fraction and transcriptomic FAD classification. Conclusion: This proof-of-concept study will prospectively assess whether FAD-based metabolic subtyping can inform treatment allocation in unresectable HCC. The results may provide early evidence supporting metabolism-informed precision therapy and the design of future biomarker-guided clinical trials. Keywords: hepatocellular carcinoma, fatty acid degradation, metabolic subtype, biomarker-informed treatment allocation, precision oncology
Cheng et al. (Fri,) studied this question.