This study is a prospective, multicenter Phase II trial evaluating a personalized treatment strategy for patients with unresectable hepatocellular carcinoma (HCC). The study uses a metabolic classification system called the fatty acid degradation (FAD) subtype to guide therapy selection. Patients will be assigned to different treatment groups based on their tumor's FAD subtype, determined through RNA-seq analysis of the tumor tissue obtained from liver biopsy.
Adults ≥18 years of age who voluntarily agree to participate and sign informed consent.
Histologically or cytologically confirmed hepatocellular carcinoma (HCC).
Unresectable or not suitable for curative local therapy, or progression after prior surgery or local therapy.
BCLC stage B or C.
Non-HCC primary liver cancers (e.g., cholangiocarcinoma, combined HCC-CCA).
F3 subtype without liver lesions on imaging.
Clinically significant ascites requiring therapeutic intervention, or uncontrolled pleural/pericardial effusion.
Interstitial lung disease, pneumonitis requiring steroids, or active pulmonary infection.
Parallel
Camrelizumab Plus Apatinib
DrugCamrelizumab is administered intravenously at 200 mg every 3 weeks, and apatinib is taken orally at 250 mg once daily.
TACE Plus Camrelizumab and Apatinib
DrugCamrelizumab (200 mg IV every 3 weeks) and apatinib (250 mg orally once daily) are administered on the same schedule as the F1/F2 arm. TACE is performed 2-4 weeks after systemic therapy initiation, with up to two treatments per tumor (maximum four sessions total). Apatinib is paused 3-5 days before TACE and restarted 3-5 days afterward.
Objective Response Rate (ORR)
ORR is defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1, as assessed by imaging every 6 weeks. ORR will be calculated separately for each FAD subtype cohort (F1/F2 and F3).
Objective Response Rate (ORR) by mRECIST
ORR defined as the proportion of participants achieving complete response or partial response according to mRECIST criteria.
Disease Control Rate (DCR)
DCR is defined as the proportion of participants achieving complete response, partial response, or stable disease according to RECIST v1.1.
Progression-Free Survival (PFS)
PFS will be estimated using RECIST v1.1 criteria and assessed every 6 weeks.
Overall Survival (OS)
OS is defined as the time from study treatment initiation to death from any cause.
Correlation Between MRI-Derived Fat Fraction and Transcriptomic FAD Subtype Score
This outcome measure evaluates the correlation between tumor fat content measured by MRI and fatty acid degradation (FAD) activity determined by transcriptomic analysis. MRI fat fraction (FF): Quantified as percentage (%) of intra-tumoral fat content, measured using chemical shift-encoded MRI. FAD subtype score: Quantified as a continuous FAD score calculated from RNA sequencing-based transcriptomic data using single-sample gene set enrichment analysis (ssGSEA). Correlation analysis will be performed between MRI-derived fat fraction percentage and the transcriptomic FAD score to assess the concordance between imaging-based and molecular-based FAD classification.
Correlation Between Molecular Biomarker Levels and Objective Tumor Response
This outcome measure evaluates the correlation between molecular biomarker levels and objective tumor response. Transcriptomic biomarkers: Gene expression levels measured in tumor tissue by RNA sequencing (RNA-seq) and expressed as normalized gene expression values. Metabolomic biomarkers: Relative metabolite levels measured in blood or tumor tissue by mass spectrometry-based metabolomic profiling, expressed as relative abundance units. Objective tumor response: Measured by RECIST v1.1 using CT or MRI and expressed as response status (complete response or partial response vs. no response). Correlation analyses will be performed between each molecular biomarker measurement (gene expression values, metabolite abundance) and objective tumor response.
Correlation Between Molecular Biomarker Levels and Treatment Response
This measure evaluates the correlation between molecular biomarker levels and treatment response. Biomarker levels will be quantified using: Transcriptomic profiling: Gene expression levels measured by RNA sequencing (RNA-seq) and expressed as normalized expression counts. Metabolomic profiling: Relative metabolite concentrations measured by untargeted mass spectrometry, expressed as relative abundance units. Treatment response will be defined using RECIST v1.1. Correlation analyses will be conducted between each biomarker measurement (gene expression counts and metabolite abundance) and tumor response outcomes.
Correlation Between FAD Metabolic Subtype and Clinical Outcomes
This outcome measure evaluates the correlation between the fatty acid degradation (FAD) metabolic subtype and overall survival (OS) or progression-free survival (PFS). FAD metabolic subtype: Classified as F1, F2, or F3 using RNA sequencing-based transcriptomic analysis with ssGSEA scoring. Overall Survival (OS): Measured in months, defined as the time from initiation of study treatment until death from any cause. Progression-Free Survival (PFS): Measured in months, defined as the time from initiation of study treatment to radiographic disease progression or death, assessed by RECIST v1.1 using CT or MRI imaging. Correlation analyses will be performed between FAD subtype classification and OS/PFS duration.
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