FAD Subtype-Guided Combination Therapy for Unresectable Hepatocellular Carcinoma

Prior treatment

• Recent use (within 2 weeks) of systemic immunosuppressive therapy \>10 mg/day prednisone equivalent.
• Receipt of live attenuated vaccines within 28 days before treatment.

Other illness

• Non-HCC primary liver cancers (e.g., cholangiocarcinoma, combined HCC-CCA).
• Interstitial lung disease, pneumonitis requiring steroids, or active pulmonary infection.
• Active or history of autoimmune disease requiring systemic treatment (exceptions allowed per protocol, e.g., controlled hypothyroidism).
• Gastrointestinal bleeding within 6 months, high-risk varices, active ulcers, fistula, perforation, or intra-abdominal abscess.
• Known bleeding or clotting disorders; therapeutic anticoagulation not permitted.
• Thromboembolic events within 6 months (e.g., stroke, PE).
• Uncontrolled hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg despite treatment), or history of hypertensive crisis.
• Major vascular disease within 6 months (e.g., arterial thrombosis, aneurysm requiring repair).
• Inability to swallow oral medication or conditions affecting drug absorption.
• Known HIV infection or other causes of immunodeficiency.
• Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of results, including substance abuse, severe psychiatric illness, or social factors.

Lab values

• Significant cardiovascular disease, including NYHA class ≥II heart failure, recent MI (within 1 year), unstable angina, clinically significant arrhythmias, or QTc prolongation.
• Severe infection within 4 weeks, therapeutic antibiotics within 14 days, fever ≥38.5°C within 7 days before enrollment, or WBC \>15 × 10⁹/L.

Other

• F3 subtype without liver lesions on imaging.
• Clinically significant ascites requiring therapeutic intervention, or uncontrolled pleural/pericardial effusion.
• Serious non-healing wounds, active ulcers, or fractures.

• 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.
• No prior systemic therapy for HCC.
• At least one measurable lesion according to RECIST v1.1.
• Availability of fresh or archival tumor tissue for FAD subtype testing; if not available at screening, MRI fat fraction may be used temporarily.
• Child-Pugh class A or B (≤7 points).
• ECOG performance status 0-1.
• Adequate organ function, including:
  • ANC ≥1.5 × 10⁹/L
  • Platelets ≥75 × 10⁹/L
  • Hemoglobin ≥90 g/L
  • Albumin ≥30 g/L
  • Total bilirubin ≤1.5 × ULN
  • ALT and AST ≤3 × ULN
  • Serum creatinine ≤1.5 × ULN or creatinine clearance \>50 mL/min
  • INR ≤1.2 or PT within 2 seconds above ULN
  • Urine protein \<2+ or 24-hour urine protein \<1.0 g
• Controlled HBV infection (HBV-DNA \<2000 IU/mL; if above this level, ≥1 week of antiviral therapy with ≥1-log reduction prior to first dose). HCV-positive individuals must be managed per clinical guidelines.
• Life expectancy ≥12 weeks.
• Women of childbearing potential must have a negative pregnancy test; participants of reproductive potential must agree to effective contraception during treatment and for 6 months afterward.