BITS-TO-HCC Study: HAIC+Iparomlimab/Tuvonralimab + Bevacizumab + Surgery/SBRT for BCLC-C HCC With PVTT and/or Oligometastases

Prior treatment

• Curative local therapy candidacy
  • Current candidacy for resection, liver transplant, or RFA
• RT infeasibility
  • Prior radioembolization
  • Single liver tumor ≥15 cm or total intrahepatic tumor diameter ≥20 cm
  • more than 5 discrete intrahepatic parenchymal foci are present
  • direct tumor extension into the stomach, duodenum, small bowel, or large bowel
  • measurable common or main-branch biliary duct involvement
  • Prior liver radiotherapy that would result in excessive overlap with the planned treatment fields
• Prior systemic therapies
  • Received targeted-immunotherapy for HCC (e.g., PD-(L)1 inhibitors + tyrosine kinase inhibitors (TKIs))
  • Prior immunotherapy: anti-PD-(L)1/CTLA-4 or chimeric antigen receptor T-cell therapy
• Hemorrhage/portal hypertension and hepatic decompensation risk
  • Variceal bleeding within 6 months.
  • Untreated or high-risk esophagogastric varices (e.g., grade ≥2 on endoscopy within 3 months) or other clinical evidence of portal hypertension with high bleeding risk per investigator.
  • Moderate or severe ascites
  • History of or active hepatic encephalopathy
  • History of hemoptysis (≥2.5 mL of bright red blood per episode) within 28 days before study treatment
  • Evidence of bleeding diathesis or significant coagulopathy
  • Current or recent (within 10 days before study treatment) use of aspirin (≥325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, or therapeutic-dose oral/parenteral anticoagulants or thrombolytic agents
• Comorbidities
  • Active autoimmune disease or a history of autoimmune or inflammatory disease that may relapse; exceptions include hypothyroidism controlled with hormone replacement only, controlled celiac disease, and skin disorders not requiring systemic treatment (e.g., vitiligo, psoriasis, or alopecia)
  • Any condition requiring systemic corticosteroids (\>10 mg/day prednisone or equivalent) or other immunosuppressive medication within 14 days before study treatment
  • Active or uncontrolled infection, including tuberculosis, or known HIV infection
  • Prior allogeneic stem cell transplantation or organ transplantation
  • Inadequately controlled hypertension, defined as systolic blood pressure ≥150 mmHg and/or diastolic blood pressure \>90 mmHg despite optimal medical management, or a history of hypertensive crisis or hypertensive encephalopathy
  • History within 6 months before study treatment of myocardial infarction, unstable angina, symptomatic heart failure (New York Heart Association class ≥II), cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other serious thromboembolic events
  • Major surgical procedure within 28 days before study treatment, or serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
  • History within 6 months before study treatment of gastrointestinal perforation, abdominal or tracheoesophageal fistula, or intra-abdominal abscess

Other illness

• Allergy to any component of iparomlimab/tuvonralimab or bevacizumab

Other

• Histopathological exclusions
  • Mixed HCC subtypes: Fibrolamellar HCC or sarcomatoid HCC or cholangiocarcinoma components

• Male or female patients aged between 18 and 70 years.
• Unresectable HCC, BCLC Stage C according to the BCLC strategy-2026 update, with staging established via biopsy pathology and/or clinical diagnosis.
• Child-Pugh class A without clinically significant hepatic decompensation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Metastatic burden and local therapy eligibility
  • Extrahepatic oligometastatic disease defined as ≤3 involved organs with ≤5 total metastatic lesions
  • All intended intrahepatic and/or extrahepatic SBRT targets must satisfy protocol-specified target-coverage, liver reserve, and organ-at-risk (OAR) constraints within a composite 5-fraction plan
• Prognosis \& measurable disease
  • Life expectancy ≥3 months
  • ≥1 measurable lesion (per RECIST 1.1):
  • Tumor: ≥10 mm (CT long axis)
  • Lymph node: ≥15 mm (CT short axis)
• Prior therapy
  • Prior locoregional therapy permitted：radiofrequency ablation (RFA), TACE, or HAIC, provided that:
  • Documented radiographic progression or intolerance after the prior therapy
  • Washout ≥28 days
  • Treatment-related toxicities recovered to ≤Grade 1 (alopecia and peripheral neuropathy ≤Grade 2 allowed)
• Laboratory and virologic requirements
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤5 × upper limit of normal (ULN); total bilirubin \<3 × ULN; serum albumin ≥28 g/L
  • Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min
  • Urine dipstick protein \<2+; if baseline dipstick proteinuria is ≥2+, 24-hour urinary protein must be \<1 g
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN