SBRT Combined With Iparomlimab and Tuvonralimab (QL1706) and Bevacizumab for Hepatocellular Carcinoma

Prior treatment

• Prior radiotherapy to any site requiring treatment in this study (risk of field overlap causing excessive irradiation of normal tissue).
• Prior selective internal radiation therapy or yttrium-90 hepatic arterial therapy.
• Live attenuated vaccination within 4 weeks before the first dose or planned during the study.
• Within 6 months before enrollment: myocardial infarction, severe or unstable angina, NYHA class \>=2 heart failure, poorly controlled arrhythmia, or symptomatic congestive heart failure.
• Coagulation abnormality with bleeding tendency, or currently receiving thrombolytic, anticoagulant, or antiplatelet therapy.

Other illness

• Hepatic encephalopathy, massive ascites, or abdominal infection within 1 month.
• Malignant pleural effusion.
• Known history of allogeneic organ or hematopoietic stem cell transplantation, or planned transplantation.
• Known allergy to iparomlimab and tuvonralimab, bevacizumab, or drug excipients, or severe hypersensitivity to any other monoclonal antibody.
• Severe active autoimmune disease.
• Any other malignancy, except adequately treated basal cell or squamous cell skin carcinoma or cervical carcinoma in situ.
• Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).
• Known hereditary or acquired bleeding or thrombotic tendency, such as hemophilia, coagulation disorders, or severe thrombocytopenia.

Lab values

• Poor liver function: Child-Pugh score \>7, or hepatic enzymes, coagulation, bilirubin, or bone marrow function not meeting the enrollment criteria.
• Risk of gastrointestinal bleeding, including: (1) active peptic ulcer; (2) melena or hematemesis within 1 month; (3) gastroscopy showing ulcer or bleeding lesions, esophagogastric varices with red color signs (+), or variceal diameter \>1 cm. Also: history of psychotropic drug abuse or drug addiction, or other severe medical or psychiatric illness, or laboratory abnormality that may increase study risk, confound results, or render the patient unsuitable in the investigator's judgment.

Age

• Age \<18 years.

Other

• ECOG performance status \>=2.
• Brain metastases.
• Tumor directly invading the stomach, duodenum, small intestine, or large intestine; or tumor within 3 mm of the spinal cord.
• Maximum diameter of any single lesion \>15 cm.
• Sum of the maximum diameters of all intrahepatic lesions, or the maximum diameter of a single confluent lesion, \>20 cm.
• More than 5 discrete intrahepatic HCC lesions.
• Normal liver volume \<700 mL.

• Age \>= 18 years, male or female.
• Histologically or radiologically confirmed hepatocellular carcinoma.
• Barcelona Clinic Liver Cancer (BCLC) stage B or C.
• Inoperable disease, not a transplant candidate, and unsuitable for ablation or transarterial therapy, including locally advanced and oligometastatic disease. 4.1 Locally advanced: no extrahepatic metastasis; portal vein, hepatic vein, or inferior vena cava tumor thrombus permitted. 4.2 Oligometastatic: a limited number (\<=5) of extrahepatic metastatic lesions (lymph node, visceral, bone, adrenal, or soft tissue; brain metastases excluded), with or without intrahepatic disease meeting the locally advanced definition. Vascular invasion is not counted in the lesion number, and lesions achieving complete response (per RECIST 1.1) after prior therapy are not counted.
• At least one measurable lesion per RECIST 1.1.
• All lesions can safely receive stereotactic body radiotherapy.
• No prior systemic therapy, or progression or intolerance after first-line systemic therapy, with more than 3 weeks since the last dose.
• ECOG performance status 0-1 within 1 week before enrollment.
• Child-Pugh class A or B (score \<=7).
• Hematology: hemoglobin \>=90 g/L; white blood cell count \>=3.0 x 10\^9/L; absolute neutrophil count \>=1.5 x 10\^9/L; platelet count \>=75 x 10\^9/L.
• INR \<=2.3, or prothrombin time exceeding the upper limit of normal by \<=6 seconds.
• ALT and AST \<=5 x upper limit of normal (ULN); alkaline phosphatase \<=5 x ULN; total bilirubin \<=3 x ULN; albumin \>=28 g/L.
• Serum creatinine \<=1.5 x ULN, or creatinine clearance \>=50 mL/min calculated by the Cockcroft-Gault formula.
• Urine protein \<2+ (patients with urine protein \>=2+ may undergo 24-hour urine protein quantification and are eligible if the 24-hour urine protein is \<1.0 g).
• Patients with active hepatitis B virus (HBV) infection: HBV-DNA \<500 IU/mL (or \<2500 copies/mL if only copy/mL is available) and willingness to receive antiviral therapy throughout the study; patients positive for hepatitis C virus (HCV) RNA must receive standard antiviral therapy, with hepatic enzyme elevation \<=CTCAE grade 1.
• Women of childbearing potential (generally 15-49 years) must have a negative serum or urine pregnancy test within 14 days before enrollment and be willing to use adequate contraception during the study and for 8 weeks after the last dose of study drug; men must be surgically sterile or agree to adequate contraception during the study and for 8 weeks after the last dose.
• Voluntary participation with signed informed consent, good compliance, and willingness to undergo follow-up.