Lenvatinib and Pembrolizumab With or Without BCAA in Unresectable HCC

Prior treatment

• Prior treatment with systemic targeted therapies (including sorafenib or lenvatinib), immune checkpoint inhibitors (including anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), or any form of cellular immunotherapy.
• Significant cardiovascular disease or cardiac dysfunction, including but not limited to:
  • New York Heart Association (NYHA) class III-IV heart failure;
  • Myocardial infarction, severe angina, coronary stent placement, or coronary artery bypass grafting within 6 months prior to enrollment;
  • Clinically significant ventricular arrhythmias or persistent atrial fibrillation;
  • Uncontrolled hypertension (blood pressure ≥150/90 mmHg despite optimal medical therapy).
• Concurrent participation in another clinical trial, unless it is an observational, non-interventional study or the follow-up phase of an interventional study.
• Participation in another interventional clinical trial within 4 weeks prior to enrollment (during the treatment phase), or currently receiving treatment in another interventional study; participants who have entered the follow-up phase of another clinical trial and do not interfere with the assessment of this study may be enrolled.

Other illness

• Active autoimmune disease requiring systemic treatment within the past 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapies (such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) are not considered systemic treatment.
• History of another malignancy within 3 years prior to enrollment, except for adequately treated localized malignancies (such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or cervical carcinoma in situ).
• Severe psychological or psychiatric disorders.
• Severe pulmonary disease, including:
  • Severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease requiring long-term oxygen therapy;
  • Active severe pulmonary infection.
• History of hepatic encephalopathy, refractory ascites, or severe portal hypertension syndrome caused by hepatic vein or portal vein thrombosis, deemed unsuitable for study treatment by the investigator.
• Known history of severe hypersensitivity reactions to lenvatinib, pembrolizumab, branched-chain amino acid preparations, or any of their excipients.
• Any other condition that, in the investigator's judgment, may compromise participant safety or interfere with the evaluation of study efficacy.

Lab values

• Active or uncontrolled infection, including but not limited to uncontrolled acute exacerbation of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, active tuberculosis, human immunodeficiency virus (HIV) infection with significantly reduced CD4 counts, or severe bacterial, fungal, or viral infections requiring intravenous antimicrobial therapy.
• Severe renal impairment, including acute or chronic renal failure with estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m² or requiring dialysis.
• History or presence of significant bleeding tendency, including but not limited to:
  • Major gastrointestinal bleeding within 6 months prior to enrollment;
  • Untreated high-risk esophageal or gastric varices;
  • Severe coagulation abnormalities (e.g., INR \>2.0, unless due to stable anticoagulation therapy).

Other

• Pregnant or breastfeeding women.
• Expected survival of less than 3 months.

• Adults aged ≥18 years and \<75 years at the time of enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically or cytologically confirmed hepatocellular carcinoma (HCC), excluding fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular-cholangiocarcinoma; or clinically diagnosed HCC according to the American Association for the Study of Liver Diseases (AASLD) criteria.
• Unresectable Barcelona Clinic Liver Cancer (BCLC) stage B or C disease, as assessed by the investigator.
• At least one measurable lesion according to RECIST version 1.1.
• Adequate liver function defined as Child-Pugh class A (score 5-6).
• Adequate hematologic function: absolute neutrophil count ≥1.5 × 10⁹/L, hemoglobin ≥9.0 g/dL, and platelet count ≥100 × 10⁹/L.
• Adequate hepatic and renal function: total bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN; serum creatinine ≤1.5 × ULN.
• Adequate coagulation function: international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
• Participants of childbearing potential must agree to use effective contraception during the study and for at least 120 days after the last dose of study treatment; female participants of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to the first dose of study treatment.
• Ability to understand and willingness to sign a written informed consent form.