Lenvatinib and Pembrolizumab With or Without BCAA in Unresectable HCC

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and most patients are diagnosed at an advanced or unresectable stage. Combination therapy with antiangiogenic agents and immune checkpoint inhibitors, such as lenvatinib plus pembrolizumab, has demonstrated promising antitumor activity; however, clinical outcomes remain heterogeneous, and strategies to further improve efficacy are needed.

Branched-chain amino acids (BCAAs) are essential amino acids that play an important role in nutritional status, liver function, and immune regulation in patients with chronic liver disease and HCC. Previous clinical and translational studies suggest that BCAA supplementation may improve nutritional balance, liver reserve, and treatment tolerance, and may potentially enhance antitumor immune responses. However, the clinical benefit of adding BCAAs to combination systemic therapy in unresectable HCC has not been prospectively evaluated.

This multicenter, open-label, randomized phase II study is designed to evaluate the efficacy and safety of lenvatinib plus pembrolizumab with or without BCAA supplementation in adult patients with unresectable hepatocellular carcinoma. Eligible participants will be randomized to receive standard combination therapy with lenvatinib and pembrolizumab, either with the addition of oral BCAAs or without BCAAs, according to the assigned treatment group. Study treatment will continue until radiographic disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment period.

Efficacy assessments will be performed using standardized radiologic evaluations at predefined intervals. Safety will be monitored throughout the study by the assessment of adverse events, laboratory tests, and clinical examinations. In addition to clinical efficacy and safety outcomes, exploratory analyses will be conducted to investigate potential biomarkers associated with treatment response and resistance. Tumor tissue and peripheral blood samples may be collected for exploratory translational research, including analyses related to immune response and metabolic status.

The results of this study are expected to provide evidence on whether BCAA supplementation can enhance the clinical benefit of lenvatinib plus pembrolizumab while maintaining an acceptable safety profile in patients with unresectable hepatocellular carcinoma, and to inform future clinical development strategies for combination systemic therapy in this population.

Inclusion criteria

• 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.

Exclusion criteria

• Pregnant or breastfeeding women.
• 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.
• 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.
• 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.
• 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.
• 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).
• Severe pulmonary disease, including:

• Severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease requiring long-term oxygen therapy;
• Active severe pulmonary infection.
• 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).
• Concurrent participation in another clinical trial, unless it is an observational, non-interventional study or the follow-up phase of an interventional study.
• 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.
• Expected survival of less than 3 months.
• 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.
• Any other condition that, in the investigator's judgment, may compromise participant safety or interfere with the evaluation of study efficacy.