BACKGROUND/AIM: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, with resistance to systemic therapies limiting outcomes. Arginine depletion with ADI-PEG 20 may enhance the efficacy of tyrosine kinase inhibitors (TKIs) such as lenvatinib. CASE REPORT: A 58-year-old man with chronic hepatitis B, cured hepatitis C, cirrhosis, diabetes, and hypertension was diagnosed with multifocal HCC and later developed para-aortic lymph node metastasis (BCLC stage C). He received lenvatinib (12 mg/d) plus compassionate-use ADI-PEG 20 due to favorable rs6025211-CC genotype. Combination therapy achieved a partial response with lymph node reduction from 3.7 to 1.7 cm and disease stability for nearly two years, with good tolerability. After switching to ADI-PEG 20 monotherapy, intrahepatic recurrence occurred but was controlled with radiofrequency ablation. Despite comorbidities and renal dysfunction, the patient has survived over four years since advanced disease was documented. CONCLUSION: This case provides clinically relevant insights into treatment selection in advanced HCC, suggesting that the combination of lenvatinib and ADI-PEG 20 may represent a promising, hypothesis-generating strategy, particularly where immunotherapy is not accessible, potentially overcoming TKI resistance through metabolic modulation. The patient achieved complete remission, with disappearance of metastatic lymph nodes and no viable liver tumor on CT in January 2026. However, these findings should be interpreted with caution given the limitations of a single case, and further studies are needed to validate this approach and define its clinical implications.
Yu et al. (2026) studied this question.