The Combined Therapeutic Effect of Lenvatinib and ADI-PEG 20 in Advanced Hepatocellular Carcinoma: A Case Report

Abstract

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.

Introduction

Hepatocellular carcinoma (HCC), arising from the liver has been recognized as the most common primary liver cancer and the third leading cause of cancer-related deaths worldwide (1). Despite improvement in surveillance and therapeutic applications, the prognosis of HCC remains largely unfavorable, mostly because of late diagnosis, and presence of liver dysfunction associated with resistance to systemic therapies. The advent of multitargeted TKIs including sorafenib, lenvatinib, and immune checkpoint inhibitors has brought forth a positive impact on therapeutic efficacy, but resistance to therapies and modest survival benefits continue to be the barriers (2, 3). New therapeutic strategies and/or rational drug combinations are thus urgently required.

Arginine metabolism is associated with many cancers, including HCC (4). Argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme for endogenous arginine synthesis, is frequently lost in malignancies, resulting in arginine auxotrophy (5). ADI-PEG 20, a pegylated form of arginine deiminase, leads to extracellular arginine deprivation and selective cytotoxicity of ASS1 deficient tumors. Preclinical investigations and phase I/IIa trials have shown that ADI-PEG 20 has anticancer activities as a result of its inhibition of protein synthesis, autophagy induction, and inducing metabolic stress in HCC and other solid tumors (6). Although a phase III trial has not demonstrated beneficial effect for patients with advanced HCC, a post-hoc analysis has identified genetic markers associated with patients with favorable responses (7, 8). Oral TKI inhibitor lenvatinib that inhibits VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT has been approved as a first-line systemic treatment for unresectable HCC. In the REFLECT trial, lenvatinib was associated with better progression-free survival (PFS) and objective response rate (ORR) than sorafenib, but not the overall survival (OS) (9). Notably, resistance to lenvatinib occurs in a multifaceted manner, mostly involving activation of other angiogenic pathways, reprogramming of metabolism, and epithelial-mesenchymal transition (EMT).

Here, we report a patient treated at Chang Gung Memorial Hospital with a combination of lenvatinib and ADI-PEG 20, where the ADI-PEG 20 was provided as a compassionate use drug.

Case Report

Written informed consent was obtained from the patient. A male patient was diagnosed with HCC at the age of 58 in 2018/08. He had a medical history of chronic hepatitis B, chronic hepatitis C and alcoholism. Advanced liver fibrosis was found during the first visit in 2018/07 and liver cirrhosis was found since 2021/06 using ultrasound. Hepatitis C had been cured at another hospital and hepatitis C virus RNA was negative when he visited our hospital; however, hepatitis B virus DNA remained positive (0.006 Meq/ml). He was found to have at least two HCC tumors in separate lobes of the liver in 2018/08 by two dynamic image studies and was then treated with chemoembolization. Alpha-fetoprotein (AFP) was 3 ng/ml and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) was 66 mAU/ml (normal <27.8) at the time of diagnosis (Figure 1A). Recurrent HCCs were found three months (2018/11) and two years (2020/07) after the first embolization. Chemoembolization was then repeated two more times. Remission was achieved and PIVKA-II returned to normal range.

Figure 1.

Clinical course and radiological findings of a patient with HCC treated with lenvatinib and ADI-PEG 20. (A) Timeline of clinical laboratory parameters, including serum calcium (Ca), HbA1c, phosphorus (P), creatinine (Cr), α-fetoprotein (AFP), PIVKA-II and glutamic pyruvic transaminase (GPT), during the treatment course. Major interventions are indicated, including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), lenvatinib (12 mg daily), ADI-PEG20 (36 mg/m² biweekly or tri-weekly), and meloxicam. The occurrence of lymph node (LN) metastasis and atrial fibrillation with rapid ventricular response (Af w RVR) are also annotated. (B) Computed tomography (CT) scans showing abdominal lymph node metastasis at different time points: CT1 (2021/06), CT2 (2023/02), and CT3 (2024/11). Only the image that contained the maximum size of the metastatic lymph node in each CT study is shown. Red arrowheads indicate the metastatic lymph node lesions.

The patient had diabetes and hypertension. Diabetes was treated with metformin and later with glipizide in combination. The treatments were shifted to linagliptin/glipizide since 2023/10 and linagliptin/repaglinide since 2024/03 because of elevated glycated hemoglobin up to 8.9% (maintained at 6-7% later) (Figure 1A). Hypertension was controlled by amlodipine and enalapril.

Unfortunately, follow-up computed tomography (CT) in 2021/06 revealed a newly enlarged para-aortic lymph node measuring 3.7 cm (Figure 1B). PIVKA-II elevated to 65 mAU/ml. Under the impression of HCC distant metastasis (BCLC stage C), lenvatinib (12 mg/day) was administered starting in 2021/06 (Figure 1A). Lenvatinib was selected instead of standard-of-care immuno-oncology (IO) combinations-specifically atezolizumab plus bevacizumab or durvalumab plus tremelimumab-because, at the time of diagnosis of distant metastasis, immunotherapy for HCC was not yet fully reimbursed by the National Health Insurance program in Taiwan. Additionally, the patient had a history of chronic joint pain, which could potentially increase concern for immune-related adverse events. In our previous study, we reported an association between ADI-PEG 20 and the rs6025211 genotype with survival outcomes, showing that patients with the rs6025211-CC genotype had better survival outcomes than those with the rs6025211-TT or rs6025211-TC genotypes (8). Genotyping in the present case was performed according to the methodology described in that study (8). Genomic DNA was isolated from the patient’s blood samples using the QIAamp DNA Mini Kit (#51306; QIAGEN, Redwood City, CA, USA). Nested PCR followed by DNA sequencing was then performed to determine the genotypes of rs6025211, which revealed that the patient carried the favorable SNP genotype (rs6025211-CC). Based on this evidence, ADI-PEG 20 was subsequently administered. After approval by local Institutional Review Board (IRB) and Ministry of Health and Welfare (MOHW), Taiwan, ADI-PEG 20 36 mg/m² per week was also provided by Polaris Pharmaceuticals (Taipei, Taiwan) in 2021/11 (Figure 1A). The combination treatment was used from 2021/11 to 2023/07, and the patient’s condition was stable. He tolerated the dosages very well with no recorded side effects during this period of time, except for slow elevation of creatinine from 1.29 to 1.4 mg/ml (Figure 1A), which was considered related to diabetes and hypertension. Lymph node decreased from 3.7 cm progressively to 1.7 cm (partial response). PIVKA-II reduced to 31 mAU/ml in 2022/11.

However, in 2023/7, exertional dyspnea developed. The anticancer treatments were then hold and he was referred to cardiologist for evaluation. Atrial fibrillation with rapid ventricular response was diagnosed. Pericardial effusion, bi-atrial enlargement, left ventricular dilatation, and mitral/tricuspid regurgitation, were found using cardiac ultrasound. Under the impression of pericarditis and endocarditis with unknown etiology, only diuretics were used, resulting in stabilized condition, with disappearance of pericardial effusion and no subjective symptom. Nevertheless, deterioration of renal function was found with creatinine elevated from 1.65 to 4.67 mg/ml before and after this episode. After discussion with the patient, only ADI-PEG 20 monotherapy was resumed but in lower administration frequency. It was given every 2 to 3 weeks from 2023/10 to 2025/07. The patient’s condition remained stable and creatinine ranged between 4.67 and 6.05 mg/dl up and down during this period of time.

In 2024/12, two recurrent tumors were found (2.16 cm in Segment 5 and 1.73 cm in Segment 6) in liver using CT and ultrasound (Figure 1B). Aspiration cytology revealed HCC Edmondson-Steiner grade 2. Radiofrequency ablation (RFA) was performed and later image examinations showed he was negative for liver tumors, while the lymph node metastasis remained 1.7 cm (Figure 1A and B).

In 2025/07, creatinine raised to 8.3 mg/dl and then back to 7.12 mg/dl, because the patient had shoulder pain and received Meloxicam treatment by local doctor (Figure 1A). ADI-PEG 20 treatment was hold, waiting for nephrologist assessment. The patient was put under supportive treatment. In the last follow-up in January 2026, the CT image showed complete disappearance of the metastatic lymph node with no viable tumor in the liver (complete remission). The patient experienced no subjective symptoms. The creatinine levels ranged between5-6 mg/dl during the follow-up period. The patient is currently not on any anticancer treatment.

Discussion

Late-stage liver cancer with lymph node metastasis is generally associated with a very poor prognosis, as metastatic lymph node is difficult to be treated. This patient with advanced HCC and multiple comorbidities achieved complete remission using a combination of a TKI (lenvatinib) and an arginine depletion drug (ADI-PEG 20). However, given the single-case nature of this report, conclusions regarding safety and efficacy cannot be generalized. Moreover, the observed long-term disease control cannot be solely attributed to the combination of lenvatinib and ADI-PEG 20, as the patient received multiple prior and subsequent interventions, including transarterial chemoembolization (TACE), treatment interruption, ADI-PEG 20 monotherapy, and radiofrequency ablation, which may also have contributed to the clinical outcome. In addition, other factors, such as relatively indolent tumor biology or delayed therapeutic effects from previous treatments, cannot be excluded. Therefore, this case should be interpreted as a clinical observation that may generate hypotheses rather than definitive evidence of treatment efficacy. However, complete disappearance of the metastatic lymph node is not likely caused by delayed effects of the previous treatments.

Previous studies have shown that the efficacy and tolerability of lenvatinib are influenced by liver reserve function, nutritional status, and treatment-related adverse events (10-12). Patients with preserved liver function and adequate nutritional status were more likely to maintain long-term treatment and achieve better clinical outcomes. In addition, renal adverse events such as proteinuria and renal impairment have been reported during lenvatinib therapy, highlighting the importance of close monitoring during treatment. In our case, despite multiple comorbidities and progressive renal dysfunction, long-term disease control was achieved with individualized treatment adjustment and careful supportive management. Lenvatinib is a standard first-line systemic treatment for unresectable HCC, but resistance often occurs after long-term use. In contrast, ADI-PEG 20 exploits the metabolic vulnerability of arginine auxotrophy in ASS1-negative tumors. Previous reports have shown that arginine deprivation may potentiate the efficacy of TKIs by regulating angiogenic, autophagy, and tumor metabolism pathways (13). In our case, the observed partial response of lymph node metastasis and prolonged disease control may suggest a possible interaction between metabolic and targeted therapies.

Despite these promising responses, the disease relapsed in the liver during a continued ADI-PEG20 monotherapy with dose adjustments, indicating that mono-therapy may not be a strategy against local relapse. This highlights the relevance of adequate treatment intensity and raises the question whether continued combined treatment could have achieved more sustainable disease control. Comorbidities, including diabetes mellitus, hypertension, atrial fibrillation, and chronic kidney disease, complicated clinical management. Renal dysfunction was observed during the treatment course and likely reflected a combination of pre-existing conditions and potential treatment-related effects. Although the patient’s underlying diseases may have contributed to the progressive decline in renal function, treatment-related toxicity cannot be excluded. Lenvatinib, a tyrosine kinase inhibitor, has been associated with renal adverse effects such as proteinuria and renal impairment. In addition, while ADI-PEG 20 is generally well tolerated, its potential impact on renal function should also be considered. Overall, the deterioration in renal function is likely multifactorial, involving both comorbidities and possible drug-related effects. Careful monitoring is therefore essential when administering these therapies in patients with complex medical conditions. Notably, renal impairment influenced treatment selection and required dose adjustments, underscoring the importance of an individualized therapeutic approach.

Conclusion

In summary, the combination of lenvatinib and ADI-PEG 20 appeared to be tolerable in this patient, resulting in reduction of the size of metastatic lymph node and maintenance of tumor-free status in the liver. ADI-PEG 20 monotherapy in reduced frequency in this patient also seemed to be safe, but not preventive of local recurrence. This patient with HCC survived more than four years after BCLC stage C was documented (and still doing well). However, he had multiple underlying conditions including diabetes, hypertension, atrial fibrillation, and renal function deterioration, which complicated his treatment. Given the single-case nature of this report and the presence of multiple prior and subsequent treatments, the therapeutic contribution of the combination therapy cannot be definitively determined. Larger prospective studies are required to validate the potential role of this treatment strategy in advanced HCC.

Conflicts of Interest

Dr Chau-Ting Yeh has served as a clinical consultant of Polaris Pharmaceuticals. The Authors declare that no financial support was provided by Polaris Pharmaceuticals for this study, and the company had no role in the study design, data collection, analysis, or interpretation. Polaris Pharmaceuticals was not involved in the writing of this manuscript or in the decision to submit it for publication. The Authors declare no other conflicts of interest.

Authors’ Contributions

Conceptualization: Jen Yu, Yang-Hsiang Lin, Chau-Ting Yeh and Chih-Lang Lin; Methodology: Chau-Ting Yeh; Data curation: Jen Yu and Chau-Ting Yeh; Formal analysis: Chau-Ting Yeh; Supervision: Chih-Lang Lin; Funding acquisition: Chih-Lang Lin; Writing - original draft: Jen Yu and Yang-Hsiang Lin; Writing - review & editing: Chih-Lang Lin.

Acknowledgements

The Authors acknowledge with gratitude the technical and administrative support from the entire team at the Liver Research Center of Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Funding

This work was supported by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPG2Q0051 to CLL) and from the National Science and Technology Council (NSTC 114-2314-B-816-001- to CLL).

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.