Regorafenib After Failure of Lenvatinib in Patients With Unresectable HCC: The RELEVANT-HCC Trial

Regorafenib After Failure of Lenvatinib in Patients With Unresectable HCC: A Phase 2 RELEVANT-HCC Trial

The purpose of this clinical trial is to evaluate the efficacy and safety of regorafenib as a subsequent therapy for patients with hepatocellular carcinoma (HCC) who have failed prior lenvatinib treatment. This investigational study aims to assess the therapeutic benefits and safety profile of regorafenib in patients whose disease has progressed following the use of lenvatinib, a targeted therapy for hepatocellular carcinoma

Lenvatinib is currently recognized as a standard first-line treatment for advanced hepatocellular carcinoma (HCC), having demonstrated non-inferiority to sorafenib in a phase 3 randomized clinical trial. It is also utilized as a second-line option following the failure of immunotherapy-based regimens. However, unlike sorafenib, there is a lack of prospective data regarding subsequent therapies following lenvatinib failure, which poses significant challenges in clinical decision-making.

Regorafenib has demonstrated clinical efficacy and significant survival benefits compared to placebo in the RESORCE trial as a second-line treatment after sorafenib for Child-Pugh class A patients. Nevertheless, evidence supporting its use specifically in patients who have failed lenvatinib remains insufficient.

This multicenter, single-arm, phase 2 study is designed to evaluate the efficacy and safety of regorafenib as a subsequent therapy for patients with unresectable HCC who have experienced disease progression or unacceptable toxicity during prior treatment with lenvatinib.

Enrolled participants will receive regorafenib orally. The starting dose for Cycle 1 will be determined by the baseline Child-Pugh classification (160 mg once daily for Child-Pugh A; 120 mg once daily for Child-Pugh B). From Cycle 2 onwards, patients will maintain a standard regimen of 3 weeks on and 1 week off at the maximum tolerated dose. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The study will assess key efficacy endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR), alongside comprehensive safety evaluations.

Inclusion Criteria:

1. Signed informed consent form.

2. Age ≥ 19 years at the time of signing the informed consent form.

3. Diagnosis of hepatocellular carcinoma (HCC) confirmed histologically or clinically according to the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines.

4. Patients with unresectable HCC who have experienced disease progression or treatment discontinuation due to toxicity during prior treatment with lenvatinib.

5. Presence of at least one measurable target lesion according to RECIST v1.1.

6. Child-Pugh classification A or B7 (score 7).

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

8. Adequate hematologic and end-organ function defined by the following laboratory test results obtained within 14 days prior to testing (or enrollment):

   • Hemoglobin ≥ 8.5 g/dL
   • Absolute neutrophil count (ANC) ≥ 1,200/mm³
   • Platelet count ≥ 60,000/μL
   • Total bilirubin < 3.5 mg/dL
   • Serum albumin ≥ 2.5 g/dL
   • AST and ALT ≤ 7 × upper limit of normal (ULN)
   • Prothrombin time (INR ≤ 1.8 × ULN)
   • Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault equation)

9. Virological status of hepatitis confirmed and recorded through HBV and HCV screening.

   • Participants with HBV or HCV infection must be receiving antiviral therapy according to institutional guidelines.

10. Women of childbearing potential must agree to maintain abstinence or use effective contraception (with an annual failure rate of < 1%) from the time of signing the informed consent until at least 6 months after the last dose of the study drug. Male participants must agree to maintain abstinence or use effective contraception (with an annual failure rate of < 1%) and refrain from sperm donation from the time of signing the informed consent until at least 6 months after the last dose of the study drug.

Exclusion Criteria:

1. Albumin-bilirubin (ALBI) grade 3.
2. Fibrolamellar carcinoma or sarcomatoid carcinoma.
3. Prior treatment with regorafenib.
4. History of allogeneic stem cell transplantation or solid organ transplantation.
5. Active brain metastases or leptomeningeal metastases.
6. History of malignancy other than hepatocellular carcinoma (HCC) within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year survival rate > 90%).
7. Severe cardiovascular disease within 3 months prior to the start of study therapy (e.g., New York Heart Association [NYHA] Class II or higher heart disease, myocardial infarction, or cerebrovascular accident); uncontrolled serious medical comorbidities, including unstable arrhythmia or unstable angina; or other significant medical conditions or abnormal findings that, in the opinion of the investigator, may increase the risk associated with study participation.
8. Female participants who are pregnant or breastfeeding, or male or female participants of reproductive potential who are unwilling to use effective contraception from screening until 6 months after the last dose of the study drug.
9. Participants deemed by the investigator to be unlikely to comply with study procedures, restrictions, and requirements.
10. Patients who have received locoregional therapy (e.g., radiofrequency ablation [RFA], microwave ablation [MWA], transarterial chemoembolization [TACE], transarterial radioembolization [TARE], transarterial embolization [TAE], radiation therapy, etc.) after discontinuation of lenvatinib treatment.