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

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.