Regorafenib After Treatment Failure of First Line Immune Checkpoint Inhibitor Treatment in Advanced Hepatocellular Carcinoma Patients

Inclusion criteria

• Voluntarily signed written informed consent form.
• Age ≥19 years at the time of signing the informed consent form.
• Histologically or clinically diagnosed hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines.
• Disease progression or treatment discontinuation due to toxicity during first-line immune checkpoint inhibitor-based combination therapy (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, or nivolumab plus ipilimumab).
• At least one measurable target lesion according to RECIST v1.1.
• Child-Pugh score B (7-8).Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Adequate hematologic and end-organ function defined by the following laboratory results obtained within 14 days prior to the test (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
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤7 times upper limit of normal (ULN)
• Prothrombin time (INR ≤1.8 times ULN)
• Serum creatinine ≤2.0 times ULN or calculated creatinine clearance ≥40 mL/min (using the Cockcroft-Gault equation)

• Virologic status of hepatitis confirmed and documented by HBV and HCV screening tests.Patients with HBV or HCV infection must receive antiviral therapy according to institutional guidelines.

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

Exclusion criteria

• ALBI (Albumin-Bilirubin) grade 3.
• Fibrolamellar carcinoma or sarcomatoid carcinoma.
• Prior treatment with regorafenib.
• Within 2 weeks since the last administration of an immune checkpoint inhibitor.
• Receipt of any other systemic or locoregional therapy after the failure of first-line immune checkpoint inhibitor-based therapy.
• History of allogeneic stem cell transplantation or solid organ transplantation.
• Active brain metastases or leptomeningeal metastases.
• 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%).
• 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); unstable arrhythmia or unstable angina; history of gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months prior to the start of study therapy; active gastrointestinal disease with a high risk of bleeding or perforation (e.g., peptic ulcer, inflammatory bowel disease, diverticulitis, cholecystitis, acute pancreatitis); untreated high-risk varices or recent history of variceal bleeding (enrollment is permitted only if at least 28 days have passed since stabilization with standard treatment); prolonged QTc interval (> 450 ms for males, > 470 ms for females); systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical therapy; or other significant medical conditions or abnormal findings that, in the opinion of the investigator, may increase the risk associated with study participation.
• 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.
• Participants deemed by the investigator to be unlikely to comply with study procedures, restrictions, and requirements.
• 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 the discontinuation of immune checkpoint inhibitor-based combination therapy.