Lenvatinib or Regorafenib for Advanced Hepatocellular Carcinoma After Immunotherapy (REVIVE)

Inclusion Criteria:

* Age 19 years or older
* Diagnosis of hepatocellular carcinoma according to the American Association for the Study of Liver Diseases (AASLD) guidelines
* Unresectable or metastatic hepatocellular carcinoma not amenable to curative treatments such as surgical resection, liver transplantation, or local ablation
* Prior first-line systemic treatment with an immune checkpoint inhibitor-based combination regimen, defined as dual immune checkpoint inhibitor therapy (e.g., nivolumab plus ipilimumab or durvalumab plus tremelimumab) for the REVIVE-1 cohort, and immune checkpoint inhibitor-based combination therapy (e.g., atezolizumab plus bevacizumab, durvalumab plus tremelimumab, nivolumab plus ipilimumab, camrelizumab plus rivoceranib, or similar regimens) for the REVIVE-2 cohort; prior participation in clinical trials using these regimens is allowed
* Radiologic disease progression after at least 2 cycles of first-line treatment
* At least one measurable lesion according to RECIST v1.1
* Recovery from toxicities related to prior therapy to grade 1 or lower, except for clinically stable or non-clinically significant toxicities
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy of at least 12 weeks
* Absolute neutrophil count ≥ 1.0 × 10⁹/L
* Platelet count ≥ 75 × 10⁹/L for REVIVE-1 or ≥ 50 × 10⁹/L for REVIVE-2
* Hemoglobin ≥ 9 g/dL
* Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 40 mL/min
* Proteinuria \<3 g in 24-hour urine collection or urine protein-to-creatinine ratio \<3 mg/mg
* Child-Pugh A (score 5-6) for REVIVE-1 cohort or Child-Pugh B (score 7-8) for REVIVE-2 cohort
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
* Patients with chronic hepatitis B infection receiving appropriate antiviral therapy if HBV DNA positive
* QTcF ≤ 480 ms on electrocardiogram obtained within 21 days prior to enrollment
* Ability to understand and willingness to sign written informed consent
* Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for 4 months after the last dose

Exclusion Criteria:

* Known fibrolamellar hepatocellular carcinoma or mixed hepatocellular-cholangiocarcinoma
* Prior treatment with lenvatinib or regorafenib
* Receipt of two or more prior systemic treatment regimens for advanced hepatocellular carcinoma
* Known brain metastases or epidural disease unless adequately treated and clinically stable for at least 3 months
* Congestive heart failure greater than New York Heart Association class II
* Unstable angina, myocardial infarction, or stroke within 6 months
* Clinically significant cardiac arrhythmia requiring treatment
* Uncontrolled hypertension despite optimal medical therapy (systolic blood pressure \>150 mmHg or diastolic blood pressure \>90 mmHg)
* Active bleeding disorders or high risk of severe bleeding
* Tumor invasion of major blood vessels with high risk of bleeding
* Gastrointestinal conditions with high risk of perforation or fistula, including active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis, or recent gastrointestinal perforation
* Major surgery within 2 months before enrollment or incomplete recovery from surgery
* Moderate to severe ascites
* Known hypersensitivity to study drugs or their components
* Pregnancy or breastfeeding
* Diagnosis of another active malignancy requiring treatment within the past 2 years, except for adequately treated low-risk cancers
* Uncorrected electrolyte abnormalities
* Any medical condition that, in the investigator's judgment, would make the participant unsuitable for the study