Fostrox Plus Lenvatinib vs Lenvatinib in Advanced Hepatocellular Carcinoma After First-line Immunotherapy

Inclusion Criteria: 1. Patients with a diagnosis of locally advanced or unresectable metastatic HCC confirmed by radiology, histology, or cytology 2. Received at least 2 cycles of first-line systemic therapy with immunotherapy (IO) combination (atezolizumab + bevacizumab, ipilimumab + nivolumab, or durvalumab + tremelimumab), with radiologically confirmed disease progression 3. Patients with measurable lesion in the liver (at least one target lesion) according to RECIST v1.1 and mRECIST \- Patients who received prior local therapy (e.g., radiofrequency ablation, cryoablation, percutaneous ethanol or acetic acid injection, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1 4. Patients who are not amenable for curative surgery or locoregional therapy 5. ECOG performance status of 0 or 1 within 7 days prior to randomization 6. Life expectancy of at least 3 months 7. Subjects age ≥19 years at the time of signing the informed consent form (ICF) 8. Subjects who are capable of providing signed informed consent to comply with requirements and limitations described in the ICF and this protocol and express obvious and voluntary agreement prior to the start of the study 9. Subjects with adequate hematological function and hepatic function without using blood transfusion or growth factors within 7 days prior to randomization * Hemoglobin (Hb) ≥9.0 g/dL * Absolute neutrophil count (ANC) ≥1,500/μl * Platelet count ≥75,000/μl * Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) estimated by Cockcroft-Gault equation ≥60 mL/min * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5.0 x ULN * Serum total bilirubin ≤3.0 x ULN * International normalized ratio (INR) ≤1.5 or prothrombin time ≤1.5 x ULN * Activated partial thromboplastin time (aPTT) ≤1.5 x ULN 10. Child Pugh A within 7 days prior to randomization 11. Negative HIV test at screening 12. Documented hepatitis virus status for HBV and HCV confirmed at screening * For patients with active HBV: HBV DNA \<500 IU/mL during screening; initiation of antiviral therapy at least 14 days prior to randomization; willingness to continue antiviral therapy during the study * For patients with active or past HCV infection: confirmed negative viral load using HCV PCR * For patients with concurrent HBV and HCV infection: not eligible 13. Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤1 before participation, except alopecia 14. Patients with a prior history of gastric or esophageal variceal bleeding may be eligible if they have received appropriate treatment with no evidence of recurrent bleeding for at least 6 months, have no high-risk features on a recent endoscopy, and are currently assessed to be at low risk of bleeding. 15. Female subjects * Eligible if postmenopausal * Female patient who is a woman of childbearing potential (WOCBP) (post menarchal) who agrees to use a highly efficient method of contraception (a method with less than 1% failure rate \[e.g. sterilization, hormone implants, hormone injections, intrauterine devices, vasectomized partner, or combined birth control pills\]) from screening until at least 6 months after the last dose of study drug * WOCBP must have a negative urine pregnancy test at screening and negative urine pregnancy test within 72 hours before the first dose of study drug. * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Female patients must agree not to breast feed after the time of consent and for at least 6 months after the administration of the last dose of study drug. 16. Male subjects * Male patient who has had a successful vasectomy (confirmed azoospermia) * Male patient agrees to use effective contraception, including condom use, from screening until at least 3 months after the last dose of study drug (no sperm donation is allowed during the study period and for at least 3 months after study drug discontinuation) * Male patient with a female partner who is a WOCBP and is using a highly efficient method of contraception as described above Exclusion Criteria: 1. Patients who have received more than 1 prior systemic therapy (i.e., fostrox + lenvatinib or lenvatinib must be administered as second-line treatment) 2. Patients who have received first-line systemic therapy for locally advanced unresectable or metastatic HCC other than an IO combination 3. Patients who have received a prior TKI (e.g. lenvatinib, regorafenib, cabozantinib etc.) in the IO combination 4. Patients with a history of hypersensitivity to lenvatinib or any of its components (active ingredient or excipients) 5. Patients with fibrolamellar HCC, sarcomoid HCC, or a mix of HCC and intrahepatic cholangiocarcinoma (iCCA) 6. Patients with central nervous system metastasis 7. Patients with VP4 portal vein tumor thrombosis (PVTT) 8. Patients with significant cardiovascular disease within 3 months prior to randomization * New York Heart Association (NYHA) Class III or IV congestive heart failure * Unstable angina * Myocardial infarction * Cardiac arrhythmia associated with hemodynamic instability 9. Subjects with Corrected QT interval (QTcF) \>470 msec at Screening (corrected by Fridericia Formula) 10. Patients with prior allogeneic stem cell or solid organ transplantation 11. Patients with systemic infection requiring treatment including active tuberculosis within 14 days prior to the first dose of study drug (prophylactic oral antibiotics are permitted) 12. Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study 1