The goal of this clinical trial is to learn if lenvatinib or regorafenib can help treat people with advanced liver cancer (hepatocellular carcinoma, HCC) that cannot be removed with surgery after first treatment with immunotherapy-based drug combinations. It will also look at the safety of these treatments.

The main questions this study aims to answer are:

• How long lenvatinib can delay cancer growth in people with good liver function (Child-Pugh)A after dual immunotherapy
• How long people with reduced liver function (Child-Pugh B7-B8) live after treatment with lenvatinib or regorafenib after first-line immunotherapy-based combination treatment
• What side effects people experience during treatment
• How many people have their tumors shrink or disappear

The study has two parts:

In REVIVE-1, participants with Child-Pugh A liver function will receive lenvatinib.

In REVIVE-2, participants with Child-Pugh B7 to B8 liver function will receive either lenvatinib or regorafenib.

Participants will:

• take lenvatinib or regorafenib by mouth
• visit the clinic regularly for physical exams, blood and urine tests, and safety checks
• have computed tomography (CT) scans every 8 weeks to check their cancer
• be followed during and after treatment to assess outcomes and side effects

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Immune checkpoint inhibitor (ICI)-based combination therapies have become standard first-line treatments for patients with unresectable or metastatic HCC. Several clinical trials have demonstrated survival benefits with these regimens, including atezolizumab plus bevacizumab (IMbrave150), durvalumab plus tremelimumab (HIMALAYA), and nivolumab plus ipilimumab (CheckMate 9DW). As a result, immunotherapy-based combinations are widely used as first-line systemic treatment for advanced HCC.

Despite these advances, most patients eventually experience disease progression and require subsequent systemic therapy. However, prospective evidence regarding optimal second-line treatment after progression on ICI-based therapy remains limited. Multikinase inhibitors such as sorafenib, lenvatinib, and regorafenib were originally approved based on studies conducted before the widespread use of immunotherapy. Therefore, their role after failure of modern ICI-based regimens remains unclear.

In addition, most clinical trials in advanced HCC have primarily enrolled patients with preserved liver function (Child-Pugh A). Evidence for patients with Child-Pugh B liver function is limited, and prospective studies evaluating systemic therapies in this population are scarce.

The REVIVE study is a multicenter phase 2 clinical trial designed to evaluate the efficacy and safety of lenvatinib or regorafenib in patients with unresectable or metastatic hepatocellular carcinoma who have progressed after first-line immunotherapy-based combination therapy.

The study consists of two cohorts.

REVIVE-1 is a prospective, multicenter, single-arm phase 2 cohort evaluating lenvatinib in participants with Child-Pugh A liver function whose disease has progressed after first-line dual immune checkpoint inhibitor therapy.

REVIVE-2 is a multicenter, randomized, non-comparative phase 2 cohort evaluating lenvatinib or regorafenib in participants with Child-Pugh B7 to B8 liver function whose disease has progressed after first-line immunotherapy-based combination therapy.

This study aims to generate prospective evidence regarding the efficacy and safety of lenvatinib and regorafenib as second-line treatments after failure of immunotherapy-based therapy in advanced hepatocellular carcinoma, , particularly in settings where evidence remains limited, such as after dual ICI therapy and in patients with Child-Pugh B liver function.

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