New hope for liver cancer patients when immunotherapy stops working

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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