Although atezolizumab-bevacizumab has been positioned as the standard first-line therapy in unresectable heptocellular carcinoma, eventually most patients progressed on this regimen. Despite of multiple drugs are approved for the management of unresectable hepatocellular carcinoma, only a few trials have been conducted to investigate their efficacy in the second-line setting after the progression on atezolizumab-bevacizumab. Lenvatinib is approved first-line multikinase inhibitor in unresectable hepatocellular carcinoma, but has not yet been investigated as second-line therapy in prospective study. In this single arm phase 2 study, the efficacy and safety of lenvatinib will be investigated for patients who progressed on first-line atezolizumab-bevacizumab.

Inclusion Criteria:

1. Diagnosis of HCC according to AASLD guidelines

2. Disease that is not amenable to a curative treatment (e.g. surgery, transplant, radiofrequency ablation)

3. Prior treatment with atezolizumab plus bevacizumab as first-line treatment for unresectable HCC

4. Progression after atezolizumab plus bevacizumab, the duration of these treatments must be 2 consecutive treatment cycles or more.

5. At least 1 RECIST v1.1 measurable untreated lesion

6. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the adverse events are clinically non-significant and/or stable on supportive therapy

7. Life expectancy of 12 weeks or longer

8. Age ≥ 19 years old

9. ECOG performance status of 0, 1

10. Adequate hematological function

    1. Absolute neutrophil count (ANC) ≥ 1.0 x109/L
    2. Platelets ≥ 75 x 109/L
    3. Hemoglobin ≥ 10 g/dL

11. Adequate renal function

    1. serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockroft-Gault equation) AND
    2. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g

12. Child-Pugh Score of 5 or 6

13. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L)

14. Serum albumin > 2 g/dL (> 20 g/L)

15. Alanine aminotransferase (ALT) < 3.0 upper limit of normal (ULN)

16. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection

17. Capable of understanding and complying with the protocol requirements and signed informed consent

18. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment

19. Females of child-bearing potential must be willing to use effective contraception during study and for 30 days after the last dose.

Exclusion Criteria:

1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma

2. Prior lenvatinib treatment

3. Prior systemic treatment for HCC, except for atezolizumab plus bevacizumab (i.e. lenvatinib must be second-line systemic treatment)

4. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization.

5. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

   a. Cardiovascular disorders including i. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.

   ii. Uncontrolled blood pressure (Systolic BP>150 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.

   iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months iv. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.

   b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation/bleeding: i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months

6. Major surgery within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before registration. Subjects with clinically relevant co d. Cavitating pulmonary lesion(s) or endobronchial disease

7. Moderate or severe ascites (Radiologically detected but clinically insignificant ascites is allowed)

8. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 21 days of registration

   * If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.

9. Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.

10. Previously identified allergy or hypersensitivity to components of the study treatment formulations

11. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).

12. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy

13. Electrolyte abnormalities that have not been corrected.

14. Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.

15. The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients.

16. Other clinically significant disorders that are judged by investigators to be unsuitable for the clinical trial

It will be determined after the analysis of the primary data.