This is an open-label, multi-center, single-arm, phase II study to evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab as a neoadjuvant therapy in subjects with resectable hepatocellular carcinoma (HCC).

The recurrence rate of hepatocellular carcinoma (HCC) after curative surgery is high and the survival benefit is limited. Neoadjuvant therapy, by targeting the disseminated tumor cells before curative surgery, may lower the incidence of tumor recurrence. In KEYNOTE-524 study, lenvatinib plus pembrolizumab combination showed promising efficacy and manageable toxicity. This study will evaluate the efficacy and safety of lenvatinib in combination with pembrolizumab as a neoadjuvant therapy in subjects with resectable HCC.

Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically/cytologically or clinically (according to American Association for the Study of Liver Diseases (AASLD) criteria) confirmed diagnosis of HCC, excluding fibrolamellar sarcomatoid or mixed cholangiocarcinoma-hepatocellular carcinoma.

2. Have not received any locoregional or systemic treatment before enrolment. Patients had recurrence for more than 2 years after the previous surgery could be included.

3. Tumor within Milan criteria should be accompanied with microvascular invasion (judged by radionics nomogram of Fudan Zhongshan Hosp); Or beyond Milan criteria without extrahepatic metastasis.

4. Resectable disease as judged by a multidisciplinary treatment group.

5. Child-Pugh A.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 and performed within 7 days prior to date of enrolment.

7. In case of hepatitis B virus (HBV) positive (HBsAg (+)) subjects:

   • HBV DNA < 2000 IU/mL within 28 days before treatment; subjects received anti-HBV therapy should stay on the same therapy throughout study treatment.
   • Subjects with HBV DNA > 2000 IU/mL without anti-HBV therapy, should receive anti-HBV therapy and stay the same therapy throughout study treatment, and 2 days before treatment, the HBV DNA should decrease for at least 1 log.
   • Subjects with HBV DNA > 2000 IU/mL with anti-HBV therapy, should receive anti-HBV therapy and stay the same therapy throughout study treatment, and 2 days before treatment, the HBV DNA should decrease at least 1 log.

8. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week prior to the treatment.

9. Have measurable disease based on RECIST 1.1.

10. Have adequate organ function. Specimens collected within 7 days prior to start of study treatment.

11. Male participants: A male participant must agree to use a contraception of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

12. Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

13. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

Exclusion Criteria:

1. Imaging findings for HCC of clear invasion into the bile duct or portal vein invasion with Vp4.
2. Positive pregnancy test in female patients with childbearing potential within 72 hours prior to enrollment.
3. Prior anticancer treatment or any investigational agent.
4. Subjects having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will be ineligible.
5. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
6. New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months.
7. Prolongation of corrected QT (QTc , Fridericia formula) interval to >480 ms.
8. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
9. Bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring therapeutic international normalized ratio (INR) monitoring, eg, warfarin or similar agents. Treatment with low molecular weight heparin is permitted. Antiplatelet agents are prohibited throughout the study.
10. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
11. Subject is known to be positive for Human Immunodeficiency Virus (HIV).
12. Serious nonhealing wound, ulcer, or bone fracture.
13. History of solid organ or hematologic transplant.
14. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
15. Active, known or suspected autoimmune disease that has required systemic treatment in the past 2 years or a documented history of clinically severe autoimmune disease, or any other syndrome that requires systemic steroids or immunosuppressive agents, patients with hypothyroidism stable on hormone replacement, or type 1 diabetes on insulin replacement will not be excluded from the study.
16. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis or has a history of interstitial lung disease.
17. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.