A Study of Neoadjuvant Tislelizumab Plus Lenvatinib in Resectable HCC at High Risk of Recurrence

Tislelizumab Plus Lenvatinib as Neoadjuvant Therapy for Patients With Resectable HCC at High Risk of Recurrence: a Prospective, Multicenter, Randomized Controlled Phase III Study

This is a prospective, multicenter, randomized controlled, phase 3 study to explore the efficacy and safety of neoadjuvant tislelizumab plus lenvatinib in patients with resectable HCC at high risk of recurrence.

Study Overview

• Status: Not yet recruiting
• Conditions: HCC - Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Tislelizumab; Drug: Lenvatinib

Detailed Description

Hepatectomy remains the primary curative treatment for HCC. However, the high rate of postoperative recurrence significantly limits long-term survival. For patients with resectable HCC at high risk of recurrence, strategies to reduce postoperative recurrence and prolong overall survival are needed. Previous studies have reported that combination regimens of immune checkpoint inhibitors plus antiangiogenic agents show promising efficacy and safety in the perioperative setting for HCC. This prospective, multicenter, randomized controlled phase 3 study aims to evaluate the efficacy and safety of neoadjuvant tislelizumab plus lenvatinib in patients with resectable HCC at high risk of recurrence.

• Study Type: Interventional
• Enrollment (Estimated): 198
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily participates in this study and provides written informed consent.
2. Aged 18 to 75 years, inclusive; male or female.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
4. Child-Pugh class A liver function.
5. China Liver Cancer (CNLC) stage Ib to IIa.
6. Histologically/cytologically confirmed HCC, or clinically diagnosed primary hepatocellular carcinoma according to accepted diagnostic criteria, with lesions meeting the criteria for surgical resection as defined in the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 edition).
7. At least one measurable lesion per RECIST v1.1.
8. Estimated life expectancy ≥ 6 months.

9. Adequate major organ function as defined below, without transfusion of any blood components or use of hematopoietic growth factors within 14 days prior to assessment:

   • Hematology

     • Absolute neutrophil count (ANC) ≥ 1,500/mm³
     • Platelet count ≥ 100,000/mm³
     • Hemoglobin ≥ 5.6 mmol/L (9 g/dL)

   • Hepatic and renal function

     • Serum creatinine (SCr) ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula)
     • Total bilirubin (TBIL) ≤ 1.5 × ULN
     • AST and/or ALT ≤ 2.5 × ULN
     • Urine protein < 2+; if urine protein is ≥ 2+, 24-hour urine protein must be ≤ 1 g.

10. Adequate coagulation function, with no active bleeding and no thrombotic disease:

    • International normalized ratio (INR) ≤ 1.5 × ULN
    • Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
    • Prothrombin time (PT) ≤ 1.5 × ULN

11. Contraception requirements:

    • Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during study treatment and for 6 months after the last dose; must have a negative serum or urine pregnancy test within 7 days prior to enrollment and must not be breastfeeding.
    • Men with partners of childbearing potential must agree to use effective contraception during the study and for 6 months after the end of study treatment.
12. Demonstrates good compliance and is able/willing to complete required follow-up.

Exclusion Criteria:

1. Prior antitumor therapy for the current HCC, including radiotherapy, chemotherapy, concurrent chemoradiotherapy, other locoregional therapies (e.g., TACE, HAIC), or prior immunotherapy or targeted therapy.

   Note: Patients who developed recurrence after prior surgery may be enrolled; if prior postoperative adjuvant therapy was given, enrollment is allowed only if ≥6 months have elapsed since completion of adjuvant therapy.

2. Known cholangiocarcinoma, sarcomatoid HCC, mixed hepatocellular-cholangiocarcinoma, or fibrolamellar carcinoma; or any other active malignancy besides HCC within the past 5 years or concurrently (except cured basal cell carcinoma of the skin and cervical carcinoma in situ).
3. Hypertension inadequately controlled with antihypertensive therapy (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg); or history of hypertensive crisis or hypertensive encephalopathy.
4. Known hypersensitivity to macromolecular protein preparations, or known allergy to tislelizumab, lenvatinib, or any of their excipients.
5. Any active autoimmune disease or history of autoimmune disease (including but not limited to autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis/colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism). Patients with vitiligo, or asthma that completely resolved in childhood and requires no intervention in adulthood, may be eligible. Patients with asthma requiring medical intervention with bronchodilators are not eligible.
6. Use of immunosuppressive agents or systemic, or absorbable topical, corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) within 2 weeks prior to enrollment.
7. Symptomatic ascites or pleural effusion requiring therapeutic paracentesis or drainage.

8. Uncontrolled clinically significant cardiac symptoms or disease, including any of the following:

   • New York Heart Association (NYHA) class > II heart failure
   • Unstable angina
   • Myocardial infarction within 1 year
   • Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention
9. Within the past 3 months, presence of gastrointestinal conditions such as esophageal varices, active gastric or duodenal ulcer, ulcerative colitis, portal hypertension, or active bleeding from an unresected tumor; or any other condition judged by the investigator to confer a risk of gastrointestinal bleeding or perforation.
10. History of or current severe bleeding (within 3 months, bleeding volume >30 mL), hemoptysis (within 4 weeks, >5 mL fresh blood), or thromboembolic events within 12 months (including stroke and/or transient ischemic attack).
11. Active infection, or unexplained fever >38.5°C during screening or prior to first dose (fever judged by the investigator to be tumor-related is allowed).
12. Objective evidence of prior or current pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function.
13. Congenital or acquired immunodeficiency, such as HIV infection.
14. Receipt of a live vaccine within 4 weeks prior to study drug administration, or anticipated need for live vaccination during the study.
15. Known history of psychotropic drug abuse, alcoholism, or illicit drug use.
16. Anticipated inability or unwillingness to comply with required study procedures, assessments, and follow-up (including completion of standard-of-care evaluations not covered by the study), as judged by the investigator.
17. Any other condition that, in the investigator's judgment, makes the subject unsuitable for the study, including factors that may lead to premature study discontinuation (e.g., other serious diseases [including psychiatric disorders] requiring concomitant treatment, severe laboratory abnormalities, or family/social factors that may compromise subject safety or the collection of data and specimens).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Arm A; The Surgery-alone Group: the patients will receive surgery alone after enrollment and randomization.
Experimental: Arm B; The Neoadjuvant Treatment Group: the patients will receive 2 cycles of neoadjuvant tislelizumab plus lenvatinib after enrollment and randomization and receive surgery in sequence.	Drug: Tislelizumab; Tislelizumab, 200mg, IV, q3w. Treatment will be given in 3-week cycles for a total of 2 cycles.; Drug: Lenvatinib; Lenvatinib, 8mg for BW<60kg or 12mg for BW≥60kg, PO, qd. Treatment will be given in 3-week cycles for a total of 2 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
1-year event-free survival rate	1 year after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate		6 weeks after randomization
Disease control rate		6 weeks after randomization
Major pathologic response rate		10 weeks after randomization
1-year recurrence-free survival rate		1 year after randomization
2-year recurrence-free survival rate		2 year after randomization
Recurrence-free survival		36 months after randomization
Event-free survival		36 months after randomization
Overall survival		48 months after randomization
Incidence of surgery delay	The proportion of patients who were scheduled to undergo surgery who did not have surgery performed in a predetermined window	10 weeks after randomization
Incidence of treatment-related adverse events(graded per CTCAE v5.0)		10 weeks after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response prediction accuracy (AUC-ROC)	Exploratory endpoint: Area under the receiver operating characteristic curve for AI-predicted response probability	36 months after randomization

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 30, 2026
• Primary Completion (Estimated): January 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; lenvatinib; tislelizumab
• Other Study ID Numbers: 2512012685

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data that underlie the results reported in the primary publication (including data dictionaries) will be made available upon reasonable request to qualified researchers. Data will be available beginning 12 months after article publication, with no end date. Requestors will need to sign a data access agreement and obtain approval from an institutional review board.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No