Neoadjuvant Tislelizumab-Lenvatinib vs Surgery Alone in Stage Ia HCC With Narrow Margin

A Phase II Study Comparing Neoadjuvant Tislelizumab Plus Lenvatinib Followed by Surgery Versus Surgery Alone in Patients With Stage Ia Hepatocellular Carcinoma and an Anticipated Narrow Surgical Margin

Postoperative recurrence remains a major limitation to long-term survival in hepatocellular carcinoma (HCC). In addition, a narrow surgical margin is widely regarded as a risk factor for recurrence. Neoadjuvant therapy may represent a strategy to reduce the risk of recurrence, thereby improving long-term outcomes. Tislelizumab plus lenvatinib has demonstrated promising efficacy with manageable safety in advanced HCC. Therefore, we will conduct a phase II study to compare neoadjuvant tislelizumab plus lenvatinib followed by surgery versus surgery alone in patients with stage IA HCC and an anticipated narrow surgical margin.

Inclusion Criteria:

1. The patient voluntarily participates in this study and provides written informed consent.

2. Age ≥18 years at the time of consent; male or female.

3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1.

4. Child-Pugh class A hepatic function.

5. Histologically/cytologically confirmed, or clinically diagnosed according to accepted diagnostic criteria, primary hepatocellular carcinoma (HCC), with a single tumor measuring 2-5 cm in greatest diameter (CNLC stage IA).

6. At enrollment, the lesion meets the criteria for surgically resectable disease per the Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2024 edition); and an anticipated narrow surgical margin (resection margin <1 cm) is expected due to tumor size and/or location, including any of the following:

   • Lesion adjacent to the main trunk of the portal vein or first-order branches;
   • Lesion adjacent to the inferior vena cava or the root of the hepatic veins;
   • Lesion located in the caudate lobe.

7. No prior local or systemic antitumor therapy for HCC.

8. At least one measurable lesion per RECIST v1.1.

9. Adequate function of major organs within 14 days prior to initiation of study treatment, as defined below:

(1) Hematology (no blood transfusion within 14 days before screening; no granulocyte colony-stimulating factor [G-CSF] use; and no pharmacologic correction except for hemoglobin): absolute neutrophil count (ANC) ≥1.5×10^9/L; platelets ≥75×10^9/L; hemoglobin ≥90 g/L.

(2) Serum chemistry (no albumin infusion within 14 days before screening): serum albumin ≥29 g/L; total bilirubin ≤1.5× upper limit of normal (ULN); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤5×ULN; serum creatinine ≤1.5×ULN or creatinine clearance (CrCl) >50 mL/min (Cockcroft-Gault formula below).

Male: CrCl = (140 - age) × weight / (72 × serum Cr) Female: CrCl = [(140 - age) × weight / (72 × serum Cr)] × 0.85 Weight in kg; serum Cr in mg/dL. (3) International normalized ratio (INR) ≤2.3, or prothrombin time (PT) prolongation ≤6 seconds above the institutional normal control.

(4) Urine protein <2+; if urine protein is ≥2+, a 24-hour urine protein quantification may be performed, and patients with 24-hour urine protein <1.0 g are eligible.

10. Viral hepatitis management:

• For patients with active hepatitis B virus (HBV) infection: HBV DNA must be <500 IU/mL (if the site reports in copies/mL only, <2,500 copies/mL), and the patient must have received anti-HBV therapy for at least 14 days before initiation of study treatment (per local standard of care, e.g., entecavir) and be willing to continue antiviral therapy throughout the study.

• Patients who are hepatitis C virus (HCV) RNA positive must receive antiviral therapy per local standard treatment guidelines, and liver function abnormalities must be no greater than CTCAE Grade 1.

  11. Contraception: 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; a negative serum or urine pregnancy test within 7 days prior to enrollment is required; women must not be breastfeeding. Male participants must agree to use effective contraception during the study and for 6 months after the end of the study.

  12. The participant is able and willing to comply with the protocol requirements and follow-up schedule.

Exclusion Criteria:

1. Known intrahepatic cholangiocarcinoma, sarcomatoid HCC, mixed-cell carcinoma, or fibrolamellar carcinoma; any other active malignancy concurrent with HCC or within the past 5 years, except for definitively treated localized tumors (e.g., basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, superficial bladder cancer, prostate carcinoma in situ, cervical carcinoma in situ, or breast carcinoma in situ).
2. Planned or prior solid-organ transplantation or allogeneic bone marrow transplantation (corneal transplantation is allowed).
3. Known hypersensitivity to macromolecular protein products, or known allergy to any excipients of tislelizumab.
4. Any active autoimmune disease or a history of autoimmune disease.
5. Use of immunosuppressive agents, or systemic or absorbable topical corticosteroid therapy for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent), that is ongoing within 2 weeks prior to enrollment.
6. Clinically symptomatic ascites or pleural effusion requiring therapeutic paracentesis, thoracentesis, or drainage.
7. Uncontrolled clinically significant cardiac symptoms or disease, including:

(1) New York Heart Association (NYHA) class II or higher heart failure; (2) Unstable angina; (3) Myocardial infarction within 1 year; (4) Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention.

8. Current (within the past 3 months) gastrointestinal conditions including esophageal varices, active gastric or duodenal ulcer, ulcerative colitis, portal hypertension, or active bleeding from unresected tumor(s), or any other condition judged by the investigator to pose a risk of gastrointestinal bleeding or perforation.

9. History or current evidence of severe bleeding (blood loss >30 mL within the past 3 months), hemoptysis (>5 mL of fresh blood within the past 4 weeks), or a thromboembolic event within the past 12 months (including stroke and/or transient ischemic attack).

10. Active infection, or fever of unknown origin >38.5°C during screening or prior to the first dose (fever judged by the investigator to be tumor-related is allowed).

11. Congenital or acquired immunodeficiency, such as HIV infection. 12. Receipt of a live attenuated vaccine within 4 weeks prior to administration of study treatment.

13. Use of traditional Chinese medicine with antitumor indications within 2 weeks prior to the first dose, or receipt of medications with immunomodulatory effects within 2 weeks prior to the first dose.

14. Known history of abuse of psychoactive drugs, alcoholism, or illicit drug use.

15. Ongoing treatment-related serious adverse events prior to enrollment in this study.

16. Any condition that, in the investigator's opinion, makes the participant unsuitable for the study, including factors that may necessitate premature discontinuation (e.g., other serious diseases [including psychiatric disorders] requiring concomitant treatment, severe laboratory abnormalities, or family/social circumstances that may compromise participant safety or interfere with data and specimen collection).