Safety and efficacy of hepatic artery infusion chemotherapy (HAIC) or lenvatinib combined with sintilimab as neoadjuvant therapy for high recurrence risk resectable stage IB solitary hepatocellular carcinoma: A prospective, randomized, two-cohort, exploratory phase II clinical study.

565 Background: Neoadjuvant treatment is recommended for resectable hepatocellular carcinoma (HCC) with high risk of postoperative recurrence. But the optimal effective neoadjuvant treatment modality remains under investigation. This study aims to compare the safety and efficacy of lenvatinib combined with sintilimab versus HAIC as neoadjuvant therapy for resectable stage IB solitary hepatocellular carcinoma. Methods: This prospective, randomized, two-cohort, exploratory, phase II study (NCT05621499) enrolled patients (pts) with histologically confirmed resectable HCC. Pts with ECOG 0-1, Child Pugh A, and no prior treatment had at least one measurable lesion according to RECIST v1.1. The high risk of recurrence was defined by the investigators before surgery as stage Ib and solitary tumor with the largest diameter > 5cm. Eligible pts were randomly assigned to receive sintilimab 200 mg Q3W and lenvatinib 8 mg QD for 2 cycles (LEN+PD1) or HAIC-FOLFOX (oxaliplatin 85 mg/m 2 , LV 400 mg/m 2 , 5-FU 400 mg/m 2 bolus and then 2400 mg/m 2 as 24h continuous infusion) for 2 cycles (HAIC), and surgery was performed within 3-4 weeks after treatment. The primary endpoint was 1-year disease-free survival (DFS) rate. The secondary endpoints were incidence of microvascular invasion, pathological complete response (pCR) rate, major pathological response (MPR, defined as less than or equal to 10% viable tumor cells), objective response rate (ORR), 2-year DFS rate, 2-year overall survival (OS) rate, and safety. Results: As of August 2025, the recruitment was completed and 60 pts were 1:1 randomly assigned to LEN+PD1 group and HAIC group. 28 pts in LEN+PD1 group and 30 in HAIC group finished preoperative treatment. According to RECIST v1.1 and mRECIST, the ORR was 34.6% and 57.7% in LEN+PD1 group, 10.3% and 24.1% in HAIC group, respectively. 51 pts (LEN+PD1 group, n=24; HAIC group, n=27) underwent radical resection. The pCR and MPR (including pCR) rates were 37.5% and 45.8% in LEN+PD1 group, while the pCR and MPR rates were 3.7% and 7.4% in HAIC group. No grade≥3 adverse events were observed during neoadjuvant treatment period in either group. Currently, no significant differences in DFS were observed between the two groups. The DFS data remained immature, with follow-up ongoing. Conclusions: For resectable stage IB solitary HCC with high recurrence risk, two cycles of sintilimab plus lenvatinib as neoadjuvant therapy demonstrated better clinical and pathological responses than HAIC. Additionally, PD-1 inhibitor-based agents offer superior accessibility, making this regimen worthy of further promotion. Clinical trial information: NCT05621499 .