Sintilimab combined with lenvatinib versus hepatic artery infusion chemotherapy (HAIC) for neoadjuvant treatment of resectable hepatocellular carcinoma with high risk of recurrence: A prospective, two-arm, randomized, phase II clinical study.

564 Background: Neoadjuvant treatment is considered to effectively reduce the postoperative recurrence rate of resectable hepatocellular carcinoma (HCC) with a high risk of recurrence. But the optimal effective neoadjuvant treatment modality remains under investigation. This study aimed to compare the safety and efficacy of lenvatinib combined with sintilimab versus HAIC as neoadjuvant treatment for resectable HCC with multiple lesions. Methods: This study (NCT05519410) enrolled patients (pts) with resectable primary HCC who met at least one of the following risk factors, as assessed by the investigators before surgery: CNLC stage Ib (2-3 tumors with the maximum diameter ≤3cm) or CNLC stage IIa (2-3 tumors, biggest >3 cm in diameter). Pts with ECOG 0-1, Child Pugh A, and without prior anti-tumor treatment had at least one measurable lesion. 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, 68 pts were screened and 58 were randomized to LEN+PD1 group (n=28) and HAIC group (n=30), 25 and 28 pts underwent surgery in both groups, respectively. In LEN+PD1 and HAIC groups, 71.4% and 66.7% of pts had CNLC stage IIa. Confirmed ORR based on RECIST v1.1 and mRECIST were 0% and 28% in LEN+PD1 group, 10.7% and 17.9% in HAIC group, respectively. The pCR and MPR (including pCR) rates were 4.0% and 12.0% in LEN+PD1 group. However, no pts achieved complete or major pathological response in HAIC group. Postoperative complications occurred in 8.0% of pts in LEN+PD1 group versus 35.7% in HAIC group. No grade 3 or higher TRAEs occurred in both groups. The trend towards longer DFS was observed in LEN+PD1 group, the date are still under follow-up. Conclusions: Two cycles of neoadjuvant sintilimab plus lenvatinib exhibited better safety and efficacy in resectable HCC with high risk of postoperative recurrence compared with HAIC. Additionally, the superior accessibility of this regimen supports its further promotion. While the date of this study are encouraging, randomized controlled phase III trials are still required to further validate the long-term survival benefit and safety. Clinical trial information: NCT05519410 .