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Background: The high recurrence rate after resection hinders the survival of patients with resectable hepatocellular carcinoma (HCC). Perioperative treatment has the potential to reduce the burden of micrometastasis and improve outcomes in many types of cancers. This study aims to evaluate the efficacy and safety of pembrolizumab plus lenvatinib as perioperative treatment in patients with resectable HCC. Methods: This was a single-arm, multi-center, phase II study (NCT05389527). Resectable HCC patients with a high risk of recurrence and naïve to systemic therapy received pembrolizumab 200 mg Q3W and lenvatinib 12 or 8 mg QD for 3 cycles followed by resection. Pembrolizumab and lenvatinib were given for up to 12 months after resection. The primary endpoint was major pathological reactions (MPR), defined as viable tumor cells in ≤ 50% of tumor bed. Secondary endpoints were complete pathological reactions (pCR), objective response rate (ORR, by RECIST v1.1 and mRECIST), disease-free survival (DFS), overall survival (OS), and safety. Results: Between Sep 30, 2022, and Aug 15, 2023, 43 patients were enrolled, and the enrollment has been completed. At the data cutoff (Dec 15, 2023), 42 patients have received at least one post-treatment radiological evaluation, ORR before surgery based on RECIST v1.1 and mRECIST were 11.9% and 47.6%, respectively. Forty (93.0%) patients completed neoadjuvant therapy and underwent R0 resection, of which 37 patients were pathologically confirmed HCC, 2 patients were combined HCC and intrahepatic cholangiocarcinoma (ICC), and 1 patient was ICC. Three patients did not proceed with planned surgery (1 patient with disease progression,1 with tumor rupture, and 1 refused surgery). Of the 37 patients with resected HCC, 14 (37.8%) patients achieved MPR, of which 3 (8.1%) patients achieved pCR. Eleven (29.7%) patients had significant tumor necrosis (necrosis tumor cells≥50% of tumor bed). The pathological response of all resected HCC lesions was evaluated in 39 patients. MPR was achieved in 15 (38.5%) patients, of which 3 (7.7%) patients achieved pCR. Twelve (30.8%) patients had significant tumor necrosis. Treatment-related adverse events (TRAE) of any grade during the neoadjuvant period occurred in 32 (74.4%) patients and grade 3 TRAEs occurred in 6 (14.0%) patients. No grade 4-5 TRAEs occurred. One patient delayed the surgery due to grade 3 immune-related hyperglycemia with ketoacidosis. The most common TRAEs of any grade during the neoadjuvant period were hypertension (10, 23.3%), stomatitis (5, 11.6%), and rash (4, 9.3%). The data of DFS and OS was immature, and follow-up is continuing. Conclusions: Pembrolizumab plus lenvatinib demonstrated promising anti-tumor efficacy with manageable toxicity in the neoadjuvant setting for resectable HCC. Clinical trial information: NCT05389527.