超过70%的肝细胞癌（HCC）患者在晚期被诊断，失去了进行根治手术的机会。靶向酪氨酸激酶抑制剂（TKIs）与抗程序性细胞死亡蛋白-1（PD-1）抗体的联合治疗在晚期HCC的一线和二线治疗中取得了较高的肿瘤反应率。然而，目前仅有少量研究对TKIs加PD-1抗体是否能够将不可切除的中晚期HCC转变为可切除性疾病进行了前瞻性评估。本单臂2期临床试验纳入了未接受系统治疗的有不可切除的巴塞罗那肝癌分期B或C期的成年患者。患者口服利瑞那他尼1次/天，并每3周静脉注射PD-1抗体（1个周期）。在第4个周期之前和每两个周期后评估肿瘤反应性和可切除性。主要终点是根据研究者评估的转化成功率。次要终点包括根据修改版RECIST（mRECIST）和实体瘤反应评价标准1.1（RECIST 1.1）独立成像评估（IIR）的客观反应率（ORR）、根据mRECIST在IIR的无进展生存（PFS）和12个月无复发生存（RFS）率、R0切除率、总生存（OS）和安全性。生物标志物将作为探索性目标进行评估。共纳入了56名符合条件的患者，其中53例（94.6%）有大血管侵犯，16例（28.6%）有肝外转移。中位随访时间为23.5个月。主要终点结果显示，转化成功率为55.4%（31/56）。根据mRECIST的ORR为53.6%，根据RECIST 1.1的ORR为44.6%。PFS中位数为8.9个月，OS中位数为23.9个月。在31名成功转化的患者中，21名患者进行了手术，R0切除率为85.7%，病理完全缓解率为38.1%，12个月RFS率为47.6%。有42.9%的患者发生≥3级的与治疗相关的不良事件。对术前样本进行的肿瘤免疫微环境分析显示，与非应答者相比，应答者中CD8+T细胞明显富集（p=0.03）。利瑞那他尼加PD-1抗体的转化治疗在不可切除HCC中表现出良好的疗效和可耐受的安全性。术前存在的CD8+细胞被确定为对该方案的疗效反应的有效生物标志物。 Chinese Clinical Trial Registry，ChiCTR1900023914. ©作者（或雇主）2023年。在CC BY-NC下允许再使用。不得进行商业再利用。详见权限和许可。由BMJ出版。

Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease.This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives.Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8+ T cells (p=0.03) in responders versus non-responders.Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8+ cells are identified as a promising biomarker for response to this regimen.Chinese Clinical Trial Registry, ChiCTR1900023914.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.