Ivonescimab与pembrolizumab治疗PD-L1阳性非小细胞肺癌（HARMONi-2）：一项在中国进行的随机、双盲、3期研究，这一成果由同济大学周彩存课题组经过不懈努力而取得。该项研究成果发表在2025年3月8日出版的《柳叶刀》上。

背景:Ivonescimab是一种针对程序性细胞死亡蛋白1和血管内皮生长因子的双特异性抗体，在早期研究中为晚期非小细胞肺癌患者带来了有希望的临床结果。该课题组研究人员比较了ivonescimab和pembrolizumab在程序性细胞死亡配体-1（PD-L1）阳性晚期非小细胞肺癌患者中的疗效和安全性。

方法:HARMONi-2是一项在中国55家医院进行的随机、双盲、三期试验。符合条件的患者年龄为18岁或以上，局部晚期或转移性PD-L1阳性非小细胞肺癌，无致敏性表皮生长因子受体突变或间变性淋巴瘤激酶易位，东部肿瘤合作组表现状态为0或1。患者被随机分配（1:1），每3周静脉注射20mg /kg ivonescimab或200mg pembrolizumab。随机分组根据组织学、临床分期和PD-L1表达进行分层。主要终点是无进展生存期（PFS），由一个独立的放射学审查委员会根据RECIST v1.1在意向治疗人群中评估。

发现:在2022年11月9日至2023年8月26日期间，879名筛选的患者中有398名（45%）被随机分配接受Ivonescimab （n=198）或pembrolizumab （n=200）。在预先计划的中期分析中，Ivonescimab组的中位PFS明显长于派姆单抗组(11.1个月vs 5.8个月；分层风险比[HR] 0·51 [95% CI 0·38–0·69]；单侧P＜0.0001)。在预先指定的亚组中，包括PD-L1肿瘤比例评分（TPS）为1-49% （HR 0.54[95%CI 0.37-0.78]）和PD-L1 TPS为50%以上（HR 0.48[0.29 - 0.79]）的患者，ivonescimab比pembrolizumab的PFS获益大致一致。ivonescimab组58例（29%）患者和pembrolizumab组31例（16%）患者发生3级或以上治疗相关不良事件。197例ivonescimab患者中有14例（7%）和199例派姆单抗患者中有16例（8%）观察到3级或以上的免疫相关不良事件。Ivonescimab在鳞状和非鳞状非小细胞肺癌患者中均显示出可控的安全性。在鳞状细胞癌患者中，3级或更高级别的治疗相关不良事件在两组之间具有可比性。

研究结果表明，与派姆单抗相比，Ivonescimab显著改善了先前未经治疗的晚期PD-L1阳性非小细胞肺癌患者的PFS。因此，Ivonescimab可能是PD-L1阳性晚期非小细胞肺癌一线治疗的另一种选择。

附：英文原文

Title: Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China

Author: Anwen Xiong, Lei Wang, Jianhua Chen, Lin Wu, Baogang Liu, Jun Yao, Hua Zhong, Jie Li, Ying Cheng, Yulan Sun, Hui Ge, Jifang Yao, Qin Shi, Ming Zhou, Bolin Chen, Zhengxiang Han, Jinliang Wang, Qing Bu, Yanqiu Zhao, Junqiang Chen, Ligong Nie, Gaofeng Li, Xingya Li, Xinmin Yu, Yinghua Ji, Daqiang Sun, Xiaohong Ai, Qian Chu, Yu Lin, Jiqing Hao, Dingzhi Huang, Chengzhi Zhou, Jinlu Shan, Hongzhong Yang, Xuewen Liu, Jing Wang, Yanhong Shang, Xiaodong Mei, Jie Yang, Dongmei Lu, Mingxiu Hu, Zhongmin Maxwell Wang, Baiyong Li, Michelle Xia, Caicun Zhou

Issue&Volume: 2025/03/08

Abstract: Background

Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer.

Methods

HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later.

Findings

Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38–0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1–49% (HR 0·54 [95% CI 0·37–0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29–0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups.

Interpretation

Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer.

DOI: 10.1016/S0140-6736(24)02722-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02722-3/abstract