Journal Article

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

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

2025

Overview

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. 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. 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. 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. Akeso Biopharma.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Adverse events / Aged / Antibodies / Antibodies, Bispecific - administration & dosage / Antibodies, Bispecific - adverse effects / Antibodies, Bispecific - therapeutic use / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Agents, Immunological - adverse effects / Antineoplastic Agents, Immunological - therapeutic use / Apoptosis / B7-H1 Antigen - metabolism / Biotechnology / Bispecific antibodies / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - mortality / Carcinoma, Non-Small-Cell Lung - pathology / Cell death / Chemotherapy / China / Clinical trials / Double-Blind Method / Female / Growth factors / Health services / Histology / Humans / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Internal Medicine / Kinases / Ligands / Lung cancer / Lung diseases / Lung Neoplasms - drug therapy / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Lymphoma / Male / Metastases / Metastasis / Middle Aged / Monoclonal antibodies / Mutation / Non-small cell lung carcinoma / Patients / PD-1 protein / PD-L1 protein / Pembrolizumab / Pharmacology / Population studies / Progression-Free Survival / Protein-tyrosine kinase / Randomization / Safety management / Small cell lung carcinoma / Squamous cell carcinoma / Subgroups / Targeted cancer therapy / Translocation / Vascular endothelial growth factor