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

in Lancet (London, England) by 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

TLDR

  • Ivonescimab showed improved progression-free survival compared to pembrolizumab in patients with advanced PD-L1-positive NSCLC, with a manageable safety profile.

Abstract

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.

Overview

  • The study investigated the efficacy and safety of ivonescimab compared to pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) who were positive for programmed death-ligand 1 (PD-L1).
  • The study involved 398 patients who were randomly assigned to receive either ivonescimab or pembrolizumab, and the primary endpoint was progression-free survival (PFS) assessed by an independent radiographic review committee.
  • The study aimed to investigate whether ivonescimab could be a viable treatment option in the first-line setting for patients with advanced PD-L1-positive NSCLC.

Comparative Analysis & Findings

  • The study found that ivonescimab significantly improved PFS compared to pembrolizumab, with a median PFS of 11.1 months compared to 5.8 months (stratified hazard ratio, 0.51; 95% CI, 0.38-0.69).
  • The PFS benefit of ivonescimab was consistently observed across prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1-49% and TPS 50% or higher.
  • The safety profile of ivonescimab was comparable to pembrolizumab, with similar rates of immune-related adverse events (IRAEs) of grade 3 or higher observed in both groups.

Implications and Future Directions

  • The results suggest that ivonescimab may be a viable treatment option in the first-line setting for patients with advanced PD-L1-positive NSCLC.
  • Future studies are needed to further investigate the efficacy and safety of ivonescimab in larger populations and to compare its effectiveness to other existing treatments.
  • The study highlights the importance of continued research into the development of novel treatments for NSCLC, particularly for patients with PD-L1-positive disease.
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