Bispecific Antibody Ivonescimab Added to Chemotherapy in <i>EGFR</i> -Variant Non–Small Cell Lung Cancer

Importance: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. Objective: To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Interventions: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. Main Outcomes and Measures: This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). Results: The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Conclusions and Relevance: Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

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Journal
JAMA
Published
2026-06-17
DOI
https://doi.org/10.1001/jama.2026.7745
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
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0.00
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article

Bispecific Antibody Ivonescimab Added to Chemotherapy in EGFR -Variant Non–Small Cell Lung Cancer

Hongyun Zhao, K P Li, Baogang Liu, Y ZHAO et al.
JAMA
Lung Cancer Treatments and Mutations
article

Bispecific Antibody Ivonescimab Added to Chemotherapy in EGFR -Variant Non–Small Cell Lung Cancer

Hongyun Zhao, K P Li, Baogang Liu, Y ZHAO, Haitao Lan, Zhongmin Maxwell Wang, Likun Chen, Yi Luo, Xin Liu, Dongqing Lv, Baiyong Li, Yi Tl, Junguo Lu, 冯卫能, Lu Liu, Wenting Li, Jianan Huang, Hui Yang, Xu Shen, Mengying Xia, Yuming Jia, Mingxiu Hu, L G Sun, Y Huang, X J Li, M Li, Michelle Y. Xia, Jiewen Peng, Wei Li, HARMONi-A Study Investigators, Zhiyu Wang, Ming He, Meiqi Shi, Hong Lu, Ying Hu, Yongxing Chen, Qibin Song, Dongmei Lu, Zhihong Zhang, Chunling Liu, Ming Zhou, Yulan Sun, Wenhua Liang, Wen Li, Li Jia, Ruiqiang Ma, Hualin Chen, Xiaorong Dong, Zhiyong He, Runxiang Yang, Yan Wang, Jun Guo, Di Wu, Yu Zhang, Ying Liu, Yun Fan, Xiaobo Du, Yubiao Guo, Kunning Yang, Xue Hou, Ningning Zhou, Lei Yang, Haichuan Su, Jianya Zhou, Yuan Chen, Xia Song, Li Zhang, Yongsheng Wang, Wenfeng Fang
article en

Abstract

Importance: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. Objective: To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Interventions: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. Main Outcomes and Measures: This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). Results: The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Conclusions and Relevance: Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

JAMA
Yuncheng University (CN), Hebei Medical University (CN), Central South University (CN), Nanchang University (CN), Army Medical University (CN), Xinjiang Medical University (CN), Harbin Medical University (CN), Sun Yat-sen University (CN), Guangdong Medical College (CN), Shanxi Medical University (CN), Capital Medical University (CN), Anhui Medical University (CN), Sichuan University (CN), Kunming Medical University (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Wuhan University (CN), Soochow University (CN), Henan University Huaihe Hospital and Huaihe Clinical Institute (CN), West China Hospital of Sichuan University (CN), Mianyang Central Hospital (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Jilin Province Tumor Hospital (CN), Zhejiang Cancer Hospital (CN), Tumor Hospital of Xinjiang Medical University (CN), Shanxi Provincial Cancer Hospital (CN), Nanfang Hospital (CN), Zhangzhou Municipal Hospital of Fujian Province (CN), Third Affiliated Hospital of Harbin Medical University (CN), Taizhou Municipal Hospital (CN), Nantong Tumor Hospital (CN), First People's Hospital of Foshan (CN), Fourth Hospital of Hebei Medical University (CN), Beijing Chest Hospital (CN), Zhongshan People's Hospital (CN), Weifang People's Hospital (CN), Gansu Provincial Hospital (CN), Xingtai People's Hospital (CN), Hunan Cancer Hospital (CN), Xiangyang Central Hospital (CN), Ningxia Medical University (CN), Hainan General Hospital (CN), Jiangsu Cancer Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Wuhan Union Hospital (CN), Anhui Provincial Hospital (CN), Sichuan Provincial Hospital of Traditional Chinese Medicine (CN), Ningxia Medical University General Hospital (CN), Renmin Hospital of Wuhan University (CN), Nanjing Chest Hospital (CN), Southern Medical University Shenzhen Hospital (CN), Sun Yat-sen University Cancer Center (CN), Fujian Provincial Cancer Hospital (CN), Second Affiliated Hospital of Anhui Medical University (CN), First Affiliated Hospital of Bengbu Medical College (CN), First Affiliated Hospital of Soochow University (CN), Second Xiangya Hospital of Central South University (CN), First Affiliated Hospital of Zhengzhou University (CN), Second People’s Hospital of Yibin (CN), Second Affiliated Hospital of Zhejiang University (CN), Affiliated Hospital of Guangdong Medical College Hospital (CN), Tongji Hospital (CN), Chinese People's Liberation Army (CN), Liaoning Cancer Hospital & Institute (CN), First Affiliated Hospital of Nanchang University (CN), Shenzhen Second People's Hospital (CN), First Affiliated Hospital Zhejiang University (CN), The Second Affiliated Hospital of Xiamen Medical College, Yuncheng Central Hospital, Guangzhou Medical University (CN), Air Force Medical University (CN)
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