Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial PMID: 38820549

Target-related Cytokines

2026-09-23

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial

JAMA. 2024 Aug 20;332(7):561-570. doi: 10.1001/jama.2024.10613.

HARMONi-A Study Investigators , Wenfeng Fang ¹ , Yuanyuan Zhao ¹ , Yongzhong Luo ² , Runxiang Yang ³ , Yan Huang ¹ , Zhiyong He ⁴ , Hui Zhao ⁵ , Mingjun Li ⁶ , Kai Li ⁷ , Qibing Song ⁸ , Xiaobo Du ⁹ , Yulan Sun ¹⁰ , Wei Li ¹¹ , Fei Xu ¹² , Zhiyu Wang ¹³ , Kunning Yang ¹⁴ , Yun Fan ¹⁵ , Baogang Liu ¹⁶ , Hongyun Zhao ¹ , Ying Hu ¹⁷ , Li Jia ¹⁸ , Shen Xu ¹⁹ , Tienan Yi ²⁰ , Dongqing Lv ²¹ , Haitao Lan ²² , Mengxia Li ²³ , Wenhua Liang ²⁴ , Yongsheng Wang ²⁵ , Hui Yang ²⁶ , Yuming Jia ²⁷ , Yuan Chen ²⁸ , Junguo Lu ²⁹ , Jifeng Feng ³⁰ , Chunling Liu ³¹ , Ming Zhou ³² , Jianya Zhou ³³ , Xianling Liu ³⁴ , Ningning Zhou ¹ , Ming He ¹³ , Xiaorong Dong ³⁵ , Hualin Chen ³⁶ , Yongxing Chen ³⁷ , Haichuan Su ³⁸ , Xiaoling Li ³⁹ , Zhihong Zhang ⁴⁰ , Lei Yang ⁴¹ , Ying Cheng ⁴² , Likun Chen ¹ , Xue Hou ¹ , Yu Zhang ⁴³ , Jun Guo ⁴⁴ , Zhen Wang ⁴⁵ , Hong Lu ⁴⁶ , Di Wu ⁴⁷ , Weineng Feng ⁴⁸ , Wen Li ⁴⁹ , Jianan Huang ⁵⁰ , Yan Wang ⁵¹ , Xia Song ⁵² , Jiewen Peng ⁵³ , Laiyu Liu ⁵⁴ , Yubiao Guo ⁵⁵ , Wenting Li ⁵⁶ , Dongmei Lu ⁵⁶ , Mingxiu Hu ⁵⁶ , Zhongmin Maxwell Wang ⁵⁶ , Baiyong Li ⁵⁶ , Michelle Xia ⁵⁶ , Li Zhang ¹

Affiliations

1. Sun Yat-sen University Cancer Center, Guangzhou, China.
2. Hunan Cancer Hospital, Changsha, China.
3. Yunnan Cancer Hospital, Kunming, China.
4. Fujian Provincial Tumor Hospital, Fuzhou, China.
5. The Second Hospital of Anhui Medical University, Hefei, China.
6. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
7. Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
8. Renmin Hospital of Wuhan University, Wuhan, China.
9. Mianyang Central Hospital, Mianyang, China.
10. Shandong Cancer Prevention and Treatment Institute, Jinan, China.
11. The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
12. The First Affiliated Hospital of Nanchang University, Nanchang, China.
13. The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
14. Weifang No. 2 People's Hospital, Weifang, China.
15. Zhejiang Cancer Hospital, Hangzhou, China.
16. Harbin Medical University Cancer Hospital, Harbin, China.
17. Beijing Chest Hospital, Capital Medical University, Beijing, China.
18. Yuncheng Central Hospital of Shanxi Province, Yuncheng, China.
19. Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou, China.
20. Xiangyang Central Hospital, Xiangyang, China.
21. Taizhou Municipal Hospital, Taizhou, China.
22. Sichuan Provincial People's Hospital, Chengdu, China.
23. Army Medical Center of Chinese People's Liberation Army, Chongqing, China.
24. The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
25. West China Hospital of Sichuan University, Chengdu, China.
26. The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China.
27. Yibin Second People's Hospital, Yibin, China.
28. Tongji Hospital of Tongji Medical College of Hust, Wuhan, China.
29. Nantong Tumor Hospital, Nantong, China.
30. Jiangsu Cancer Hospital, Nanjing, China.
31. Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China.
32. Affiliated Cancer Hospital and Institution of Guangzhou Medical University, Guangzhou, China.
33. The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
34. The Second Xiangya Hospital of Central South University, Changsha, China.
35. Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.
36. Affiliated Hospital of Guangdong Medical University, Guangzhou, China.
37. Hainan General Hospital, Haikou, China.
38. Tangdu Hospital of the Fourth Military Medical University, Xi'an, China.
39. Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China.
40. Anhui Provincial Cancer Hospital, Hefei, China.
41. Gansu Provincial Cancer Hospital, Lanzhou, China.
42. Jilin Cancer Hospital, Changchun, China.
43. Nanjing Chest Hospital, Nanjing, China.
44. Xingtai People's Hospital, Xingtai, China.
45. Linyi Cancer Hospital, Linyi, China.
46. Huaihe Hospital of Henan University, Kaifeng, China.
47. Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University), Shenzhen, China.
48. The First People's Hospital of Foshan, Foshan, China.
49. The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.
50. The First Affiliated Hospital of Soochow University, Suzhou, China.
51. General Hospital of Ningxia Medical University, Yinchuan, China.
52. Shanxi Cancer Hospital, Taiyuan, China.
53. Zhongshan City People's Hospital, Zhongshan, China.
54. Nanfang Hospital Nanfang Medical University, Guangzhou, China.
55. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
56. Akeso Biopharma, Inc, Zhongshan, China.

Abstract

Importance: For patients with Non-Small Cell Lung Cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited.

Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic Non-Small Cell Lung Cancer with the epidermal growth factor receptor (EGFR) variant.

Design, setting, and participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled.

Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed.

Main outcomes and measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported.

Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group.

Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated Non-Small Cell Lung Cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT05184712.