2. Academic Validation
  3. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial

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

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.
PMID: 38820549 DOI: 10.1001/jama.2024.10613
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.

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