Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant
Authors:   HARMONi-A Study Investigators, Fang Wenfeng , Zhao Yuanyuan , Luo Yongzhong , Yang Runxiang , Huang Yan , He Zhiyong , Zhao Hui , Li Mingjun , Li Kai , Song Qibing , Du Xiaobo , Sun Yulan , Li Wei , Xu Fei , Wang Zhiyu , Yang Kunning , Fan Yun , Liu Baogang , Zhao Hongyun , Hu Ying , Jia Li , Xu Shen , Yi Tienan , Lv Dongqing , Lan Haitao , Li Mengxia , Liang Wenhua , Wang Yongsheng , Yang Hui , Jia Yuming , Chen Yuan , Lu Junguo , Feng Jifeng , Liu Chunling , Zhou Ming , Zhou Jianya , Liu Xianling , Zhou Ningning , He Ming , Dong Xiaorong , Chen Hualin , Chen Yongxing , Su Haichuan , Li Xiaoling , Zhang Zhihong , Yang Lei , Cheng Ying , Chen Likun , Hou Xue , Zhang Yu , Guo Jun , Wang Zhen , Lu Hong , Wu Di , Feng Weineng , Li Wen , Huang Jianan , Wang Yan , Song Xia , Peng Jiewen , Liu Laiyu , Guo Yubiao , Li Wenting , Lu Dongmei , Hu Mingxiu , Wang Zhongmin Maxwell , Li Baiyong , Xia Michelle , Zhang Li 
Published: May 2024

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 &amp;lt; .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