SCI
21 June 2024
Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant
A Randomized Clinical Trial
（IF: JAMA, 120.7）
HARMONi-A Study Investigators; Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Xu F, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Feng J, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Cheng Y, Chen L, Hou X, Zhang Y, Guo J, Wang Z, Lu H, Wu D, Feng W, Li W, Huang J, Wang Y, Song X, Peng J, Liu L, Guo Y, Li W, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhang L. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA. 2024 May 31.
Corresponding Author: Li Zhang, MD, Sun Yat-sen University Cancer Center, Guangzhou, No. 651 Dong Feng Road E, Guangdong 510060, China (zhangli@sysucc.org.cn).
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.
对于在接受表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗，尤其是第三代TKIs期间疾病进展的非小细胞肺癌患者，最佳的治疗选择仍然有限。
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.
比较ivonescimab联合化疗与单独化疗对携带表皮生长因子受体（EGFR）变异的复发晚期或转移性非小细胞肺癌患者的疗效。
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.
从2022年1月至2022年11月共招募了322名符合条件的患者，在中国的55个中心进行了双盲、安慰剂对照、随机分配的三期试验。
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.
参与者每 3 周接受一次ivonescimab（n = 161）或安慰剂（n = 161）联合培美曲塞和卡铂治疗，共 4 个周期，随后接受ivonescimab联合培美曲塞或安慰剂联合培美曲塞进行维持治疗。
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.
主要终点是意向治疗人群的无进展生存期，由独立放射学审查委员会 (IRRC) 根据《实体肿瘤疗效评估标准》1.1 版进行评估。报告了第一次计划中期分析的结果。
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.
在ivonescimab和安慰剂组的322名入组患者中，中位年龄分别为59.6岁和59.4岁，女性患者比例分别为52.2%和50.9%。截至2023年3月10日，中位随访时间为7.89个月。ivonescimab组的中位无进展生存期为7.1个月（95% CI，5.9-8.7），而安慰剂组为4.8个月（95% CI，4.2-5.6）（差异为2.3个月；风险比[HR]，0.46 [95% CI，0.34-0.62]；P < .001）。预设的亚组分析显示，几乎所有亚组中接受ivonescimab治疗患者的无进展生存期均优于接受安慰剂的患者，包括在接受第三代EGFR-TKI治疗期间疾病进展的患者（HR，0.48 [95% CI，0.35-0.66]）和有脑转移的患者（HR，0.40 [95% CI，0.22-0.73]）。Ivonescimab组的客观缓解率为50.6%（95% CI，42.6%-58.6%），安慰剂组的为 35.4%（95% CI，28.0%-43.3%）（差异为 15.6% [95% CI，5.3%-26.0%]；P = .006）。中位总生存期数据尚未成熟；在数据截止时，已有69 名患者（21.4%）去世。Ivonescimab组有99名患者（61.5%）出现了3 级或更高级别的治疗引起的不良事件，安慰剂组有79名患者（49.1%）出现，其中最常见的是与化疗相关的不良事件。Ivonescimab组有10名患者（6.2%）出现 3 级或更高级别的免疫相关不良事件，安慰剂组有4名患者（2.5%）出现。 ivonescimab组有5名患者（3.1%）出现3级或更高级别的血管内皮生长因子相关不良事件，安慰剂组有4名患者（2.5%）出现。
Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non–small cell lung cancer.
Ivonescimab联合化疗显著改善了接受TKI治疗的NSCLC的无进展生存期，且安全性可耐受。
