依沃西单抗联合化疗对比安慰剂联合化疗用于EGFR突变非小细胞肺癌经EGFR酪氨酸激酶抑制剂治疗后进展的患者(HARMONi):一项多中心、随机、双盲、III期试验
Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.
作者
作者单位
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- European Institute of Oncology IRCCS, Milan, Italy.
- Sun Yat-sen University Cancer Center, Guangzhou, China.
- British Columbia Cancer and University of British Columbia, Vancouver, BC, Canada.
- Complejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Spain.
- Hospital General Universitario Gregorio Marañón, Madrid, Spain.
- Moores Cancer Center, UC San Diego, San Diego, CA, USA.
- Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
- UHN Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
- Regina Elena National Cancer Institute, Rome, Italy.
- Institut Curie, Paris, France.
- Lung Unit, Royal Marsden Hospital, London, UK; Division of Clinical Studies, Institute of Cancer Research, London, UK.
- Hunan Cancer Hospital, Changsha, China.
- Akeso Biopharma, Zhongshan, China.
- Fujian Provincial Tumor Hospital, Fuzhou, China.
- The Second Hospital of Anhui Medical University, Hefei, China.
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- Renmin Hospital of Wuhan University, Wuhan, China.
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
- Service de Pneumologie, CHI Créteil, Créteil, France.
- Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
- Hospital Universitario A Coruña, Health Research Institute, Coruña, Spain.
- SCRI Oncology Partners, Rocky Mountain Cancer Centers, Lone Tree, CO, USA.
- Valkyrie Clinical Trials, Los Angeles, CA, USA.
- Virginia Cancer Specialists Research Institute, Fairfax, VA, USA; NEXT Oncology, Fairfax, VA, USA.
- Léon Bérard Cancer Center of Lyon, Lyon, France.
- UCI Health Chao Family Comprehensive Cancer Center, Orange, CA, USA.
- Summit Therapeutics, Palo Alto, CA, USA.
- UCLA Health, Los Angeles, CA, USA.
- Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: zhangli6@mail.sysu.edu.cn.
摘要
中文
依沃西单抗在非小细胞肺癌(NSCLC)中显示出临床疗效。我们旨在评估依沃西单抗联合化疗对比安慰剂联合化疗在接受第三代EGFR酪氨酸激酶抑制剂(TKI)治疗后疾病进展的晚期EGFR突变NSCLC患者中的疗效和安全性。HARMONi是一项随机、安慰剂对照、双盲、III期试验,在亚洲、欧洲和北美的114个癌症中心和医院进行。符合条件的患者年龄至少18岁(亚洲地区上限75岁),患有IIIB/IIIC或IV期非鳞状EGFR突变NSCLC,经第三代EGFR-TKI治疗后疾病进展,美国东部肿瘤协作组体能状态评分为0或1。患者通过中央交互式语音应答系统或交互式网络应答系统按1:1随机分配,接受依沃西单抗(20 mg/kg)或安慰剂联合培美曲塞(500 mg/m²)和卡铂(目标曲线下面积5 mg/mL·min)静脉给药,每3周一次。随机化按入组时脑转移状态和地理区域分层。主要终点是盲态独立放射学审查委员会评估的意向治疗人群的无进展生存期和总生存期。安全性在接受至少一剂试验治疗的患者中评估。本研究已在ClinicalTrials.gov注册(NCT06396065),已完成入组,正在继续治疗和随访。2022年1月25日至2024年10月1日期间,筛选了660名个体;其中438人入组并随机分配接受依沃西单抗联合化疗或安慰剂联合化疗(每组219人)。入组患者中,257例(59%)为女性,181例(41%)为男性;306例(70%)报告种族为亚洲人,105例(24%)为白人。中位随访22.3个月(95%CI 21.5-23.0)时,345例患者中发生了275例进展或死亡事件(依沃西单抗联合化疗组172例患者中129例事件,安慰剂联合化疗组173例患者中146例事件)。依沃西单抗联合化疗组的中位无进展生存期为6.8个月(95%CI 5.7-7.1),安慰剂联合化疗组为4.4个月(4.1-5.5)(风险比[HR]0.52;95%CI 0.41-0.66;p<0.0001)。中位随访29.7个月(95%CI 27.7-31.0)时,438例患者中发生262例死亡(依沃西单抗联合化疗组122例,安慰剂联合化疗组140例)。依沃西单抗联合化疗组的中位总生存期为16.8个月(14.3-19.0),安慰剂联合化疗组为14.0个月(12.8-15.7)(HR 0.79;0.62-1.01)。依沃西单抗联合化疗组与安慰剂联合化疗组最常见的3-4级治疗相关不良事件为中性粒细胞计数降低(42/218[19%]对36/218[17%])、白细胞计数降低(28/218[13%]对24/218[11%])、血小板计数降低(27/218[12%]对14/218[6%])和贫血(22/218[10%]对27/218[12%])。依沃西单抗联合化疗组有61例(28%)患者发生严重治疗相关不良事件,安慰剂联合化疗组有33例(15%)。依沃西单抗联合化疗组有4例患者因治疗相关不良事件死亡(疾病进展、多器官功能障碍综合征和肝功能衰竭各1例;消化道出血和肺栓塞1例),安慰剂联合化疗组有5例(肺炎、心肌梗死、脑血管意外、认知障碍和栓塞性卒中各1例)。依沃西单抗联合化疗在EGFR-TKI治疗进展后的EGFR突变NSCLC患者中显示出有临床意义且统计学显著的无进展生存获益。依沃西单抗联合化疗的临床获益且无新的安全信号,支持该联合方案作为此类患者新治疗选择的潜力。Summit Therapeutics。
English
Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. Summit Therapeutics.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 109.0
- 新锐分区
- 1区