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Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

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作者：
Zhang Pin[1] ; Zhang Qingyuan[2] ; Tong Zhongsheng[3] ; Sun Tao[4] ; Li Wei[5] ; Ouyang Quchang[6] ; Hu Xichun[7] ; Cheng Ying[8] ; Yan Min[9] ; Pan Yueyin[10] ; Teng Yuee[11] ; Yan Xi[12] ; Wang Ying[13] ; Xie Weimin[14] ; Zeng Xiaohua[15] ; Wang Xiaojia[16] ; Hu Changlu[17] ; Geng Cuizhi[18] ; Zhang Hongwei[19] ; Li Wenxin[20] ; Wu Xinhong[21] ; Zhong Jincai[22] ; Xu Jingwei[23] ; Shi Yanxia[24] ; Wei Wenhua[25] ; Bayaxi Nayima[25] ; Zhu Xiaoyu[25] ; Xu Binghe[26,*1] ;
机构： [1]Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [2]Ward One of Mammary Department, Harbin Medical University Cancer Hospital, Harbin, China. [3]Breast Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. [4]Breast Internal Medicine Department, Liaoning Cancer Hospital and Institute, Shenyang, China. [5]Department of Medical Oncology, The First Hospital of Jilin University, Changchun, China. [6]Breast Internal Medicine Department, Hunan Cancer Hospital, Changsha, China. [7]Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. [8]Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China. [9]Department of Breast, Henan Cancer Hospital, Zhengzhou, China. [10]Oncology Chemotherapy Department First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China. [11]Department of Medical Oncology, First Hospital of China Medical University, Shenyang, China. [12]Department of Head and Neck Cancer, West China Hospital, Sichuan University, Chengdu, China. [13]Phase I Clinical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [14]Breast, Bone and Soft Tissue Oncology, Guangxi Medical University Cancer Hospital, Nanning, China. [15]Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China. [16]Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China. [17]The Fourth Ward of Medical Oncology, Anhui Provincial Cancer Hospital, Hefei, China. [18]Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. [19]General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [20]Medical Oncology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China. [21]Department of Breast Oncology, Hubei Cancer Hospital, Wuhan, China. [22]Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China. [23]Breast Surgery, The Second Hospital of Jilin University, Changchun, China. [24]Department of Internal Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [25]Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals, Shanghai, China. [26]Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出处：
DOI： 10.1016/S1470-2045(23)00172-9
ISSN：

摘要：
Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting.DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment.Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes).Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape.Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.For the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2023 Elsevier Ltd. All rights reserved.

基金：
This study was funded by Jiangsu Hengrui Pharmaceuticals and partly supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS; 2021-I2M-1-014). We are grateful to all patients and their families and all members of the collaborative group in this trial. Preclinical data interpretation in the manuscript was provided or reviewed by Xin Li (Jiangsu Hengrui Pharmaceuticals, Shanghai, China). We acknowledge KNOWLANDS MedPharm Consulting (Shanghai, China) for statistical analyses (funded by Jiangsu Hengrui Pharmaceuticals). Medical writing support was provided by Lin Dong (Jiangsu Hengrui Pharmaceuticals) according to Good Publication Practice Guidelines.
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出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学
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出版当年[2023]版：
Q1 ONCOLOGY
最新[2023]版：
Q1 ONCOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
共同第一作者：
通讯作者：
通讯机构： [26]Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [*1]National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
推荐引用方式(GB/T 7714)：
Zhang Pin,Zhang Qingyuan,Tong Zhongsheng,et al.Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial[J].LANCET ONCOLOGY.2023,24(6):646-657.doi:10.1016/S1470-2045(23)00172-9.
APA：
Zhang Pin,Zhang Qingyuan,Tong Zhongsheng,Sun Tao,Li Wei...&Xu Binghe.(2023).Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.LANCET ONCOLOGY,24,(6)
MLA：
Zhang Pin,et al."Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial".LANCET ONCOLOGY 24..6(2023):646-657

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