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Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial

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收录情况： ◇ 卓越：领军期刊

作者：
Ruan Dan-Yun[1] * ; Huang Wen-Wen[1] * ; Li Yongsheng[2] ; Zhao Yanqiu[3] ; Shi Yehui[4] ; Jia Yuming[5] ; Cang Shundong[6] ; Zhang Wei[6] ; Shi Jianhua[7] ; Chen Jun[8] ; Lin Jie[9] ; Liu Yunpeng[10] ; Xu Jianming[11] ; Ouyang Weiwei[12] ; Fang Jian[13] ; Zhuang Wu[14] ; Liu Caigang[15] ; Bu Qing[16] ; Li Manxiang[17] ; Meng Xiangjiao[18] ; Sun Meili[19] ; Yang Nong[20] ; Dong Xiaorong[21] ; Pan Yueyin[22] ; Li Xingya[23] ; Qu Xiujuan[10] ; Zhang Tongmei[24] ; Yuan Xianglin[25] ; Hu Sheng[26] ; Guo Wei[27] ; Li Yalun[28] ; Li Shengqing[29] ; Liu Dongying[4] ; Song Feixue[30] ; Tan Liping[31] ; Yu Yan[32] ; Yu Xinmin[33] ; Zang Aimin[34] ; Sun Chang[35] ; Zhang Qian[35] ; Zou Kai[35] ; Dan Mo[35] ; Xu Rui-Hua[36,37] ; Zhao Hongyun[1] ;
机构： [1]Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of China. [2]Department of Phase 1 Ward, Chongqing University Cancer Hospital, Chongqing Cancer Hospital, Chongqing, People’s Republic of China. [3]Department of Respiratory Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China. [4]Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, People’s Republic of China. [5]Department of Oncology, The second people’s hospital of Yibin, Yibin, Sichuan, People’s Republic of China. [6]Department of Medical Oncology, Phase 1 Clinical Research Unit, Department of Medical Oncology, Henan Provincial People’s Hospital, Zhengzhou, Hannan, People’s Republic of China. [7]Department of the Second General Medicine, Linyi Cancer Hospital, Linyi, Shandong, People’s Republic of China. [8]Department of Pulmonary Oncology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China. [9]Department of Oncology, The Second Affiliated hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China. [10]Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China. [11]Department of Medical Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China. [12]The Phase1 Clinical Center, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China. [13]Department of the Second Thoracic Oncology, Beijing Cancer Hospital, Beijing, People’s Republic of China. [14]Department of Respiratory Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, People’s Republic of China. [15]Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China. [16]Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China. [17]Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi, People’s Republic of China. [18]Department of the Fourth Thoracic Radiotherapy Ward, Shandong Cancer Hospital & Institute, Jinan, Shandong, People’s Republic of China. [19]Department of Oncology, General Hospital Affiliated Shandong First Medical University, Jinan, Shandong, People’s Republic of China. [20]Department of Pulmonary and Gastrointestinal Medicine, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China. [21]Department of Cancer Center, Wuhan Union Hospital of China, Wuhan, Hubei, People’s Republic of China. [22]Department of Oncology Chemotherapy, The First Affiliated Hospital of USTC, Hefei, Anhui, People’s Republic of China. [23]Department of the Second Oncology Ward, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China. [24]General Department, Beijing Chest Hospital, Beijing, People’s Republic of China. [25]Department of Oncology, Tongji Hospital, Tongji Medical College of HUST, Wuhan, Hubei, People’s Republic of China. [26]Department of Oncology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China. [27]Respiratory Department, Shanxi Cancer Hospital, Taiyuan, Shanxi, People’s Republic of China. [28]Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China. [29]Respiratory Department, Huashan Hospital Fudan University, Shanghai, People’s Republic of China. [30]Department of Medical Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China. [31]Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital & Guangxi Cancer Institute, Nanning, Guangxi, People’s Republic of China. [32]Department of the Third Respiratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People’s Republic of China. [33]Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China. [34]Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei, People’s Republic of China. [35]CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, Hebei, People’s Republic of China. [36]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of China. [37]Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, People’s Republic of China.
出处：
DOI： 10.1038/s41392-025-02155-5
ISSN：

摘要：
HA121-28, a promising multikinase inhibitor, mainly targets rearranged during transfection (RET) fusions and selectively targets vascular endothelial growth factor receptor-2, endothelial growth factor receptor, and fibroblast growth factor receptor 1-3. The safety, pharmacokinetics, and efficacy of HA121-28 were assessed in advanced solid tumors (phase 1, ClinicalTrials.gov NCT03994484) and advanced RET fusion-positive non-small-cell lung cancer (RET-TKI naive NSCLC, phase 2, ClinicalTrials.gov NCT05117658). HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial. The recommended dose identified in phase 1 (450 mg) was administered for patients during phase 2. The primary endpoints were the maximum tolerated dose (MTD) in phase 1 and the objective response rate (ORR) in phase 2. 162 patients were enrolled in phase 1 and 48 in phase 2. A total of 600 mg once daily was set as MTD. Across 100-800 mg, the exposure of HA121-28 increased in a dose-dependent manner. Consistent between both trials, diarrhea, rash, and prolonged QTc interval, were the most reported treatment-emergent adverse events. 40.0% (phase 1) and 62.5% (phase 2) patients experienced grade ≥3 treatment-related adverse events, respectively. The overall ORR was 26.8% and the median progression-free survival (PFS) was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at ≥450 mg once daily. HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients. Nevertheless, cardiotoxicity is a notable concern that warrants careful attention.© 2025. The Author(s).

基金：
This study was funded by Sun Yat-sen University clinical research 5010 program (84000-31630002), Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0004), the National Natural Science Foundation of China (82073396), CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-036), the Guangdong Basic and Applied Basic Research Foundation (2021A1515110697), the Guangzhou Key Research and Development Plan (202206010141), and CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
无
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
第一作者：
第一作者机构： [1]Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of China.
共同第一作者：
通讯作者：
通讯机构： [36]Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of China. [37]Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, People’s Republic of China.
推荐引用方式(GB/T 7714)：
Ruan Dan-Yun,Huang Wen-Wen,Li Yongsheng,et al.Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial[J].Signal Transduction And Targeted Therapy.2025,10(1):62.doi:10.1038/s41392-025-02155-5.
APA：
Ruan Dan-Yun,Huang Wen-Wen,Li Yongsheng,Zhao Yanqiu,Shi Yehui...&Zhao Hongyun.(2025).Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial.Signal Transduction And Targeted Therapy,10,(1)
MLA：
Ruan Dan-Yun,et al."Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial".Signal Transduction And Targeted Therapy 10..1(2025):62

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