Novel CDK2/4/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative advanced breast cancer: a randomized, double-blind, phase 3 trial

CDK2 is a principal mediator of CDK4/6 resistance. Concurrent CDK2/4/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2/4/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable versus 7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26-0.51; stratified log rank test P < 0.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3-47.5) for culmerciclib compared to 12.1% (95% CI 6.4-20.2) for placebo (stratified Mantel-Haenszel χ<sup>2</sup> test P < 0.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-12-18
DOI
https://doi.org/10.1038/s41392-025-02475-6
Primary Topic
Advanced Breast Cancer Therapies
Type
article
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article

Novel CDK2/4/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative advanced breast cancer: a randomized, double-blind, phase 3 trial

Yanrong Hao, Fuguo Tian, Juliang Zhang, Ruizhen Luo et al.
Signal Transduction and Targeted Therapy
Advanced Breast Cancer Therapies
article

Novel CDK2/4/6 inhibitor culmerciclib (TQB3616) plus fulvestrant in previously treated, HR-positive, HER2-negative advanced breast cancer: a randomized, double-blind, phase 3 trial

Yanrong Hao, Fuguo Tian, Juliang Zhang, Ruizhen Luo, Jingfen Wang, Haibo Wang, Haichuan Su, Zhenhua Zhai, Zhaofeng Niu, Shikai Wu, Hongwei Yang, Qun Hu, Hong Zong, Xinyu Qian, Shihong Wei, Fangling Ning, Meng Han, Jiuda Zhao, Ying Cheng, Tao Sun, Xinghua Han, Aimin Zang, Jing Sun, Yi Zhai, Jinsheng Wu, Yunjiang Liu, Lina Liu, Xian Wang, Yongsheng Wang, Gang Liu, Hui Li, Zhihong Wang, Yanxia Shi, Huiping Li, Qingyuan Zhang, Yongmei Yin, Liming Gao, Lu Gan, Wenyan Chen, Xiaojia Wang, Xinshuai Wang, Jianyun Nie, Quchang Ouyang, Bing Zhao, Peng Shen, Lijia He, Zhengwen Cai, Jin Yang, Hongqiang Guo, Mingli Ni, Man-Hua Ding, Xianjun Tang, Chunfang Hao, Hongmei Sun, Zefei Jiang, Man Li, Lian Liu
article en

Abstract

CDK2 is a principal mediator of CDK4/6 resistance. Concurrent CDK2/4/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2/4/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable versus 7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26-0.51; stratified log rank test P < 0.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3-47.5) for culmerciclib compared to 12.1% (95% CI 6.4-20.2) for placebo (stratified Mantel-Haenszel χ<sup>2</sup> test P < 0.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.

Signal Transduction and Targeted TherapyVol. 10(1)
Qingdao University (CN), Yuncheng University (CN), Hebei Medical University (CN), Binzhou Medical University (CN), Guiyang Medical University (CN), Jiamusi University (CN), Xinjiang Medical University (CN), Harbin Medical University (CN), Sun Yat-sen University (CN), Guangxi Medical University (CN), Dalian Medical University (CN), Peking University (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Chinese PLA General Hospital (CN), Affiliated Hospital of Southwest Medical University (CN), Qinghai University Affiliated Hospital (CN), People 's Liberation Army 451 Hospital (CN), Second People's Hospital of Yunnan Province (CN), Binzhou Medical College Hospital (CN), Mudanjiang Medical University (CN), Peking University Cancer Hospital (CN), Suizhou Central Hospital (CN), Linyi People's Hospital (CN), Jilin Province Tumor Hospital (CN), Zhejiang Cancer Hospital (CN), Shandong Tumor Hospital (CN), Second Affiliated Hospital of Dalian Medical University (CN), Cangzhou Central Hospital (CN), Tumor Hospital of Xinjiang Medical University (CN), Guizhou Cancer Hospital (CN), First Affiliated Hospital of Jiamusi University (CN), Shanxi Provincial Cancer Hospital (CN), Third Affiliated Hospital of Harbin Medical University (CN), Fourth Hospital of Hebei Medical University (CN), Xi'an Medical University (CN), Affiliated Hospital of Guizhou Medical University (CN), People's Hospital of Cangzhou (CN), Gansu Provincial Hospital (CN), Third Hospital of Nanchang (CN), Nanyang Institute of Technology (CN), Hunan Cancer Hospital (CN), The People's Hospital of Guangxi Zhuang Autonomous Region (CN), Affiliated Hospital of Qingdao University (CN), Sichuan Cancer Hospital (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Luoyang Central Hospital Affiliated to Zhengzhou University (CN), First Affiliated Hospital of GuangXi Medical University (CN), Anhui Provincial Hospital (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Peking University First Hospital (CN), First Affiliated Hospital of Henan University of Science and Technology (CN), Affiliated Hospital of Hebei University (CN), Henan Cancer Hospital (CN), Sun Yat-sen University Cancer Center (CN), Central Hospital of Zibo (CN), Chongqing Cancer Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Liaoning Cancer Hospital & Institute (CN), Qilu Hospital of Shandong University (CN), Anyang Tumor Hospital (CN), Shandong First Medical University (CN), First Hospital of Qinhuangdao (CN), Hangzhou Cancer Hospital (CN), First Affiliated Hospital Zhejiang University (CN), Lu'an First People's Hospital (CN), Inner Mongolia Medical University (CN), Zhejiang University (CN), Hainan Medical University (CN), Nanjing Medical University (CN), Jinzhou Medical University (CN), Chongqing Medical University (CN)
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