Abstract GS1-06: A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer
Authors: Xu Binghe , Zhang Qingyuan , Hu Xichun , Li Qing , Sun Tao , Li Wei , Ouyang Quchang , Wang Jingfen , Tong Zhongsheng , Yan Min , Li Huiping , Zeng Xiaohua , Shan Changping , Wang Xian , Yan Xi , Zhang Jian , Zhang Yue , Wang Jiani , Zhang Liang , Lin Ying , Feng Jifeng , Chen Qianjun , Huang Jian , Lu Yongkui , Li Hongsheng , Wu Jinsheng , Cheng Jing , Hao Yanrong , Geng Cuizhi , Lu Min , Li Yanping , Chen Xi , Song Lihua , Wu Xueying , Hu Changlu , Wu Xinhong , Wang Xiaojia , Pan Yueyin , Cui Yuehong , Yu Guohua , Sun Sanyuan 
Published: March 2022

Abstract
Background Entinostat is a novel, potent, once weekly, orally bioavailable, class I selective histone deacetylase (HDAC) inhibitor. In a previous Phase II study, the combination of entinostat with exemestane showed significant improvement of overall survival in patients with advanced hormone receptor (HR) positive breast cancer. To verify and further confirm the benefit of HDAC inhibitor in combination with exemestane we designed a randomized, controlled trial to assess the efficacy and safety in a larger population of Chinese patients with advanced, HR positive breast cancer. Methods We carried out the randomized, double-blind, placebo-controlled, Phase III trial at 35 sites in China. Eligible patients were women (aged ≥18 years) with HR positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, ECOG performance status of 0-1, and adequate haematological and biochemical parameters. Patients were randomly assigned (2:1) via an interactive web-response system to orally take 5 mg entinostat or placebo. Both groups received oral administration of 25 mg exemestane daily. Randomization was stratified according to previous usage of CDK4/6 (yes vs no), fulvestrant (yes vs no), chemotherapy (yes vs no), and the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was Independent Radiographic Committee (IRC)-assessed progression free survival (PFS). Efficacy and safety analyses were done in all patients who received at least one dose of any study treatment. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. This study was registered with ClinicalTrials.gov with the number of NCT03538171. Results From April 16th, 2019 to May 13th, 2020, 354 patients were enrolled and randomly assigned as 235 to the entinostat group and 119 to the placebo group. IRC-assessed median PFS was 6.32 months (95% CI 5.30-9.11) in the entinostat group and 3.72 months (95% CI 1.91-5.49) in the placebo group (HR 0.74 [95% CI 0.57-0.96]; p&lt;0.001). The most common Grade 3 or 4 adverse events in the entinostat group vs placebo group were neutropenia (103 [43.8%] vs 119 [0.8%] ), thrombocytopenia (20 [8.5%] vs 1 [0.8%]), and leucopenia (15 [6.4%] vs 0). Serious adverse events occurred in 28 out of 235 patients (11.9%) in the entinostat group and 11 out of 119 patients (9.2%) in the placebo group. Conclusions Entinostat and exemestane combination treatment significantly improved PFS compared with exemestane alone in patients with advanced, HR positive, HER2 negative breast cancer that progressed after previous endocrine therapy. Entinostat and exemestane combination was generally tolerated and can offer meaningful clinical benefit in these patients with unmet medical need. This phase III trial was sponsored by Taizhou EOC Pharma Co., Ltd.
Citation Format: Binghe Xu, Qingyuan Zhang, Xichun Hu, Qing Li, Tao Sun, Wei Li, Quchang Ouyang, Jingfen Wang, Zhongsheng Tong, Min Yan, Huiping Li, Xiaohua Zeng, Changping Shan, Xian Wang, Xi Yan, Jian Zhang, Yue Zhang, Jiani Wang, Liang Zhang, Ying Lin, Jifeng Feng, Qianjun Chen, Jian Huang, Yongkui Lu, Hongsheng Li, Jinsheng Wu, Jing Cheng, Yanrong Hao, Cuizhi Geng, Min Lu, Yanping Li, Xi Chen, Lihua Song, Xueying Wu, Changlu Hu, Xinhong Wu, Xiaojia Wang, Yueyin Pan, Yuehong Cui, Guohua Yu, Sanyuan Sun. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-06.