Phase III trial of chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, in combination with exemestane in patients with hormone receptor-positive advanced breast cancer

Background: Chidamide (CS055/Tucidinostat/Epidaza®) is an oral subtype-selective HDAC inhibitor. An exploratory clinical study has demonstrated the encouraging antitumor activity of chidamide in combination with exemestane in hormone receptor (HR)-positive advanced breast cancer (ABC) patients. Methods: This randomized, double-blind, placebo-controlled study involved postmenopausal patients with HR-positive, HER2-negative ABC that had failed with tamoxifen and/or nonsteroidal aromatase inhibitor. Eligible patients were randomly assigned (2:1) to two arms (chidamide 30 mg twice a week plus exemestane 25 mg daily or placebo plus exemestane). The primary endpoint was progression-free survival (PFS), assessed by investigator. Secondary endpoints were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Results: 365 patients were enrolled at 22 centers in China, with 244 in the chidamide group and 121 in the placebo group. The median PFS was 7.4 months [95% confidence interval (CI), 5.5 to 9.2] with chidamide–exemestane and 3.8 months (95% CI, 3.7 to 5.5) with placebo–exemestane (hazard ratio for disease progression or death, 0.755; 95% CI, 0.582 to 0.978; P = 0.0336). ORR were 18.4% and 9.1% (P=0.026), and CBR were 46.7% and 35.5% (P = 0.034) in the chidamide group and placebo group, respectively. Overall survival results were not mature at the time of the analysis. The most common grade 3 or 4 adverse events (AE) in the chidamide group were neutropenia (50.8% vs. 2.5% in the placebo group), thrombocytopenia (27.5% vs. 2.5%), and leucopenia (18.8% vs. 2.5%). Serious adverse events occurred in 51 (20.9%) patients in the chidamide group and 7 (5.8%) patients in the placebo group. No treatment-related death was reported. Conclusions: This is the first oral HDAC inhibitor combined with exemestane in a pivotal clinical study to demonstrate PFS benefit and manageable adverse effect in HR–positive ABC patients progressed after prior endocrine therapy. Clinical trial identification: NCT02482753. Legal entity responsible for the study: Jiang Zefei. Funding: Chipscreen Biosciences Co., Ltd. Disclosure: All authors have declared no conflicts of interest.