Dalpiciclib combined with chidamide and letrozole as neoadjuvant therapy for HR-positive, HER2-negative early or locally advanced breast cancer: A single-arm, prospective, exploratory clinical study.

e12593 Background: Hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) exhibits lower rates of pathologic complete response and objective response rate (ORR) to neoadjuvant therapy, highlighting an urgent clinical need for more effective alternatives. Dalpiciclib is a novel CDK4/6 inhibitor, and chidamide is an orally selective histone deacetylase inhibitor. This study aims to explore the efficacy and safety of dalpiciclib plus chidamide and letrozole as neoadjuvant therapy for HR-positive/HER2-negative BC. Methods: This is a single-arm, open-label study that enrolled patients with early or locally advanced HR-positive/HER2-negative BC. After enrollment, patients received six 28-day cycles of dalpiciclib (100 mg, po, qd, d1-21) plus chidamide (20mg, biw, po, d1-21) and letrozole (2.5 mg, qd, po) as neoadjuvant therapy. Tumor response was assessed according to RECIST 1.1 by MRI examination every 2 cycles until surgery. Surgical treatment will be performed within 2-4 weeks after the end of neoadjuvant therapy, and subsequent adjuvant therapy will be carried out by the investigator according to the actual situation of the subject. The primary endpoint was residual cancer burden score of 0 or I (RCB 0/I), and the secondary endpoints were the total pathological complete response rate (tpCR; ypT0/is and ypN0), objective response rate (ORR) and safety analysis. This study is registered with China Clinical Trials Registry (ChiCTR2400081280). Results: From August 2023 to January 2025, 23 patients were enrolled in our study. All patients had ER expression ≥ 50%, and 74% (17/23) had Ki67 expression ≥ 20%. Among the 12 patients completed neoadjuvant therapy and underwent surgery, the postoperative RCB 0/I was 25% (95% CI, 5.5%-49.5%), tpCR was 25% (95% CI, 5.5%-49.5%), ORR was 92% (95% CI, 61.5%-100.0%). Among the 20 patients who completed the assessment after 2 cycles, the ORR was 75% (95% CI, 50.9%-94.0%). The most common adverse events (AEs) were decreased neutrophil count (100%) and decreased white blood cell count (86%), with grade ≥3 AEs occurring in 82% and 55% of patients, respectively. While other AEs were predominantly grade 1 or 2. Conclusions: Our results showed thatthe combination of dalpiciclib, chidamide and letrozole demonstrates an acceptable safety profile and promising clinical efficacy, suggesting its potential as an alternative fully oral, chemotherapy-free neoadjuvant treatment for HR-positive, HER2-negative early or locally advanced breast cancer. Further research is needed to validate these findings. Clinical trial information: ChiCTR2400081280 .