Abstract PS3-07-02: An Exploratory Clinical Trial of CDK4/6 Inhibitor Dalpiciclib Combined with Aromatase Inhibitors as Neoadjuvant Therapy for Stage II-III HR-positive HER2-negative Breast Cancer

Abstract Background Hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer accounts for ∼60% of all breast cancer cases. Neoadjuvant endocrine therapy (NET) offers comparable objective response rate (ORR) and breast-conserving rate to chemotherapy but with lower toxicity. Dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), arrests the cell cycle to suppress tumor proliferation. This trial evaluates its combination with aromatase inhibitors (AIs) in stage II-III HR+/HER2- breast cancer, seeking an optimized, low-toxicity neoadjuvant strategy. Methods This single-arm, multicenter, open-label phase II trial enrolled 45 treatment-naive women with stage II-III HR+ (estrogen receptor >10%) and HER2- breast cancer. Participants receive dalpiciclib 150 mg/d (d1-21 every 28 days) + AIs (letrozole 2.5 mg/d, anastrozole 1 mg/d, or exemestane 25 mg/d); premenopausal women add ovarian suppression (goserelin/leuprolide). The primary endpoint was ORR. Secondary endpoints encompassed pathological complete response (pCR, ypT0/is ypN0), Ki-67 reduction from baseline, preoperative endocrine prognostic index (PEPI), Miller/Payne (MP), and safety. Results From March 2023 to June 2025, 45 patients were enrolled. Median age was 57 years (28-79). Among the subjects, 48.8% (21/45) were pre/perimenopausal women. Most patients had T2 (55.6%), N1 (53.3%), Stage III (53.3%) tumors. 24 completed the neoadjuvant treatment and underwent surgery (8 patients are still receiving treatment, 12 patients withdrew from the study, and 1 patient showed progression). ORR was 46.9% (95% CI: 29.6%-64.2%), with 32 patients having completed at least one cycle of treatment and undergone efficacy evaluation, including 3.2% (1/32) complete response (CR) and 45.2% (14/32) partial response (PR). No patient achieved pCR. Ki-67 decreased from a baseline of 20% (IQR: 10%-40%) to 5% (IQR: 3%-26.25%) before surgery, indicating suppressed tumor proliferation; the interquartile range may suggest heterogeneous patient responses. The median MP grade was 3 (IQR: 2.75-3), with the majority (70.8%) showing grade 3, indicating moderate pathological response to therapy. Median PEPI was 4 (IQR: 3-5), and 33.3% (8/24) patients were classified as medium-risk (1≤PEPI≤3). Grade ≥3 adverse event was neutropenia (35.2%), with no treatment-related deaths. Conclusion Dalpiciclib combined with AIs demonstrates promising efficacy and manageable toxicity as neoadjuvant therapy for stage II-III HR+/HER2- breast cancer, offering a new chemotherapy-free option. Future research should focus on biomarker-guided patient selection, long-term outcomes assessment, and comparative trials with other neoadjuvant therapies, aiming to improve the treatment paradigm for HR+/HER2- breast cancer. Citation Format: Q. Yang, W. Chen, S. Chen, M. Meng, Q. Yang, G. Lin, L. Lin, Z. Zheng, R. Zeng, B. Chen, W. Li, Q. Zhao. An Exploratory Clinical Trial of CDK4/6 Inhibitor Dalpiciclib Combined with Aromatase Inhibitors as Neoadjuvant Therapy for Stage II-III HR-positive HER2-negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-02.