Abstract PS3-08-04: Dalpiciclib Combined with Letrozole as Neoadjuvant Therapy for Stage II-III HR-Positive, HER2-Negative Breast Cancer: A Phase II Study

Abstract Background: Hormone receptor -positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) typically shows lower rates of pathologic complete response (pCR) and objective response rates (ORR) to neoadjuvant therapy, underscoring a critical need for more effective strategies. Phase III DAWNA-1/2 trials have demonstrated that adding dalpiciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, to endocrine therapy significantly prolongs progression-free survival in patients with HR+/HER2- advanced BC. However, its efficacy and safety in the neoadjuvant setting remain underexplored. This study aims to explore the efficacy and safety of dalpiciclib plus letrozole in patients with stage II-III HR+/HER2- BC. Methods: In this single-arm, open-label study (NCT05512416), early or locally advanced HR+/HER2- BC patients received six 28-day cycles of dalpiciclib (150 mg orally, once daily on days 1-21) plus letrozole (2.5 mg orally, once daily), with or without goserelin (3.6 mg, intramuscularly). Tumor response was evaluated every two cycles by MRI according to RECIST v1.1 criteria until surgery. Surgical resection was scheduled 2-4 weeks after completion of neoadjuvant therapy. The primary endpoint was complete cell cycle arrest (CCCA), defined as Ki-67 ≤ 2.7% on Day 15 of Cycle 1 (C1D15). Secondary endpoints included ORR, residual cancer burden score of 0 or I (RCB 0/I), total pCR (tpCR; ypT0/is and ypN0), and safety. Results: From August 2022 to December 2024, a total of 37 patients were enrolled. All patients with estrogen receptor (ER) expression ≥ 50%, 43.2% (16/37) had Ki-67 expression ≥ 20%. Among the 35 patients with biopsy at C1D15, 74.3% (26/35) achieved CCCA. Of 34 patients who completed neoadjuvant therapy and underwent surgery, the RCB 0/I was 3.0% (1/34), breast pCR rate was 11.8% (4/34), and ORR was 60.0% (21/35). The most common adverse events (AEs) were neutropenia (100%) and leukopenia (94.6%), with grade ≥ 3 AEs reported in 59.5% and 16.2% of patients, respectively. Most other AEs were grade 1-2. Translational biomarkers analyses are ongoing. Conclusion: Our results showed that dalpiciclib plus letrozole demonstrates a promising safety profile and antitumor activity in HR+/HER2− early/locally advanced BC, with significant suppression of proliferation (Ki-67). These results support its potential as a fully oral, chemotherapy-free neoadjuvant regimen. Further studies are warranted to confirm these preliminary results. Citation Format: Y. Mao, H. Wang, W. Li, T. Ma, X. Gao, W. Cao, X. Wang, Z. Niu, J. Cui, H. Hu, C. Liu, D. Jiang, G. Nie, C. Liu, X. Sun. Dalpiciclib Combined with Letrozole as Neoadjuvant Therapy for Stage II-III HR-Positive, HER2-Negative Breast Cancer: A Phase II Study [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 PS3-08-04.