Abstract PS3-11-30: Neoadjuvant pyrotinib, trastuzumab, dalpiciclib, and exemestane in triple-positive breast cancer: a multicenter phase II trial

Abstract Background: Triple-positive breast cancer (TPBC), defined by concurrent expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for 10-15% of breast cancers. Standard neoadjuvant regimens combining trastuzumab-based HER2-targeted therapy with chemotherapy show limited efficacy in this subtype. Resistance is attributed to HER receptor heterodimerization, HER2-ER signaling cross-talk, and activation of PI3K/AKT/mTOR pathways. Integrating HER2-targeted therapy with endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors may help overcome this resistance. The NA-PHER2 study demonstrated the potential benefit of a chemotherapy-free regimen, trastuzumab, pertuzumab, palbociclib, and fulvestrant, in TPBC. Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, shows synergistic activity with CDK4/6 blockade in preclinical models. In the phase II MUKDEN 01 trial, pyrotinib combined with dalpiciclib and letrozole showed promise in TPBC, though efficacy remains suboptimal. Building on this rationale, we evaluated a novel, chemotherapy-free neoadjuvant regimen of pyrotinib, trastuzumab, dalpiciclib, and exemestane in patients with stage II-III TPBC. Methods: Eligible patients had previously untreated stage II-III TPBC, defined as ER >10%, PR >1%, and HER2 positivity (immunohistochemistry 3+ or in situ hybridization positive). Patients received pyrotinib (320 mg orally once daily, every 4 weeks, for 5 cycles), trastuzumab (intravenously: loading dose 8 mg/kg, then 6 mg/kg every 3 weeks for 6 cycles; or subcutaneously: 600 mg every 3 weeks for 6 cycles), dalpiciclib (125 mg orally once daily on days 1-21 of a 4-week cycle, for 5 cycles), and exemestane (25 mg orally once daily, every 4 weeks, for 5 cycles), followed by surgery. The primary endpoint was total pathological complete response (tpCR), defined as ypT0/is ypN0. Results: Between September 2022 and February 2025, 33 patients were enrolled. The median age was 48 years (range, 29-75). Disease stage at baseline included 17 patients (51.5%) with stage IIA, 11 (33.3%) with stage IIB, 4 (12.1%) with stage IIIA, and 1 (3.0%) with stage IIIC. Ki-67 expression at baseline was ≥30% in 25 patients (75.8%). As of June 10, 2025, 25 patients had undergone surgery with available pathological data. The tpCR rate was 24% (6 of 25; 95% confidence interval [CI], 10-46%). Residual cancer burden 0-1 was observed in 19 patients (76%; 95% CI, 54-90%), and 21 (84%; 95% CI, 63-95%) achieved a Miller-Payne grade 4-5 response. Among 31 patients with evaluable radiographic data, 12 achieved complete response and 19 had partial response, yielding an objective response rate of 100% (95% CI, 86-100%). Adverse events occurred most frequently during the first two treatment cycles. No grade ≥4 events were reported. The most common grade 3 adverse events were diarrhea (41.9%) and neutropenia (22.6%). Conclusions: This chemotherapy-free, quadruple-targeted neoadjuvant regimen demonstrated promising activity and manageable toxicity in early-stage TPBC. These data support further evaluation of this regimen as a potential alternative to standard chemotherapy-based neoadjuvant approaches in TPBC. Citation Format: P. Fu, L. Chen, M. Yao, C. Du, Y. Li, J. Zhou, S. Chen, S. Cai, Q. Feng. Neoadjuvant pyrotinib, trastuzumab, dalpiciclib, and exemestane in triple-positive breast cancer: a multicenter phase II trial [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 PS3-11-30.