Abstract PS5-01-18: Dalpiciclib Plus Pyrotinib Plus Letrozole for Patients with Estrogen Receptor-Positive and HER2-Positive Metastatic Breast Cancer (DAPLET)

Abstract Background: Estrogen receptor-positive and HER2-positive breast cancer accounts for approximately 10-15% of breast cancers. Standard metastatic regimens combining trastuzumab-based HER2-targeted therapy with chemotherapy show limited efficacy in this subtype. In SYSUCC-002 trial, trastuzumab plus endocrine therapy was not inferior to trastuzumab plus chemotherapy therapy in first-line HER2+HR+ metastatic breast cancer, suggesting the possibility of omission of chemotherapy. The CDK4/6 pathway may be involved in HER2-targeted therapy resistance due to the HER2-ER signaling cross-talk and thus CDK4/6 inhibitor may become a strategy for patients with HER2+ER+ breast cancer. Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, shows synergistic activity with CDK4/6 blockade in preclinical models. Building on this rationale, we evaluated a novel, chemotherapy-free regimen of pyrotinib, dalpiciclib, and letrozole in patients with HER2+ER+ metastatic breast cancer. Methods: Eligible patients had ER+HER2+ metastatic breast cancer, defined as ER≥1%, and HER2 positivity (immunohistochemistry 3+ or in situ hybridization positive). Patients should previously receive at most one systemic treatment containing trastuzumab for metastatic breast cancer. Patients with stable brain metastases and no clinical symptoms could be enrolled. Eligible patients received pyrotinib (320 mg orally once daily, every 4 weeks), dalpiciclib (125 mg orally once daily on days 1-21 of a 4-week cycle), and letrozole (2.5 mg orally once daily, every 4 weeks) until disease progression or intolerable toxicity. Pre/peri-menopausal patients received GnRH agonist. Radiographic evaluation was conducted every two cycles. The primary endpoint was objective response rate (ORR). In SYSUCC-002 trial, the ORR of trastuzumab plus endocrine arm was 37.2%, thus we hypothesized ORR of 55% in this trial. Using Simon’s optimal two-stage design, at the significance level of type I error rate at 0.05 and power of 0.8, a total of 22 patients was accrued in stage I. If there were more than 9 responses among these evaluable 22 patients, the study would enter stage II. The registration number of this trial was NCT07014410. Results: Between February 2023 and March 2025, 18 patients were enrolled. The median age was 54.5 years (range, 34-71). Ki67 expression at baseline included 12 patients (66.7%) with ≥30%. Of these 18 patients, 12 (66.7%) previously received trastuzumab, of whom 6 patients (33.3%) injecting with trastuzumab at metastatic stage. As of June 20, 2025, 16 of 18 patients had evaluable radiographic data (two patients withdrew from the study within two cycles because of intolerable toxicity). In these evaluable 16 patients, 11 patients achieved confirmed responses (1 complete response, 10 partial responses), yielding an ORR of 68.9% (95% confidence interval [CI], 41-88%). Despite inadequate patients in stage I, outstanding efficacy result indicated the study could enter stage II. The most common grade 3 adverse events were white blood cell count decreased (61.1%) and neutropenia (50.0%). No grade≥4 events were reported. Conclusions: This chemotherapy-free, trigeminy-targeted regimen demonstrated promising antitumor activity and manageable toxicity in first or second line HER2+ER+ metastatic breast cancer. The data supported this regimen as a potential alternative to standard chemotherapy-based approaches in this subtype. Efficacy of this regimen needs to be further evaluated in Simon stage II. Citation Format: Z. Chen, P. Huang, H. Zhou, J. Chen. Dalpiciclib Plus Pyrotinib Plus Letrozole for Patients with Estrogen Receptor-Positive and HER2-Positive Metastatic Breast Cancer (DAPLET) [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 PS5-01-18.