Trastuzumab/Pertuzumab With Fulvestrant and Kurmoxilil in HR+/HER2+ Early Breast Cancer

Patients with HR-positive/HER2-positive breast cancer have a suboptimal response to neoadjuvant chemotherapy combined with dual HER2 blockade, and an optimal treatment strategy for this population has not been established. Trastuzumab and pertuzumab are monoclonal antibodies that target HER2, while kurmoxilil is a novel CDK2/4/6 inhibitor with enhanced inhibitory activity against CDK2 and CDK4 compared with abemaciclib and palbociclib. Fulvestrant is a selective estrogen receptor downregulator. Concurrent inhibition of HER2, ER, and CDK4/6 pathways may synergistically overcome cross-talk-mediated resistance and improve antitumor efficacy. This study will explore whether the chemotherapy-sparing regimen of trastuzumab plus pertuzumab combined with fulvestrant and kurmoxilil improves pathological response in patients with previously untreated stage II-III HR-positive/HER2-positive early breast cancer. This is a single-arm, open-label, phase II study. Approximately 31 women with stage II-III (T2-4, any N, M0 or any T, N1-3, M0 according to AJCC 8th edition) HR-positive/HER2-positive early or locally advanced breast cancer will be enrolled. Eligible participants must be treatment-naïve with histologically confirmed HER2-positive (IHC 3+ or ISH-positive) and HR-positive (ER-positive and/or PR-positive, ≥1% staining) invasive breast carcinoma. Participants will receive neoadjuvant trastuzumab (loading dose 8 mg/kg, then 6 mg/kg q3w) plus pertuzumab (loading dose 840 mg, then 420 mg q3w) for six cycles, combined with kurmoxilil 180 mg orally once daily (28-day cycle) and fulvestrant 500 mg intramuscularly (day 1 and day 15 of cycle 1, then day 1 of each subsequent cycle). Premenopausal and perimenopausal participants will receive ovarian function suppression with LHRH agonists. Surgery will be performed within 3-6 weeks after completion of neoadjuvant treatment. The primary endpoint is total pathological complete response (tpCR; ypT0/Tis, ypN0) assessed by the investigator after surgery. Secondary endpoints include breast pathological complete response (bpCR; ypT0/Tis), objective response rate (ORR) per RECIST 1.1, residual cancer burden (RCB) class, changes in Ki-67 expression from baseline to surgery, and patient-reported outcomes (EORTC QLQ-C30). Safety endpoints include the incidence of adverse events and serious adverse events. Exploratory analyses will assess the correlation between ctDNA dynamics and pCR using peripheral blood and tumor tissue specimens collected at protocol-specified time points.