This phase II single-arm study is designed to evaluate the neoadjuvant efficacy of a chemotherapy-free regimen consisting of trastuzumab, pertuzumab, kurmoxilil, and fulvestrant in patients with treatment-naïve stage II-III hormone receptor-positive, HER2-positive breast cancer. The pathological complete response (pCR) rate serves as the primary endpoint. The study aims to assess whether the pCR rate meets or exceeds that achieved with standard chemotherapy plus dual HER2-targeted therapy, and to generate preliminary evidence to support the design of a future phase III randomized controlled trial.
The participant voluntarily joins this study, signs the informed consent form, and has good compliance.
Has undergone bilateral oophorectomy, or is aged ≥60 years;
Aged <60 years, with continuous amenorrhea for 12 months without pathological or physiological cause, and postmenopausal levels of estradiol (E2) and follicle-stimulating hormone (FSH);
Premenopausal or perimenopausal female, willing to receive luteinizing hormone-releasing hormone (LHRH) agonist therapy during the study.
Female who has received any form of prior antitumor therapy (chemotherapy, radiotherapy, molecular targeted therapy, or endocrine therapy).
Currently receiving other antitumor drug therapy.
Has bilateral invasive breast cancer, inflammatory breast cancer, or occult breast cancer.
Clinical stage IV breast cancer.
Single group
Trastuzumab (or biosimilar)
DrugTrastuzumab will be administered intravenously at an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for six cycles. The first infusion will last approximately 90 minutes; if the initial infusion is well tolerated, subsequent infusions may be shortened to 30 minutes. If the interval between two consecutive trastuzumab infusions reaches 6 weeks or longer due to adverse events or other reasons, a re-loading dose of 8 mg/kg should be given over approximately 90 minutes, followed by 6 mg/kg every 3 weeks thereafter, with each infusion lasting 30 minutes, for a total of six cycles.
Pertuzumab
DrugPertuzumab will be administered intravenously at an initial loading dose of 840 mg over 60 minutes, followed by 420 mg every 3 weeks, with each infusion lasting 30 to 60 minutes, for six cycles. A 30- to 60-minute observation period is recommended after each pertuzumab infusion before proceeding with trastuzumab or chemotherapy. If the interval between two consecutive pertuzumab infusions reaches 6 weeks or longer due to adverse events or other reasons, a re-loading dose of 840 mg should be given over 60 minutes, followed by 420 mg every 3 weeks thereafter, with each infusion lasting 30 to 60 minutes, for a total of six cycles.
Kurmoxilil
DrugKurmoxilil will be administered orally at 180 mg once daily on a continuous schedule in 28-day cycles, taken with meals or within 2 hours after meals. Dosing at a fixed time each day is recommended. If a dose is missed and the next scheduled dose is within 10 hours, the missed dose should not be taken.
Fulvestrant
DrugFulvestrant will be administered intramuscularly at 500 mg on Day 1 and Day 15 of Cycle 1, and thereafter on Day 1 of each subsequent 28-day cycle.
Investigator-Assessed tpCR
Total pathological complete response (tpCR) will be assessed by the investigator after completion of neoadjuvant therapy. tpCR is defined as the percentage of participants with no evidence of invasive cancer in the breast primary tumor and no involvement of regional lymph nodes on microscopic examination after resection of the primary tumor (i.e., ypT0/Tis, ypN0 per AJCC 8th edition).
Investigator-Assessed bpCR
Breast pathological complete response (bpCR) rate is defined as the percentage of participants with no evidence of invasive cancer in the breast primary tumor on microscopic examination after resection of the primary tumor (i.e., ypT0/Tis per AJCC 8th edition), as assessed by the investigator after completion of neoadjuvant therapy. This outcome is reported as a percentage of participants.
Objective Response Rate (ORR)
ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) as determined by the investigator according to RECIST version 1.1 during neoadjuvant therapy.
Changes in Ki-67 Expression
Changes in Ki-67 expression are defined as the change from baseline in the percentage of Ki-67-positive tumor cells assessed by immunohistochemistry (IHC) at baseline and after completion of neoadjuvant therapy, and are reported as percentage change (%).
Residual Cancer Burden (RCB) Index
Residual Cancer Burden (RCB) index is a continuous composite measure derived by combining the primary tumor residual tumor dimensions (mm × mm), residual tumor cellularity (%), proportion of ductal carcinoma in situ (%), number of positive lymph nodes, and size of the largest lymph node metastasis (mm) using the standard RCB formula, and is reported as a unitless score, assessed pathologically after completion of neoadjuvant therapy and surgery.
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