An Interventional, Multicenter Study of Trastuzumab Rezetecan as Neoadjuvant Therapy in Patients With THP-Insensitive HER2-Positive Early Breast Cancer
This study is a response-adapted, multicenter, interventional trial enrolling patients with HER2-positive early or locally advanced breast cancer. All enrolled patients will first receive 2 cycles of standard neoadjuvant THP regimen, consisting of a taxane, trastuzumab, and pertuzumab. After the initial 2-cycle treatment, tumor response will be evaluated by radiologic imaging and patient-derived organoid (PDO) drug sensitivity testing. Patients with an inadequate response to THP are defined as those with \<50% tumor size reduction on imaging, or failure to reach the PDO sensitivity threshold (\<80% tumor cell killing for HER2+/HR- tumors; \<60% for HER2+/HR+ tumors). These non-responders will switch to receive 4 cycles of trastuzumab rezetecan (SHR-A1811), a novel HER2-targeted antibody-drug conjugate (ADC). Patients with a favorable response (≥50% tumor reduction or meeting the PDO threshold) will continue with an additional 4 cycles of THP. The primary objective is to evaluate the pathologic complete response (pCR) rate in THP non-responders after switching to trastuzumab rezetecan. Secondary objectives include objective response rate (ORR), event-free survival (EFS), overall survival (OS), 3-year invasive disease-free survival (iDFS), and safety profiles of both treatment strategies. Outcomes in patients who continue THP will be described for exploratory purposes. A total of 124 patients will be enrolled. This response-adapted, individualized strategy aims to provide an effective option for HER2-positive breast cancer patients with an inadequate early response to conventional THP neoadjuvant therapy.
• 1.Age ≥18 years. For premenopausal and perimenopausal patients, a negative pregnancy test is required, and the patient must agree to use effective contraception during treatment.
• 2.Pathologically confirmed invasive breast cancer, stage II-III according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system, with HER2-positive disease defined as: immunohistochemistry (IHC) 3+; or IHC 2+ with confirmed HER2 gene amplification by fluorescence in situ hybridization (FISH).
• 3.At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• 4.No prior chemotherapy, immunotherapy, endocrine therapy, radical surgery, or radiotherapy for breast cancer.
• 5.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• 6.Ability to understand and provide written informed consent.
• 7.Adequate organ function as evidenced by the following laboratory values:
• Hemoglobin ≥90 g/L
• White blood cell count ≥3.5×10⁹/L
• Platelet count ≥100×10⁹/L
• Neutrophil count ≥1.5×10⁹/L
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3× upper limit of normal (ULN)
• Total bilirubin ≤1.5×ULN
• Serum creatinine ≤1.5×ULN
• 8.No evidence of myocardial ischemia on electrocardiogram (ECG); New York Heart Association (NYHA) functional class I; left ventricular ejection fraction (LVEF) ≥55% on echocardiogram; cardiac biomarkers (cardiac troponin I \[cTnI\] and B-type natriuretic peptide \[BNP\]) within normal limits.
• 9.All required baseline laboratory and radiologic examinations completed prior to neoadjuvant therapy.
• 10.No dysphagia.
• 11.Availability of complete clinical data.