SHR-A1811 Monotherapy or Sequential THPy as Neoadjuvant Therapy for Stage II-III HER2-Positive Breast Cancer

Inclusion Criteria:

• Female aged ≥18 years and ≤75 years.
• Histopathologically confirmed invasive breast cancer with no prior systemic anti-tumor therapy for breast cancer.
• Histopathologically confirmed HER2-positive status in accordance with the 2018 ASCO-CAP HER2 testing guideline criteria: immunohistochemistry (IHC) score of 3+, or IHC 2+ with positive in situ hybridization (ISH) test (ISH amplification ratio ≥2.0); hormone receptor status must be available.
• Stage II-III breast cancer per the 8th edition AJCC Breast Cancer Staging System.
• At least one measurable target lesion according to RECIST Version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate function of major organs as defined below (no blood transfusion, granulocyte-stimulating factors or thrombopoietic agents administered within 2 weeks prior to screening):

  1. Hematology: absolute neutrophil count (ANC) >1.5×10⁹/L; platelet count (PLT) >75×10⁹/L; hemoglobin (Hb) >90 g/L.
  2. Serum biochemistry: total bilirubin (TBIL) <1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <1.5×ULN; alkaline phosphatase <2.5×ULN; blood urea nitrogen (BUN)/urea and creatinine (Cr) <1.5×ULN.
  3. Echocardiogram: left ventricular ejection fraction (LVEF) ≥55%.
  4. 12-lead electrocardiogram: Fridericia-corrected QT interval (QTcF) <470 msec.
• For premenopausal women of childbearing potential: serum or urine pregnancy test must be negative within 7 days before treatment initiation; not breastfeeding. All participants must use effective barrier contraception throughout treatment and for 6 months after completion of study treatment.
• Voluntarily provide written informed consent, demonstrate good compliance and willingness to complete scheduled visits and study-related procedures.

Exclusion Criteria:

• Stage IV breast cancer.
• Inflammatory breast cancer.
• Prior anti-tumor therapy or radiotherapy for any malignancy, or concurrent other malignant tumors, except cured carcinoma in situ of cervix, basal cell carcinoma or squamous cell carcinoma.
• Concurrent receipt of anti-tumor therapy in another clinical trial, including but not limited to chemotherapy, endocrine therapy, biotherapy, bone-modifying agent therapy or immune checkpoint inhibitor therapy.
• Major surgery unrelated to breast cancer performed within 4 weeks prior to the first dose of study drug, or participants who have not fully recovered from such surgery.

• Severe cardiac disorders, including but not limited to:

  1. Confirmed history of heart failure or systolic dysfunction (LVEF <50%).
  2. High-risk uncontrolled arrhythmias, such as atrial tachycardia with resting heart rate >100 bpm, significant ventricular arrhythmia (e.g., ventricular tachycardia), or advanced atrioventricular block (Mobitz type II second-degree or third-degree atrioventricular block).
  3. Angina requiring anti-anginal medication.
  4. Electrocardiogram evidence of transmural myocardial infarction.
  5. Poorly controlled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg) despite medical treatment.
• Uncontrolled active infection requiring treatment; history of immunodeficiency including positive HIV test, other acquired or congenital immunodeficiency disorders, or history of organ transplantation.
• Known hypersensitivity to any components of study drugs specified in this protocol.
• Pregnant or breastfeeding women; women of childbearing potential with positive baseline pregnancy test; women of childbearing potential unwilling to use effective contraception throughout the study and for 6 months after the last study drug administration.
• Known or suspected interstitial lung disease; moderate to severe pulmonary diseases that may interfere with detection or management of drug-related pulmonary toxicity and severely impair respiratory function within 3 months before the first dose, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), obstructive/restrictive lung disease; any autoimmune, connective tissue or inflammatory diseases involving the lung such as rheumatoid arthritis, Sjogren's syndrome, sarcoidosis; or prior history of pneumonectomy.
• Severe concomitant illnesses or other comorbidities that would interfere with planned treatment, or any other conditions rendering the participant unsuitable for participation in the study as judged by the investigator.