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

A Prospective, Multicenter, Exploratory Clinical Study Evaluating the Efficacy and Safety of SHR-A1811 Monotherapy or Sequential THPy as Neoadjuvant Therapy in Stage II-III HER2-positive Breast Cancer

This is a prospective, open-label, phase II, multicenter exploratory clinical study. Eligible female patients aged 18-75 years with stage II-III HER2-positive breast cancer will receive 4 cycles of SHR-A1811 (4.8 mg/kg, intravenous infusion every 3 weeks). After 4 cycles, tumor response will be assessed per RECIST 1.1 criteria. Patients with a ≥50% reduction in tumor burden will continue with another 4 cycles of SHR-A1811 followed by definitive surgery. Patients with <50% reduction will receive 4 cycles of the THPy regimen (docetaxel + trastuzumab + pyrotinib) before surgery. Circulating tumor DNA (ctDNA) will be assessed for minimal residual disease (MRD) at baseline, after 4 cycles of treatment, and postoperatively. The primary endpoint is total pathological complete response (tpCR), assessed by an independent review committee (IRC). This study aims to evaluate the efficacy, safety, and feasibility of imaging- and MRD-guided neoadjuvant therapy in 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.