Trastuzumab Rezetecan (T-DXh) in HER2+ Breast Cancer With Non-pCR After TCbHP

A Single-Arm, Exploratory Study of 4 Additional Cycles of Trastuzumab Rezetecan (T-DXh) as Neoadjuvant Therapy in Patients With Early or Locally Advanced HER2-Positive Breast Cancer Who Have Non-pCR After TCbHP Neoadjuvant Therapy

This is a prospective, multi-center, single-arm, phase 2 exploratory study to evaluate the efficacy and safety of adding 4 cycles of Trastuzumab Rezetecan (T-DXh), an anti-HER2 antibody-drug conjugate, as continued neoadjuvant therapy in patients with early or locally advanced HER2-positive breast cancer who have residual invasive disease after standard 6-cycle TCbHP (taxane, carboplatin, trastuzumab, pertuzumab) neoadjuvant therapy. Patients will receive 4 cycles of T-DXh (4.8 mg/kg IV Q3W) followed by radical surgery. The primary endpoint is tpCR rate. Secondary endpoints include ORR, EFS, OS, 3-year iDFS, and safety. Simon's two-stage design (H0: pCR ≤10%, H1: pCR ≥25%, α=0.05, β=0.2) requires 43 evaluable patients; with 10% dropout, 48 patients will be enrolled.

Inclusion Criteria:

• Age ≥ 18 years.
• For premenopausal and perimenopausal patients: negative pregnancy test and agreement to use reliable contraception during the treatment period.
• Pathologically confirmed HER2-positive invasive breast cancer (IHC 3+ or IHC 2+ with FISH+).
• Completed standard neoadjuvant TCbHP (taxane + carboplatin + trastuzumab + pertuzumab) with imaging assessment not achieving clinical complete remission (non-cCR).
• Agree to undergo a core needle biopsy.
• ECOG performance status 0 or 1.
• Adequate organ function meeting the following criteria: hemoglobin ≥ 90 g/L, white blood cell count ≥ 3.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, absolute neutrophil count ≥ 1.5 × 10^9/L, AST/ALT ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN, serum creatinine ≤ 1.5 × ULN.
• No myocardial ischemia on ECG; New York Heart Association (NYHA) functional class I; left ventricular ejection fraction (LVEF) ≥ 55% by echocardiography; cardiac troponin I (cTnI) and brain natriuretic peptide (BNP) within normal limits.
• Signed informed consent.

Exclusion Criteria:

• Male breast cancer or inflammatory breast cancer.
• Metastatic breast cancer (Stage IV).
• Concurrent other malignancy or history of other malignancy within the past 5 years, except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
• Concurrent other anti-tumor therapy or participation in another clinical trial.
• Severe non-malignant disease that would affect compliance or place the patient at risk.
• Major surgery within 4 weeks prior to start of study treatment or anticipated need for major surgery during the study.

History of allergic reaction or contraindication to any component of the study drug.

• Dementia, mental abnormality, or any psychiatric illness that interferes with understanding of the informed consent.
• Any other condition assessed by the investigator as unsuitable for inclusion.