A Prospective, Single-center, Phase II Study of Sacituzumab Tirumotecan in Combination With Pembrolizumab for Neoadjuvant Treatment of Triple-Negative Breast Cancer (TNBC)

Inclusion criteria

• Histologically or cytologically confirmed stage II-III (T1cN1-2 or T2-4N0-2) triple-negative breast cancer (TNBC), defined as:

• Immunohistochemistry (IHC) showing ER and PR <1%
• HER2-negative per 2028 ASCO-CAP guidelines (IHC 0/1+ or IHC 2+/ISH-)
• Available tumor tissue sample for biomarker analysis.
• At least one measurable lesion as per RECIST 1.1 criteria.
• ECOG performance status 0-1.
• Adequate organ function as evidenced by:

• Absolute neutrophil count ≥1.5×10⁹/L (no G-CSF support within 14 days)
• Platelets ≥100×10⁹/L (no transfusion within 14 days)
• Hemoglobin >9 g/dL (no transfusion/ESA within 14 days)
• Total bilirubin ≤1.5×ULN
• AST/ALT ≤1.5×ULN
• Alkaline phosphatase ≤2.5×ULN
• Serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault)
• INR/PT ≤1.5×ULN
• TSH within normal range (or normal FT3/FT4 if TSH abnormal)
• Normal cardiac enzymes (isolated abnormalities allowed if clinically insignificant)
• No prior anti-cancer therapy for current diagnosis.
• For women of childbearing potential and men with WOCBP partners: agreement to use effective contraception from screening until 6 months post-treatment.
• Willing and able to comply with study procedures and provide written informed consent.

Exclusion criteria

• LVEF <50% by ECHO/MUGA or significant cardiac disease (NYHA Class III/IV).
• Prior chemotherapy, targeted therapy, or radiotherapy for current breast cancer.
• Previous treatment with immune checkpoint inhibitors (anti-PD-1/L1, anti-CTLA-4) or T-cell targeting therapies.
• Prior Trop-2 directed therapy or topoisomerase I inhibitor treatment.
• Other malignancies within 5 years (except adequately treated CIS of cervix, BCC, or cutaneous SCC).
• Severe ocular surface disease (dry eye syndrome, meibomian gland dysfunction, or corneal disorders impairing healing).
• Known hypersensitivity to study drug components.
• History of immunodeficiency disorders or organ transplantation.
• Current or history of:

• Steroid-requiring interstitial lung disease/pneumoniti Unresolved ILD/pneumonitis on screening imaging

Clinically significant pulmonary conditions including:

• Recent pulmonary embolism (≤3 months)
• Severe asthma/COPD/restrictive lung disease
• Pleural effusion requiring intervention
• Connective tissue disease with pulmonary involvement
• Prior pneumonectomy
• Active autoimmune disease requiring systemic treatment (past 2 years), except:

• Hormone replacement therapy
• Physiologic corticosteroid replacement
• Active infection requiring systemic therapy within 14 days prior to initiation.
• Uncontrolled comorbidities that may:

• Compromise patient safety
• Interfere with study completion
• Any condition that in the investigator's judgment may:

• Affect study drug evaluation
• Compromise safety assessments
• Interfere with data interpretation
• Otherwise contraindicate participation