A Two-cohort Study of SHR-A1811 in the Treatment of HER2-positive Breast Cancer With Brain Metastases

Inclusion criteria

• Women aged 18-75 years (inclusive).
• Histologically or cytologically confirmed HER2-positive advanced breast cancer (IHC 3+, or IHC 2+ with ISH amplification).
• Radiologically documented brain metastases, with or without baseline leptomeningeal disease:

• Cohort A (leptomeningeal metastasis cohort): leptomeningeal involvement demonstrated by contrast-enhanced MRI or positive cerebrospinal fluid (CSF) cytology.
• Cohort B (no leptomeningeal metastasis cohort): ≥1 measurable intracranial lesion; either CNS-naïve or progressive after prior local therapy.
• Anticipated life expectancy >12 weeks.
• ECOG performance status 0-2.
• Adequate organ function as defined by the following laboratory criteria:

• Hematologic: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, hemoglobin (HGB) ≥90 g/L.
• Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN in patients with liver metastases); total serum bilirubin (TBIL) ≤1.5 × ULN; serum albumin ≥30 g/L.
• Renal: serum creatinine (Cr) ≤1.5 × ULN or calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula.
• Coagulation: prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5 × ULN.
• Cardiac: left ventricular ejection fraction (LVEF) ≥50%.
• Negative serum pregnancy test; women of childbearing potential must use a highly effective contraceptive method from study initiation until at least 6 months after the last dose of study medication.
• Voluntary participation with written informed consent obtained prior to any study-related procedures.

Exclusion criteria

• Cohort A participants must be excluded if any of the following apply:

• Cerebrospinal fluid (CSF) circulation obstruction that cannot be adequately controlled by therapeutic measures.
• MRI evidence of nodular leptomeningeal (LM) disease in the setting of negative CSF cytology.
• Active central nervous system (CNS) infection.
• Clinically significant coagulopathy.
• Cohort B participants must be excluded if leptomeningeal metastasis is documented, defined as either: radiographic evidence of leptomeningeal involvement, or positive CSF cytology, or unequivocal clinical signs or symptoms attributable to leptomeningeal disease.
• Presence of clinically significant third-space fluid accumulation (e.g., massive pleural or peritoneal effusion) that cannot be adequately controlled by drainage or other interventions.
• Known hypersensitivity to any study drug or its excipients, or to any prior humanized monoclonal antibody products (e.g., trastuzumab, pertuzumab).
• Prior or current exposure to antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor, including but not limited to fam-trastuzumab deruxtecan (DS-8201a).
• Clinically significant cardiovascular disease, including but not limited to: severe or unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association class ≥ II), clinically relevant supraventricular or ventricular arrhythmias requiring therapy or intervention, myocardial infarction within 6 months prior to first study dose, or cerebrovascular accident (including transient ischemic attack).
• Participants known or suspected to interstitial lung disease.
• Concurrent participation in any other interventional drug clinical trial.
• Refusal to comply with protocol-mandated follow-up.
• Presence of any additional severe physical or psychiatric disorder, or any laboratory abnormality that, in the investigator's judgment, could increase the subject's risk, confound study results, or render the patient unsuitable for enrollment.