Efficacy and Safety of Disitamab Vedotin Plus Pyrotinib or Naratinib in HER2-positive Breast Cancer Patients With Brain Metastasis

Inclusion Criteria:

* Patients who can voluntarily sign an informed consent form;
* Females aged ≥18 years old when signing the informed consent form;
* ECOG PS physical status score of 0 to 2 points;
* Histologically confirmed HER2-positive metastatic breast cancer patients; Note: HER2 positivity refers to at least one occurrence of tumor cell immunohistochemical staining intensity of 3+ or confirmed as positive by fluorescence in situ hybridization \[FISH\] in the pathological testing/re-review of the primary or metastatic lesions conducted by the participating center's pathology department;
* Brain metastases confirmed by MRI/enhanced CT, with at least one measurable lesion in the brain based on RECIST 1.1 criteria;
* Expected survival period ≥3 months;
* Patient types: Cohort A - newly diagnosed brain metastases patients; Cohort B - patients with progression after whole-brain radiotherapy or stereotactic radiosurgery;
* Left ventricular ejection fraction (LVEF) ≥50%;
* QT interval corrected by Fridericia formula (QTcF) of 12-lead electrocardiogram: \<450ms for males, \<470ms for females;
* The following conditions should be met in the blood routine examination:① Absolute neutrophil count (ANC) ≥1.5×10\^9/L, ② Platelet count ≥100×10\^9/L, ③ Hemoglobin ≥90g/L, ④ White blood cell count ≥3.0×10\^9/L;
* Liver function meets the following conditions: ① Serum total bilirubin ≤1.5×upper limit of normal (ULN), or ≤3×ULN if there are liver metastases, ② Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3×ULN, or ≤5×ULN if there are liver metastases;
* Renal function meets the following conditions: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50mL/min (calculated according to the Cockroft-Gault formula);
* Female patients who meet the following conditions can participate in this study: ① Infertility; ② Capable of fertility, with a negative blood pregnancy test result within 7 days before the first administration of the investigational drug, not breastfeeding, and adopting effective contraceptive measures during the screening period, throughout the study, and within 6 months after the last administration of the study drug.

Exclusion Criteria:

* Patients who have received treatment with anti-HER2 ADC drugs;
* Patients who have received sequential treatment with pyrotinib and neratinib;
* Patients with extensive leptomeningeal metastases and poor response to steroid dehydration therapy for brain metastases;
* Presence of third space fluid accumulation (such as significant pleural effusion or ascites) that cannot be controlled by drainage or other methods;
* Patients who have received chemotherapy, major surgery, or molecular targeted therapy within 2 weeks prior to enrollment; patients who have received endocrine therapy within 1 week prior to enrollment; patients who have received nitrosoureas or mitomycin chemotherapy within 6 weeks prior to enrollment;
* Concurrent use of any other anticancer treatment;
* History of or current concurrent malignancies within the past 5 years, excluding cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder carcinoma \[Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading the lamina propria)\];
* Underwent major surgery (including thoracotomy biopsy), experienced significant trauma (such as fractures), had unhealed wounds or fractures at the time of screening, or anticipated the need for major surgery during the study treatment period, within the 4 weeks prior to randomization;
* History of myocardial infarction within the past 6 months; history of New York Heart Association (NYHA) class ≥II congestive heart failure that is not controlled by medication, severe arrhythmias that cannot be controlled (excluding atrial fibrillation and paroxysmal supraventricular tachycardia); known decrease in LVEF to below 50% during or after previous treatment with trastuzumab;
* Known allergy to the drugs and excipients involved in this trial;
* Known history of hypersensitivity reactions to any investigational drugs;
* Subjects deemed unsuitable for participation by other investigators.