A Phase II Study of Trastuzumab Deruxtecan (T-DXd) Plus Pyrotinib in HER2-Positive Advanced Breast Cancer After Progression on T-DXd

Inclusion Criteria:

1. Voluntarily signed written informed consent; age ≥ 18 years; either sex.
2. Histologically or cytologically confirmed unresectable locally advanced or metastatic breast cancer.
3. HER2-positive status confirmed by a central laboratory or the institutional pathology department according to the current ASCO/CAP guidelines, defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive.
4. Prior treatment with T-DXd in the second-line or later setting, with radiologically documented disease progression during or after T-DXd therapy according to RECIST v1.1.
5. At least one measurable lesion according to RECIST v1.1.
6. Patients with brain metastases are eligible if the metastases are untreated and do not require immediate local therapy, or if previously treated with local therapy (e.g., radiotherapy, surgery) with a washout period of at least 4 weeks.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy of at least 3 months.
9. Adequate organ function as defined below, without transfusion or hematopoietic growth factor support within 14 days prior to the first dose:

   a. Absolute neutrophil count ≥ 1.5 × 10\^9/L; b. Platelet count ≥ 100 × 10\^9/L; c. Hemoglobin ≥ 80 g/L; d. Total bilirubin ≤ 1.5 × ULN; e. ALT and AST ≤ 2.5 × ULN within 7 days prior to the first dose (≤ 5 × ULN in patients with hepatic metastases); f. Serum creatinine ≤ 1.25 × ULN and creatinine clearance ≥ 60 mL/min.
10. Women of childbearing potential must agree to use highly effective contraception during the study and for 7 months after the last dose; men must agree to use highly effective contraception during the study and for 4 months after the last dose. Serum or urine pregnancy test must be negative within 7 days before enrollment.

Exclusion Criteria:

1. History of severe hypersensitivity to the study drugs (T-DXd, pyrotinib) or to any of their excipients.
2. Patients with brain metastases meeting any of the following: clinically significant central nervous system symptoms requiring continuous corticosteroid or anticonvulsant therapy to control symptoms; brain metastases assessed as requiring immediate local therapy; poorly controlled (more than 1 week) generalized or complex partial seizures.
3. History of clinically significant pulmonary disease, including but not limited to: any history of interstitial lung disease (ILD) or pneumonitis requiring steroid treatment; current active ILD/pneumonitis, or suspected ILD/pneumonitis on screening imaging that cannot be excluded.
4. Clinically significant cardiovascular disease, including but not limited to: acute myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within 6 months prior to screening; clinically uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg); New York Heart Association (NYHA) class III or higher heart failure; QTc prolongation with QTcF \> 470 ms using Fridericia's correction.
5. Severe or uncontrolled systemic disease that, in the investigator's judgment, would compromise protocol compliance or safety assessment, such as active infection or poorly controlled diabetes mellitus.
6. Known human immunodeficiency virus (HIV) infection, or untreated active hepatitis B (HBsAg positive with HBV DNA \> 500 IU/mL) or hepatitis C (HCV antibody positive with HCV RNA above the lower limit of quantification).
7. Major surgery or significant unhealed trauma within 4 weeks prior to the first dose of study treatment.
8. Chemotherapy, other targeted therapy, or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study treatment.
9. Participation in another interventional clinical study within 4 weeks, or within 5 half-lives of the investigational product (whichever is shorter), prior to the first dose of study treatment.
10. Chronic diarrhea, malabsorption syndrome, or other gastrointestinal disorder that may affect the absorption of orally administered medication.