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

Prior treatment

• Major surgery or significant unhealed trauma within 4 weeks prior to the first dose of study treatment.
• Chemotherapy, other targeted therapy, or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of study treatment.
• 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.

Other illness

• History of severe hypersensitivity to the study drugs (T-DXd, pyrotinib) or to any of their excipients.
• 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.
• 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.
• 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.
• 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).
• Chronic diarrhea, malabsorption syndrome, or other gastrointestinal disorder that may affect the absorption of orally administered medication.

Lab values

• 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.

• Voluntarily signed written informed consent; age ≥ 18 years; either sex.
• Histologically or cytologically confirmed unresectable locally advanced or metastatic breast cancer.
• 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.
• 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.
• At least one measurable lesion according to RECIST v1.1.
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 3 months.
• Adequate organ function as defined below, without transfusion or hematopoietic growth factor support within 14 days prior to the first dose:
  • 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.
• 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.