This is a single-arm, exploratory, phase II study evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pyrotinib in patients with HER2-positive advanced breast cancer whose disease has progressed after prior treatment with T-DXd.T-DXd is the established standard second-line therapy for HER2-positive advanced breast cancer. However, acquired resistance inevitably develops, and there is currently no approved standard treatment for patients progressing after T-DXd. Real-world studies report an objective response rate (ORR) of approximately 14.5% and a median progression-free survival of only 3 to 4 months in this setting, representing a major unmet medical need.Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that potently inhibits HER1, HER2 and HER4 kinase activity and blocks downstream PI3K/AKT and MAPK signaling. Preclinical and clinical data (including the HER2CLIMB-02 and TROPHY studies) support the synergistic potential of combining an anti-HER2 antibody-drug conjugate with a tyrosine kinase inhibitor.Participants receive T-DXd 5.4 mg/kg intravenously on Day 1 of each 21-day cycle plus pyrotinib 320 mg orally once daily, continuously, until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. Tumor response is assessed using RECIST v1.1.The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Approximately 28 participants will be enrolled.
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.
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.
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.
Single group
Trastuzumab Deruxtecan (T-DXd)
DrugIntravenous infusion at 5.4 mg/kg on Day 1 of each 21-day cycle. The first infusion is administered over not less than 90 minutes; if well tolerated, subsequent infusions may be shortened to approximately 30 minutes. Protocol-defined dose reduction levels are 4.4 mg/kg (first reduction) and 3.2 mg/kg (second reduction); further reduction requires treatment discontinuation.
Pyrotinib
DrugOral tablet, 320 mg once daily on a continuous schedule, taken with or immediately after a meal. A single dose reduction to 240 mg once daily is permitted for toxicity management; multiple interruptions and dose adjustments are allowed.
The objective response rate（ORR） was evaluated according to the RECIST v1.1 standard
The Disease Control Rate (DCR) was evaluated according to the RECIST v1.1 standard
progression-free survival (PFS)
Overall Survival (OS)
The safety was according to the classification standard of drug AE in NCI-CTCAE 5.0
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Fujian Medical University
Lead sponsor
Fujian Cancer Hospital
Sponsor institution
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