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

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.