eligibility_summary
Eligibility: Adults with metastatic/locally progressive HER2‑low/ultra‑low/null breast cancer (Ventana 4B5), HR+ must have failed ET, ≥1 prior chemo, protocol washouts, ECOG 0–1, measurable disease, biopsy if safely accessible, adequate organ function, not pregnant/breastfeeding, contraception, prior toxicities resolved. Exclude prior anti‑HER2/T‑DXd or EZH, active/symptomatic CNS mets, recent cancer, major cardiac/QTc issues, steroids>10 mg, infections, HIV/active HBV/HCV, ILD/lung disease, CYP3A inducers, prior pneumonectomy, hypersensitivity.
trial_source
clinical_trials.gov from Dec 2, 2025
annotation_status
ai
ai_summary
Phase 1b trial in HER2 low/ultra-low/null metastatic breast cancer testing: 1) Valemetostat: oral small-molecule dual EZH1/EZH2 inhibitor (epigenetic/PRC2 histone methyltransferase blocker) that reduces H3K27me3 and lifts transcriptional repression. 2) Trastuzumab deruxtecan (T-DXd): IV HER2-targeted antibody-drug conjugate (humanized anti-HER2 IgG1 linked via cleavable linker to a topoisomerase I inhibitor payload, DXd), binds HER2, is internalized, releases payload to cause DNA damage, with Fc-mediated ADCC and bystander killing. Targets/pathways: HER2 on tumor cells (even at low levels), PRC2/EZH1/2 epigenetic axis, and DNA replication/repair via topo I inhibition.