T-DXd (HER2 ADC) + pertuzumab: CRs deepen slowly (8.4mo) but track with NC PFS in 1L HER2+ mBC

Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody–drug conjugate (topoisomerase I payload) combined with pertuzumab (HER2 dimerization-blocking mAb) in the Phase 3 DESTINY-Breast09 first-line setting (NCT04784715) for HER2+ advanced/metastatic breast cancer (no prior systemic therapy for a/mBC; 1 prior endocrine line allowed). In this exploratory best-response analysis (interim cutoff Feb 26, 2025), among 377 evaluable pts on T-DXd+P, 15.4% achieved CR (n=58), 71.1% PR (n=268), and 13.5% SD/PD (n=51); median time to PR was 1.5mo and time to CR was 8.4mo, with nadir around ~11mo (16 cycles). Outcomes stratified strongly by best response: median PFS was not calculable (NC) for CR and 40.7mo for PR (12-mo PFS 94.8% and 89.8%; 24-mo PFS 85.1% and 72.9%), vs 13.0mo for SD/PD (24-mo PFS 35.5%); median DOR was NC for CR and 39.2mo for PR. Safety by exposure-adjusted incidence showed drug-related grade ≥3 AE rates of 0.30/pt-year (CR), 0.30/pt-year (PR), and 0.57/pt-year (SD/PD); adjudicated drug-related ILD/pneumonitis rates were similar (~12%) across groups, but SD/PD included two Grade 5 events, and time-to-ILD onset was later in CR (median 484d) vs PR (227d) vs SD/PD (99d). Versus the historical 1L standard taxane+trastuzumab+pertuzumab benchmark (CLEOPATRA median PFS 18.7mo), PR-level PFS here (40.7mo) is well beyond the expected SOC range, while the SD/PD subgroup (13.0mo) sits below that benchmark.