T-DXd HER2 ADC nearly doubles PFS over chemo in HER2-low HR+ mBC

Trastuzumab deruxtecan (T-DXd), an anti-HER2/topo-I antibody-drug conjugate, was pitted against capecitabine or taxane chemotherapy in the phase 3 DESTINY-Breast06 trial (NCT04494425). In the 625-patients with ctDNA biomarker set of HR-positive, HER2-low/ultralow metastatic disease after ≥1 endocrine regimen, blinded median PFS rose from 8.1 mo to 13.2 mo (HR 0.64) with T-DXd and remained superior across key subgroups: PI3K-mut 13.2 vs 7.1 mo (HR 0.65), ESR1-mut 11.3 vs 7.0 mo (HR 0.64) and BRCA1/2-mut 21.4 vs 5.6 mo (HR 0.14), accompanied by cORR boosts of 15–41%. The chemo control arm’s 5-8 mo PFS aligns with modern salvage benchmarks (e.g., 4.9 mo in the TROPION-Breast01 chemo arm), underscoring an absolute ~5-15 mo gain for T-DXd; no new safety data were reported, though known interstitial-lung-disease risk warrants monitoring.