T-DXd (HER2 ADC) drives ~45–58% ORR in pretreated HER2-expressing endometrial / cervical / ovarian cancers

Trastuzumab deruxtecan (T-DXd; Enhertu) is a HER2-targeted antibody–drug conjugate delivering a topoisomerase I inhibitor payload, evaluated at 5.4mg/kg in the open-label Phase 2 DESTINY-PanTumor02 study (NCT04482309) in pretreated locally advanced/metastatic/unresectable HER2-expressing (IHC 3+ or 2+) gynecologic cancers (n=120; 40 each endometrial, cervical, ovarian). Investigator-assessed confirmed ORR was 57.5% in endometrial (23/40), 50.0% in cervical (20/40), and 45.0% in ovarian (18/40); by independent central review, ORR was 57.5%, 37.5%, and 42.5%, respectively, with highest responses in IHC 3+ tumors. Cross-trial, these response rates sit well above typical single-agent chemotherapy activity in platinum-resistant ovarian cancer (often ~13–21% ORR in older phase 2 datasets) and are directionally higher than historical post–platinum doublet options in recurrent/metastatic cervical cancer, but interstitial lung disease/pneumonitis remains the key risk: adjudicated ILD occurred in 10.8% (13/120), including 1 Grade 5 event. Proportions for HER2-positive (IHC 2+ or 3+) tumors vary across gynecological cancers: endometrial is ~30% to 45% for advanced stage; cervical cancer is ~8% to 14% and ovarian cancer is ~ 10% to 20%.