Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09.

LBA1008 Background: DESTINY-Breast09 (NCT04784715) is a global, randomized Phase 3 study assessing the efficacy and safety of 1L T-DXd ± P vs THP in 1157 pts with HER2+ a/mBC. The CLEOPATRA study established THP as standard of care in this setting over a decade ago. Methods: Eligible pts had centrally confirmed HER2+ (IHC 3+ or ISH+) a/mBC and no prior chemotherapy or HER2-directed therapy for a/mBC ([neo]adjuvant HER2-directed therapy / chemotherapy with a disease-free interval of >6 months [mo] and ≤1 line of endocrine therapy for metastatic disease permitted). Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg (+ placebo), T-DXd + P, or THP, stratified by de-novo vs recurrent disease, and hormone receptor (HR) and PIK3CA mutation status. In this planned interim analysis, data for T-DXd + P vs THP are presented; the T-DXd + placebo arm remains blinded until final PFS analysis. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in the intent-to-treat population. Other endpoints included overall survival (OS), PFS by investigator (INV), objective response rate (ORR), duration of response (DOR), and safety. Results: Among the pts randomized to T-DXd + P (n=383) and THP (n=387), 52% had de-novo disease and 54% had HR+ status; demographic and disease characteristics were well balanced. At this interim data cutoff (Feb 26, 2025; median follow up 29 mo; 38% mature for PFS), T-DXd + P significantly improved PFS by BICR (hazard ratio 0.56; 95% CI 0.44, 0.71; P<0.00001) and INV (Table). PFS benefit was consistent across all subgroups. OS data were immature. Median response duration with T-DXd + P exceeded 3 years (Table). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 63.5% and 62.3%, and serious TEAEs in 27.0% and 25.1%, of pts in the T-DXd + P and THP groups, respectively. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 46 (12.1%; predominantly Gr 1/2; n=2 [0.5%] Gr 5) pts who received T-DXd + P, and 4 (1.0%; all Gr 1/2) who received THP. Conclusion: T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS vs THP that was consistently observed across all subgroups and may represent a new 1L standard of care in HER2+ a/mBC; no new safety signals were identified. Clinical trial information: NCT04784715 . T-DXd + P(n=383) THP(n=387) Median PFS by BICR (95% CI), mo 40.7(36.5, NC) 26.9(21.8, NC) Hazard ratio (95% CI) vs THP 0.56(0.44, 0.71); P<0.00001 – 24-mo PFS rate (95% CI), % 70.1(64.8, 74.8) 52.1(46.4, 57.5) Median PFS by INV (95% CI), mo 40.7 (36.5, NC) 20.7 (17.3, 23.5) Hazard ratio (95% CI) vs THP 0.49 (0.39, 0.61) – Confirmed ORR by BICR (95% CI), % 85.1(81.2, 88.5) 78.6(74.1, 82.5) Complete response rate, % 15.1 8.5 Median DOR by BICR (95% CI), mo 39.2 (35.1, NC) 26.4 (22.3, NC) NC, not calculable.