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.
Sara M. Tolaney, Zefei Jiang, Qingyuan Zhang, Romualdo Barroso‐Sousa, Yeon Hee Park, Mothaffar F. Rimawi, C. Saura Manich, Andreas Schneeweiß, Masakazu Toi, Yee Soo Chae, Yasemi̇n Kemal, Mukesh Chaudhari, Toshinari Yamashita, M.L. Casalnuovo, Michael A. Danso, Jie Liu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl
Abstract
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.