With: Sara M Tolaney MD MPH, Chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston USA And interviews with: Rebecca Dent MD, Deputy Chief Executive Officer, National Cancer Center, Singapore And: Giuseppe Curigliano MD PhD, Director, Early Drug Development for Innovative Therapies Division, European Institute of Oncology, University of Milan, Milan, Italy CHICAGO, USA—Patients with HER2 positive advanced or metastatic breast cancer lived significantly longer without having any return of their disease after treatment with a combination including the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in comparison with similar patients treated with the current standard of care: a taxane plus trastuzumab and pertuzumab. This was revealed in interim finding from the the DESTINY-Breast09 study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago by Sara M Tolaney MD MPH of the Dana-Farber Cancer Institute in Boston USA. To comment on the DESTINY findings Peter Goodwin interviewed Rebecca Dent, from the National Cancer Center, in Singapore. Giuseppe Curigliano MD PhD of the University of Milan explained how T-DXd had already contributed to the emerging landscape of antibody drug conjugate therapies for breast cancer. ASCO ABSTRACT TITLE: 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. 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. Conclusions: 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.

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