Abstract RF6-01: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk human epidermal growth factor receptor 2-positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy:

Abstract Background: In the phase 3 DESTINY-Breast05 study (NCT04622319) of T-DXd vs. T-DM1 in patients with residual invasive HER2+BC after neoadjuvant treatment (NAT), T-DXd demonstrated statistically significant and clinically meaningful improvement vs T-DM1 in the primary endpoint of invasive disease-free survival (IDFS) and the key secondary endpoint of disease-free survival (DFS; Geyer, ESMO 2025). ∼80% of patients had invasive residual disease in the axillary lymph nodes, 93% received adjuvant radiotherapy (56% concurrent [n = 918]; 37% sequential [n = 605]), and 79%received dual HER2-targeted NAT. Safety was generally manageable with no new safety signals. Here we report additional efficacy and safety data from the DESTINY-Breast05interim analysis. Methods: Patients with residual invasive HER2+ BC following NAT consisting of anti-HER2 therapy and taxane-based chemotherapy and at high risk for recurrence (cT4, N0-3, M0 or cT1-3, N2-3, M0 at presentation prior to NAT, or cT1-3, N0-1, M0, with axillary node-positive disease [ypN1-3] following NAT)were randomized 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg once every 3 weeks for 14 cycles. All patients receiving adjuvant radiotherapy (RT) were required to have serial chest computed tomography (CT) scans; details to be presented. RT could be administered concurrently with study therapy or prior to initiating study therapy (sequential). Patients receiving sequential therapy had an additional CT scan at the end of the RT. Results: At data cutoff (July 2, 2025), 1635 patients were randomized to T-DXd (n = 818) or T-DM1 (n = 817). Median treatment duration was similar in both arms; more than 70% of patients in both arms received 14 cycles of study therapy. Efficacy results in clinically relevant subgroups will be presented. Adjudicated drug-related interstitial lung disease(ILD) and investigator-reported radiation pneumonitis by timing of adjuvant RT are summarized in the Table. Adjudicated drug-related ILD occurred in 9.6% of patients who received T-DXd; most ILD events were grade 1 or 2, and 0.2% had grade 5 events. No notable differences were observed based on adjuvant RT timing. Incidence of investigator-reported radiation pneumonitis was similar in both arms (31.4% with T-DXd and 30.5% with T-DM1), with no grade ≥3 events and being grade 1. Conclusions: The additional analyses further characterize the positive benefit of T-DXd over T-DM1 in the post-neoadjuvant HER2+ BC residual disease setting, supporting T-DXd as a potential new standard-of-care in this setting. Timing of adjuvant RT did not impact incidence of adjudicated drug-related ILD with T-DXd. Additional results will be presented. Citation Format: S. Loibl, Y. Park, Z. Shao, C. Huang, C. H. Barrios, J. Abraham, A. Prat, N. Niikura, M. Untch, S. Im, W. Li, H. Li, Y. Wang, H. Yao, S. Kim, E. Mathias, J. Petschauer, W. Lu, H. Abdel-Monem, C. E. Geyer Jr.. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk human epidermal growth factor receptor 2-positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy: Interim analysis of DESTINY-Breast05 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF6-01.