Abstract RF6-02: DESTINY-Breast11 (DB-11) safety: neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+

Abstract Background: Neoadjuvant standard-of-care for HER2+ eBC consists of dual HER2 blockade and cytotoxic agents associated with short- and long-term toxicities. In DB-11, T-DXd-THP showed a statistically significant and clinically meaningful pathologic complete response benefit and improved safety profile vs ddAC-THP. We report data for clinically relevant adverse events (AEs). Methods: Patients (pts) with high-risk (≥T3, node positive [N1-3] or inflammatory), HER2+ eBC were randomized to neoadjuvant T-DXd (8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). Chest HRCT scans were performed every 6 weeks. AEs of special interest were adjudicated interstitial lung disease (ILD)/pneumonitis (systemic steroids recommended) and left ventricular dysfunction (LVD). Clinically relevant AEs (nausea/vomiting [N/V], neutropenia, and peripheral neuropathy) are also described. Outcomes are reported in the safety analysis set (≥1 dose of any study drug). Results: At primary analysis (data cutoff Mar 12, 2025; N=915), all-grade adjudicated drug-related ILD/pneumonitis rates were low across arms (Table) and were maintained (T-DXd-THP) or higher (ddAC-THP) in the THP phase (Cycles 5-8) vs Cycles 1-4. Rates of serious AEs (T-DXd 0.4%; T-DXd-THP 0.6%; ddAC-THP 2.9%), Grade ≥3 adjudicated drug-related ILD/pneumonitis, and all-grade/Grade ≥3 LVD were highest with ddAC-THP (Table). For T-DXd, T-DXd-THP, and ddAC-THP, respectively, steroids were received by 71.4%, 64.3%, and 56.3% of pts with adjudicated drug-related ILD/pneumonitis; 57.1%, 71.4%, and 81.3% of cases resolved. N/V was more common with T-DXd and T-DXd-THP than ddAC-THP, but use of 3 recommended prophylactic antiemetics before Cycle 1 was lower (T-DXd 14.1%; T-DXd-THP 16.9%; ddAC-THP 39.7%); 2 recommended antiemetics were used in 55.5% (T-DXd), 57.2% (T-DXd-THP), and 40.4% (ddAC-THP) of pts. N/V was mainly low grade and nonserious, and rates decreased after Cycles 1-4. Neutropenia rates were highest with ddAC-THP across cycles; granulocyte colony-stimulating factor use was lower with T-DXd (16.1%) and T-DXd-THP (22.7%) than ddAC-THP (87.2%). Peripheral neuropathy rates were lowest with T-DXd; across all treatments, events were predominantly low grade and nonserious, and most occurred during the THP phase. Conclusion: Across arms, adjudicated drug-related ILD/pneumonitis rates were low, with fewer Grade ≥3 events with T-DXd and T-DXd-THP than ddAC-THP. LVD and neutropenia rates were highest with ddAC-THP. Although rates of N/V were higher with T-DXd and T-DXd-THP than ddAC-THP and peripheral neuropathy rates were higher with T-DXd-THP, events were generally low grade and nonserious, demonstrating a safety profile that is manageable with recommended treatment. Citation Format: G. Curigliano, N. Harbeck, J.-F. Boileau, S. Modi, J. Wu, S. Ohno, C. Kelly, X. Cao, A. Fabi, S. Escrivá-de-Romaní, A. Shimomura, É. Poirier, R. Joseph, L. Seneviratne, S.-C. Chen, M. Tiambeng, J. Pedrini, M. Schwaederle, M. Gufran, A. Darilay, L. Pusztai. DESTINY-Breast11 (DB-11) safety: neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage breast cancer (eBC) [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 RF6-02.