Abstract P1-11-01: Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04

Abstract Background: DESTINY-Breast04 demonstrated that the HER2 targeting antibody–drug conjugate trastuzumab deruxtecan (T-DXd) significantly prolonged progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization negative) metastatic breast cancer (mBC) in pts in the hormone receptor−positive (HR+) cohort and all pts (HR+ and HR-; median PFS, 9.9 vs 5.1 months [mo], hazard ratio: 0.50; median OS, 23.4 vs 16.8 mo, hazard ratio: 0.64; both P < 0.0001; Modi et al. N Engl J Med 2022). Objective response rate (ORR) with T-DXd was ≥50% across cohorts. These subgroup analyses examine pt history and disease characteristics that may correlate with response to therapy. Methods: N = 557 pts with centrally confirmed HER2-low mBC were randomized 2:1 to T-DXd or TPC. Randomization was stratified by HER2 status (IHC 1+ vs 2+), 1 vs 2 prior lines of chemotherapy, and HR+ (with vs without prior treatment with cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) vs HR−. With the exception of the PFS and OS analyses by prior CDK4/6i use, all other described efficacy analyses were assessed post-hoc. Results: Benefit of T-DXd vs TPC was consistent in pts with or without prior CDK4/6i use (Table 1). Pts with high disease burden (ie, ≥3 metastatic sites) also benefited from T-DXd vs TPC (Table 2). There was a small subgroup (n = 22) among all pts (HR+ [n = 18] and HR− disease [n = 4]) with rapid progression prior to enrollment (disease progression within 6 mo of concluding a prior course of chemotherapy in early breast cancer). T-DXd showed responses in 7/14 (50%) pts in this subgroup vs 0/8 with TPC; this subgroup also had prolonged median PFS with T-DXd vs TPC (Table 3). Efficacy data for HER2 IHC 1+ vs 2+ and prior chemotherapy subgroups will be presented. Median OS was not reached for many subgroups (insufficient events in each group [data not shown]); however, subgroups in general showed OS benefit consistent with the primary analysis. With T-DXd, rates of interstitial lung disease/pneumonitis were similar in pts with/without prior CDK4/6i use. Conclusions: T-DXd treatment for HER2-low mBC in the phase 3 study DESTINY-Breast04 showed consistent efficacy independent of disease burden, prior CDK4/6i treatment, or rapid progression status. ILD is an important identified risk and requires proactive monitoring and management. These data continue to support the use of T-DXd as the new standard of care across subgroups of pts with HER2-low mBC. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Eileen McIver, PhD, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table 1. Efficacy by Prior CDK4/6i Treatment in Pts With HER2-Low Breast Cancer, HR+ Cohort. Table 2. Efficacy by Disease Burdena in Pts With HER2-Low Breast Cancer, ITT. Table 3. Efficacy by Rapid Progressor Statusa in Pts With HER2-Low Breast Cancer, ITT. Citation Format: Nadia Harbeck, Shanu Modi, William Jacot, Toshinari Yamashita, Joo Hyuk Sohn, Maria Vidal, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Naoki Niikura, Binghe Xu, Hope Rugo, Konstantinos Papazisis, Javier Cortés, Ian Krop, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, David Cameron. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Subgroup analyses from DESTINY-Breast04 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-01.