Abstract PS5-05-20: Real-world treatment patterns and outcomes in patients with HER2+ metastatic breast cancer after treatment with trastuzumab deruxtecan (T-DXd) in the US

Abstract Background: Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) accounts for 15% to 20% of approximately 300,000 new BC cases diagnosed annually in the US. The treatment landscape for HER2+ metastatic BC (mBC) has evolved significantly, and trastuzumab deruxtecan (T-DXd a HER2 antibody-drug conjugate) is now the preferred standard of care in the second-line (2L) setting. Optimal post-T-DXd treatment pathways are unclear due to the lack of data for regimens in the 3L or 4L setting for patients with HER2+ mBC. This study aimed to better characterize real-world (rw) treatment patterns and clinical outcomes in patients with HER2+ mBC who were previously treated with T-DXd in the rw practice setting. Methods: This was a noninterventional, retrospective, observational cohort study of patients diagnosed with HER2+ mBC who initiated a subsequent treatment after receiving T-DXd in the metastatic setting, using the US-based Flatiron Health Enhanced Datamart. The study observation period was from January 1, 2011, to March 31, 2024. Patients with HER2+ mBC treated with ≥1 T-DXd-containing line of therapy (LOT) and a subsequent LOT, with an index date ≥90 days prior to the end of the observation period, were included. Index date was defined as the start of the LOT that followed the first T-DXd-containing LOT. Patient demographics, clinical characteristics, and treatment utilization were assessed descriptively. The primary (rw progression-free survival rwPFS) and secondary (rw overall survival rwOS, rw time to discontinuation or death rwTTD/D, and rw time to next treatment or death (rwTTNT/D)] endpoints were assessed using Kaplan-Meier methods. Results: The study included 228 patients (mean age, 60.3 years; 99.6% were female and 66.7% were White). Most patients initiated their index treatment in the 4L setting (median of 3 LOTs prior to index date; line of index treatment: 2L 4.4%, 3L 22.4%, 4L 31.1%, 5L 22.8%, 6L 11.0%, 7L+ 8.3%). 64.5% of patients had ≥3 metastatic sites at the index date; 31.6% had CNS metastases. With a median follow-up of 10.4 months (range, 0.5-42.4 months), the median rwPFS was 4.3 months (95% CI, 3.5-5.0 months) and the median rwOS was 15.7 months (95% CI, 12.1-20.0 months). The median rwTTD/D and rwTTNT/D were 6.2 and 6.9 months, respectively. The most common regimens received as the index LOT were trastuzumab + tucatinib + chemotherapy (TTC; 34.2%), other anti-HER2 (18.9%), trastuzumab + chemotherapy (12.7%), other (12.7%), margetuximab + chemotherapy (8.8%), trastuzumab emtansine (T-DM1; 6.6%), and anti-HER2 TKI + chemotherapy (6.1%). Treatment sequencing varied by index line number. T-DM1-based regimens were more common when the index LOT was 3L (15.7%) vs 4L (5.6%) or 5L (3.8%), and 21% to 22% of patients with index 3L or 4L treatment received other anti-HER2 therapies immediately post T-DXd vs 13.5% with index 5L treatment. Conclusions: Treatment sequencing data suggest that TTC and other anti-HER2 therapies are being used in the post-T-DXd rw setting, though potential differences by line exist. This study demonstrates an ongoing and substantial unmet need for more effective treatments among patients with HER2+ mBC previously treated with T-DXd, as shown by the short rwPFS/OS and short times on subsequent treatments following T-DXd. Citation Format: S. M. Tolaney, S. Valliant, S. Hunter, O. Tymejczyk, A. Yu, J. Earla, E. Pang. Real-world treatment patterns and outcomes in patients with HER2+ metastatic breast cancer after treatment with trastuzumab deruxtecan (T-DXd) in the US 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 PS5-05-20.