Abstract PS5-05-27: Real-world Clinical Outcomes in Patients with HER2+ Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan After One or More Prior Lines of Therapy: Data from U.S Community Oncology Practices

Abstract Background: Trastuzumab deruxtecan (T-DXd) was initially (12/2019) approved by the FDA for treatment of patients (pts) with HER2+ unresectable or metastatic breast cancer (mBC) with two or more prior anti-HER2 regimens. T-DXd was later (5/2022) approved for use by pts with one prior anti-HER2 regimen. This study examined clinical outcomes in pts with HER2+ mBC treated with T-DXd 2L and 3L+ settings. Methods: This retrospective cohort study used deeply-curated electronic medical record data from practices affiliated with ONCare Alliance. Adult pts with mBC diagnosis, confirmed HER2+ status, who received T-DXd in the 2L or later setting 1/2020 to 8/2024 were included. Pt characteristics, treatment utilization and medical events of interests were assessed descriptively by 2L and 3L+ cohorts. Clinical outcomes (duration of therapy DoT, real-world time to treatment failure rwTTF, overall survival OS and real-world progression-free survival rwPFS) were assessed by 2L and 3L+ cohorts using Kaplan-Meier methods. Clinical outcomes of 1L and 2L rwTTF were examined in an exploratory subgroup of pts with 1L taxane+trastuzumab+pertuzumab based regimen (THP) followed by 2L T-DXd vs. 2L trastuzumab emtansine (T-DM1). Results: A total of 300 pts (70 2L and 230 3L+ pts 61.3% in 3L/4L) treated with T-DXd were included (overall mean age = 59.3 yrs; 82.3% White). At mBC diagnosis, a greater proportion of pts in the 2L T-DXd cohort vs. 3L+ cohort had distant bone / visceral metastasis (45.7% vs. 38.3%) and visceral only metastasis (47.1% vs. 42.2%), where a significantly lower proportion had bone only metastasis (7.1% vs. 19.6%; p = 0.0493). Fewer 2L pts had brain metastasis at initiation of T-DXd (14.3% vs. 37.0% in 3L+, p = 0.0031), but a higher rate of baseline comorbidities was seen in 2L pts (50.0% vs. 30.4%, p = 0.0027). Prior to the initiation of 2L T-DXd, 64.3% (n=45) pts received a trastuzumab+pertuzumab based regimen and 22.8% (n=16) received T-DM1 in 1L; prior to 3L+ T-DXd use, 38.7% (n=89) received T-DM1 in 2L. Within a median follow-up of 17.0 months (mo), pts receiving T-DXd in 2L had longer median DoT than 3L+ pts (20.5 mo vs. 12.5 mo, p = 0.0390), longer rwPFS (15.3 mo in 2L vs. 12.4 mo in 3L+, p = 0.0179), longer OS (median NR in 2L vs. 29.0 mo in 3L+, p = 0.0050), and numerically longer rwTTF (13.6 mo in 2L vs. 10.4 mo in 3L+, p = 0.0565). Of pts with a response assessment (66 2L, 205 3L+ pts), an overall objective response was observed in 80.3% 2L vs. 71.7% 3L+ pts (p = 0.1672). The overall rates of any grade medical event of interest were consistent across 2L and 3L+ cohorts (fatigue 72.9% vs. 73.0%, nausea/vomiting 78.6% vs. 72.2%, diarrhea 55.7% vs. 43.9%, and interstitial lung disease (ILD)/pneumonitis 8.6% vs. 10.4%, except respiratory infection, which was higher in 2L T-DXd 38.6% vs. 18.7%, p = 0.0006). Of the pts who had discontinued T-DXd at any point (45 2L and 180 3L+), the most common reason for discontinuation was disease progression (51.1% vs. 55.0%), followed by toxicity other than nausea/vomiting/ILD (17.8% vs. 11.7%), pt choice (8.9% vs. 6.1%) and toxicity related to ILD (6.7% vs. 6.7%). Among exploratory subgroups, median rwTTF was 1L THP 11.6 mo à 2L T-DXd 14.2 mo (n=38) vs. 1L THP 11.6 mo à 2L T-DM1 8.4 mo (n=60) (2L p = 0.0367). Conclusion: The study findings affirm the real-world clinical effectiveness and safety of T-DXd in pts with HER2+ mBC as observed in the DESTINY clinical trials. Despite higher disease and comorbidity burden in this small sample of pts with 2L T-DXd use, longer delays in time to progression and discontinuation were observed compared to later line use of T-DXd; and longer rwTTF compared to 2L T-DM1 use, reinforcing the importance of utilizing T-DXd as early as possible in the treatment pathway to improve long-term pt outcomes. Citation Format: S. Mehta, H. Neuhalfen, A. Peevyhouse, D. Adhikari, C. Williams, M. Garretson, S. Blau, M. Walker, D. Peevyhouse. Real-world Clinical Outcomes in Patients with HER2+ Metastatic Breast Cancer Treated with Trastuzumab Deruxtecan After One or More Prior Lines of Therapy: Data from U.S Community Oncology Practices 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 PS5-05-27.