76 Real-World Safety of Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer: Insights From US Community Oncology Practices

Background

Trastuzumab deruxtecan (T-DXd) was approved in 2022 for HER2-low metastatic breast cancer after prior chemotherapy, with a 2025 label expansion for HR-positive (HR+), HER2-low/ultralow disease following endocrine therapy. Despite rapid uptake, real-world data on safety and treatment-related toxicities remain limited. This study evaluates T-DXd use and tolerability in US community oncology settings.

Methods

This retrospective study used structured and curated electronic medical records from ONCare Alliance, a national network of 31 US community oncology practices. Eligible patients had metastatic breast cancer, initiated T-DXd as metastatic therapy at any point, and had documented HER2-low status. Medical events of interest (MEOIs) of all grades during and up to 30 days following T-DXd were summarized overall.

Results

T-DXd was started among 300 patients (77.0% HR+; 23.0% HR-negative [HR–]) from 2021 to 2025, with most initiating in 2022 (n = 98) or 2023 (n = 176). Baseline characteristics were similar by HR status; median age was 65 years and 79.7% were White. One-fourth (24.7%, n = 74) were de novo metastatic, and 22.7% (n = 68) had ECOG 2 or more at T-DXd start. Comorbid disease burden was modest (≥ 1 condition: 39.3%, n = 118). Most patients (80.7%, n = 242) received T-DXd in the third line or beyond. The most common MEOIs were fatigue, reported in 79.3% of patients, nausea/vomiting in 73.0%, diarrhea in 45.0%, and anemia in 29.7%. Serious MEOIs (Table) occurred in 5% or less and included congestive heart failure (n = 4, 1.3%), febrile neutropenia (n = 5, 1.7%), infusion reactions (n = 1, 0.3%), and reduced ejection fraction (n = 15, 5%). Interstitial lung disease/pneumonitis was reported in 10.0% (n = 30) of patients. Among those with interstitial lung disease/pneumonitis, 80.0% (n = 24) received corticosteroids, 56.7% (n = 17) received hold/delay, and 66.7% (n = 20) discontinued T-DXd. Toxicity-related discontinuation overall occurred in 15.0% (n = 45), including for fatigue (n = 5, 2.1%), reduced ejection fraction (n = 5, 33.3%), anemia (n = 4, 4.5%), diarrhea (3, 2.2%), and nausea/vomiting (n = 3, 1.4%).

Conclusions

In this real-world cohort, rates of T-DXd discontinuation due to toxicity were consistent with those observed in DESTINY-Breast04. Despite higher disease burden among community oncology patients (eg, older, fewer HR+, higher ECOG, more heavily pretreated), the safety profile of T-DXd remained aligned with clinical trial data, supporting its use and tolerability in US community oncology settings.