70 Real-World Outcomes and Toxicity of Trastuzumab Deruxtecan in Older Adults With Breast Cancer: A Mayo Clinic Multi-Site Analysis

Background

Fam-trastuzumab deruxtecan-nxki (T-DXd) has revolutionized the management of metastatic breast cancer. However, older adults, particularly those aged 80 years and above (octogenarians), were underrepresented in pivotal clinical trials. We conducted an institutional review board (IRB)–approved, multisite study across the Mayo Clinic enterprise to evaluate adverse events (AEs) and survival outcomes with T-DXd in patients 70 years and older, with a subset analysis for octogenarians.

Materials and Methods

Patients treated with T-DXd between January 2020 and December 2025 were identified. Demographics, disease characteristics, and treatment-related data were collected. Kaplan-Meier methodology was used to estimate overall survival (OS) and time on treatment (TOT). Responses were evaluated per RECIST v1.1 criteria.

Results

Of 127 patients, 43 (33.9%) had HER2-positive disease; 60 (47.2%) hormone receptor (HR)–positive, HER2-low; 21 (16.5%) HR-negative, HER2-low; and 3 (2.4%) HER2 ultralow. One-hundred (78.7%) patients were aged 70 to 79, and 27 (21.3%) patients were octogenarians. Most were Caucasian (n = 120; 94.4%) and Medicare insured (n = 99; 77.9%).

Any-grade interstitial lung disease (ILD) occurred in 18 patients (14.1%), with 4 (3.1%) having grade 3 or higher ILD. Gastrointestinal events were reported in 58 patients (45.6%). Symptomatic heart failure occurred in 7 patients (5.5%). Fatigue was noted in 59 patients (46.4%). Treatment discontinuation due to AEs occurred in 28 patients (22%). Among octogenarians, any-grade ILD occurred in 7 patients (25.9%), with 3 (11.1%) having grade 3 or higher ILD. Fatigue was reported in 14 (51.8%), and AE-related discontinuation in 12 (44.4%) patients. No grade 5 ILD was seen.

For HER2-positive disease, the median TOT was 8.3 months; median OS was 24.47 months, with complete response (CR) in 3 (6.9%) and partial response (PR) in 14 (32.5%) patients. Among 9 octogenarians, median OS was 19.38 months, with PR in 3 patients (33%). For HER2-low, HR-positive disease, the median TOT was 4.83 months, and median OS was 13.67 months, with PR in 21 patients (35%). Among 14 octogenarians, median OS was 12.58 months, with PR in 6 patients (43%). For HER2-low, HR-negative disease, the median TOT was 3.48 months, and median OS was 8.9 months, with PR in 4 patients (19%). Among 3 octogenarians, 1 patient had PR. Among 3 patients with HER2 ultralow disease, 2 achieved PR. Prior sacituzumab govitecan (P = .2) and chemotherapy (P = .97) were not associated with significant difference in survival outcomes with T-DXd.

Conclusions

T-DXd demonstrated clinically meaningful efficacy in older adults, including octogenarians, across all HER2 expression levels; however, it was associated with increased incidence of ILD and toxicity-related treatment discontinuation. These findings underscore the significance of vigilant toxicity monitoring and individualized treatment approaches to optimize outcomes in geriatric oncology.