2947 - Characterizing Patterns of Failure on Trastuzumab-Deruxtecan (T-DXd) among Patients with HER2 Low Metastatic Breast Cancer

03:00pm - 04:00pm PT

Hall F

Screen: 15

POSTER

Presenter(s)

Emily Hollis, MD - UNC School of Medicine, Chapel Hill, NC

E. S. Hollis¹, D. L. Casey², Y. Abdou³, E. C. Dees³, E. L. Jones⁴, J. L. Wright⁴, G. P. Gupta⁵, and S. Sud⁴; ¹University of North Carolina Hospitals, Chapel Hill, NC, ²Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, ³University of North Carolina at Chapel Hill, Chapel Hill, NC, ⁴Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, ⁵UNC, Chapel Hill, NC

Purpose/Objective(s): T-DXd is FDA approved for the treatment of HER2 low metastatic breast cancer (MBC). Understanding patterns of disease progression on this targeted therapy may help identify opportunities where stereotactic body radiotherapy (SBRT) or external beam radiotherapy (EBRT) could enhance disease control. The study aims to quantify (1) the frequency of disease progression occurring at sites of pre-existing metastases, and (2) the proportion of patients experiencing progression at =5 sites, potentially amenable to SBRT/EBRT.

Materials/Methods: We retrospectively identified 52 patients evaluated at a single NCI-Designated Cancer Center with HER2 low MBC who received T-DXd from 2022 to 2024. HER2 low disease was defined as IHC 1+ or 2+ and HER2 FISH not amplified, as per the DESTINY-04 trial. The reason for T-DXd discontinuation was abstracted from the electronic medical record. For patients who discontinued due to disease progression, re-staging imaging at the time of progression was compared with baseline imaging prior to T-DXd initiation. Oligometastatic and oligoprogressive disease were defined as 5 or fewer radiographically detectable lesions (total or new/progressing sites, respectively).

Results: Among the 52 patients identified, the median age was 60 years, 79% had ER+ disease, and the median follow up time after starting T-DXd was 6.6 months. T-DXd was administered as the median 4^th line of systemic therapy for MBC, with patients receiving a median of 6 cycles (range: 1-35). Reasons for T-DXd discontinuation included disease progression (31/52, 57%), toxicity (4/52, 8%), death (5/52, 10%), or other reasons (4/52, 8%); 8/52 (15%) patients remained on T-DXd at the time of analysis. At initial presentation, 16/52 (31%) patients had oligometastatic disease but only 3/52 (6%) remained oligometastatic by time of T-DXd initiation. A total of 32/52 (62%) patients had disease progression on T-DXd; of these, 1 patient continued T-DXd given stable extracranial disease post stereotactic radiosurgery to limited brain metastases. Progression occurred at a previous site (present at or before T-DXd start) in 84% of patients (previous site only: 18.8%, new site only: 15.6%, both previous and new site: 65.6%). Among these patients, 19/32 (59%) had =5 sites of progression. Nearly half of the patients with oligoprogression (10/19, 53%) had progressive sites amenable to SBRT, 3/19 (16%) had sites amenable to a combination of SBRT or EBRT, and 6/19 (32%) had less targetable sites (most commonly pleural effusion). Despite this, only 5 patients underwent RT during T-DXd treatment, primarily for symptom palliation at a single site.

Conclusion: Most (84%) progression events on T-DXd in HER2 low MBC involve pre-existing metastatic sites, and ~1/3 of patients with progression may be amenable to SBRT/EBRT for oligoprogressive disease sites. These findings could support exploration of SBRT/EBRT as a consolidation and/or salvage strategy to enhance disease control in patients receiving T-DXd.