Real world clinical outcomes with standard dose (SD) and reduced dose (RD) trastuzumab deruxtecan (TDxD) in metastatic HER2-positive and HER2-low breast cancer.

569 Background: TDxD is a human epidermal growth factor 2 (HER2) directed antibody-drug conjugate (ADC) utilized in the treatment of metastatic breast cancer (mBC) and is currently approved for HER2+ and HER2 low breast cancer. In the DESTINY-Breast trials, TDxD prolonged both progression-free survival (PFS) and overall survival (OS) compared with physician’s choice chemotherapy. This benefit carries the risk of rare but significant toxicities such as interstitial lung disease/pneumonitis and heart failure. Cancer drug dosing is traditionally based on the maximum tolerated dose, which may not apply to targeted therapies such as ADCs. A lower TDxD dose may offer comparable efficacy and less toxicity than the FDA approved dose. This study aimed to assess treatment patterns and clinical outcomes in mBC patients (pts) who received TDxD. Methods: This retrospective single institutional chart review study was performed to obtain de-identified patient data. Study population included all mBC pts who received at least 1 cycle of TDxD between 2/10/2020 -12/27/2024. TDxD treatment parameters and patient characteristics were obtained. Real-world progression-free survival (PFS) and overall survival (OS) from date of TDxD initiation and the date of last follow-up was assessed using Kaplan-Meier methods. Differences of OS, PFS between groups were examined by log-rank. Results: This analysis included 66 eligible mBC pts (median age of 67 at TDxD initiation; 29% non-White). 37 pts received TDxD at the initial SD (5.4 mg/kg); 29 received a median RD of 4.4 mg/kg. In the overall cohort, 40.9% had HER2+ mBC (16/37 SD vs. 11/29 RD) and 59.1% HER2-low (21/37 SD vs 18/29 RD). In the overall cohort: 44% were stage IV at time of diagnosis; 74% had baseline visceral metastases, 28% brain metastases, and a median of 3 metastatic sites of disease. Overall, pts had received a median of 4 prior lines of therapy for metastatic disease. 90.6% of ER+/HER2-low pts had received prior CDK4/6 inhibitors. The median treatment duration for SD and RD were similar (251 vs 301 days; p = ns). Among HER2+ and ER+/HER2-low pts, ORR were 18.5% (60% SD & 40% RD) and 17.2% (20% SD & 80%), respectively. The median PFS (10.4 vs 11.2 months; p = 0.8) and OS (18.3 vs 28.1 months; p > 0.09) were similar for SD and RD, respectively. The median PFS (11.5 vs. 20.1 months; p = 0.05) for HER2+ and for ER+/HER2-low (7.6 vs 10.0 months; p = 0.05) between SD and RD were similar. Median OS for HER2+ (not reached vs. 28.1 months; p > 0.09) and ER+/HER2-low (14.1 vs. 19.1; p = 0.5) were similar between SD and RD, respectively. The reported pneumonitis rate for SD was 8% vs 0% for RD. At the end of the follow-up period, 50% of patients were alive. Conclusions: In this small real world data set, PFS, and OS were similar between SD and RD groups in HER2 positive and HER2 low groups. These data provide rationale for dose reduction of ADCs in the metastatic setting.