Abstract PS5-02-08: Impact of Prior T-DM1 Exposure on the Efficacy of Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer

Abstract Introduction: Trastuzumab deruxtecan (T-DXd) has emerged as a highly effective antibody-drug conjugate for patients with HER2-positive metastatic breast cancer, particularly following progression on prior HER2-directed therapies. However, the clinical relevance of prior exposure to another HER2-targeted ADC, trastuzumab emtansine (T-DM1), on the efficacy of subsequent T-DXd remains unclear. Clarifying this sequencing effect is essential for optimizing treatment strategies in the advanced disease setting. Methods: This multicenter, retrospective cohort study evaluated patients with HER2-positive metastatic breast cancer who received T-DXd therapy. The primary objective was to assess the impact of prior exposure to another antibody-drug conjugate, T-DM1, on progression-free survival (PFS) following T-DXd treatment. Eligible patients were identified from institutional records across 21 oncology centers in Turkey, and clinical, pathological, and treatment data were collected. PFS was defined as the time from initiation of T-DXd to radiologic or clinical disease progression or last follow-up. Cox proportional hazards regression was used to estimate hazard ratios for progression. Results: A total of 199 patients were included, with a mean age of 45.8 ± 12.0 years (range: 21-83). T-DXd was administered at a median line of 3 (range: 1st-9th line). The majority of patients received T-DXd as a third (29.2%) or fourth-line therapy (25.6%). The median follow-up was 8.3 months, and the mean follow-up was 10.5 months (95% CI: approximately 9.5-11.5). Comorbidities were present in 31.2% of patients, and 57.3% were premenopausal. ER and PR positivity rates were 65.3% and 47.7%, respectively. HER2 status was IHC 3+ in 75.9% and IHC 2+/ISH+ in 24.1%. Prior to T-DXd, 67.3% of patients received T-DM1. Disease progression after T-DXd occurred more frequently in patients previously treated with T-DM1 (47.0% vs. 13.8%, p<0.001). In the univariate analysis, prior exposure to T-DM1 was significantly associated with a higher risk of progression under T-DXd treatment (HR = 3.03, 95% CI: 1.51-6.10, p = 0.002). Consistent with this finding, progression-free survival (PFS) was significantly shorter in the T-DM1-pretreated group compared to the T-DM1-naive group (p = 0.001, log-rank test). The median PFS was 12.1 months (95% CI: 7.7-16.5) in the T-DM1 group, whereas the median was not reached in the T-DM1-naive group during the study period. Conclusion: Prior exposure to T-DM1 was associated with significantly shorter progression-free survival and a higher risk of disease progression following T-DXd treatment in patients with HER2-positive metastatic breast cancer. These findings highlight the potential impact of treatment sequencing on T-DXd efficacy and underscore the need for personalized therapeutic strategies in the advanced setting. Citation Format: F. Kemik, T. K. Sahin, H. Ozcelik, A. Sezer, G. Basaran, S. Biter, D. Erdem, S. Tunbekici, A. Oruc, A. K. Guren, K. Kaban, M. B. Aykan, O. B. Ekinci, I. Deliktas Onur, A. Kalem, O. Altunok, M. Seyyar, B. Guney, O. Akdogan, M. Yazici, N. Majidova, B. Koylu, C. I. Kikili, N. Demir, D. Tunali, S. Lacin, D. Tural, A. Bilici, E. Bayram, E. Goker, M. Araz, I. V. Bayoglu, N. Molinas Mandel, N. Karadurmus, E. Celik, O. Ates, H. Yesil Cinkir, M. Yimaz, R. U. Gursu, O. Yazici, D. Cabuk, D. C. Guven, F. Selcukbiricik, S. Aksoy, S. Gunduz. Impact of Prior T-DM1 Exposure on the Efficacy of Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer [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 PS5-02-08.