Abstract PS5-04-18: Real-world patterns of trastuzumab deruxtecan discontinuation in metastatic breast cancer: insights from a single-center experience

Abstract Background Trastuzumab deruxtecan (T-DXd) is an approved standard-of-care treatment for patients (pts) with both HER2-positive (HER2+) and HER2-low, previously treated metastatic breast cancer (MBC). Clinical trials have shown that a substantial proportion of pts (approximately 30–50%) discontinue treatment for reasons other than disease progression, most commonly due to adverse events (AEs) or patient choice. Early discontinuation may negatively impact overall treatment efficacy in clinical practice, and discontinuation rates may be influenced by physician and institutional experience with T-DXd management. This study aimed to evaluate the reasons for T-DXd discontinuation in a real-world setting at a single institution with established experience in T-DXd management. Methods We conducted a retrospective observational study using the electronic health records of pts with MBC who received T-DXd at San Raffaele Hospital, Milan, between July 2018 and September 2025. Only pts who permanently discontinued treatment for any reason were included in this analysis. Tumors were categorized as HER2+ (IHC 3+ or 2+ ISH amplified) or HER2-low (IHC 1+ or 2+ ISH not amplified) based on at least one biopsy prior to T-DXd initiation, or HER2-0 if all biopsies showed IHC 0. Reasons for discontinuation were classified as clinical or radiological progressive disease (PD; including death due to progression), AEs (including death due to AE), patient decision, or other causes. Duration of treatment (DoT) was defined as the time from T-DXd initiation to permanent discontinuation. Rates and reasons for dose reductions in this population were also analyzed. Results A total of 89 pts permanently discontinued T-DXd up to September 2025. Among them, 71.9% (n=64) had HER2+, 25.8% (n=23) HER2-low, and 2.3% (n=2) HER2-0 tumors. All pts were female, with a mean age of 56.9 years range 24–85. T-DXd was administered as 1st line therapy in 5.6% (n=5), 2nd line in 16.9% (n=15), 3rd line in 31.5% (n=28), and ≥4th line in 46.0% (n=41) of pts. Visceral metastases were present in 74.2% (n=66), and 29.2% (n=26) had brain metastases.The median DoT among pts who discontinued T-DXd was 7.1 months range 0.7–81.4 overall: 9.6 months 0.7–81.4 in HER2+, 5.6 months 0.7–15.1 in HER2-low, and 3.9 months 2.6–5.1 in HER2-0 tumors. Reasons for discontinuation were PD in 82.0% (n=73), AEs in 14.6% (n=13), patient decision in 1.1% (n=1), and non–treatment-related causes in 2.2% (n=2; one COVID pneumonia and one polytrauma).AEs leading to discontinuation included ILD in 11.2% (n=10), fatigue (n=1), liver function test (LFT) increase (n=1), and persistent neutropenia (n=1). Among the 10 ILD cases, 4 were Grade 1, 1 Grade 2, 2 Grade 3, and 3 Grade 5. The three pts with Grade 5 ILD were managed for this AE at facilities near their homes, since they lived far from our center. In one case, a concomitant opportunistic aspergillus infection was documented. Dose reductions were implemented in 21.3% (n=19) of pts before permanent discontinuation, mainly due to fatigue (9.0%, n=8), LFT increase (6.7%, n=6), and nausea (4.5%, n=4). Conclusions In this real-world study, most pts permanently discontinued T-DXd due to disease progression, while AE-related discontinuations were primarily driven by ILD. Discontinuations due to other AEs were uncommon, and those due to patient decision were also rare and occurred less frequently than in clinical trials. These findings suggest that treatment experience, along with improved prevention, monitoring, and management of AEs, may enhance treatment adherence and reduce unnecessary discontinuations. Given the retrospective design of this study, it is not possible to establish the most effective management strategies. Citation Format: L. Licata, G. Viale, F. Patanè, A. Chiavassa, C. Zanibelli, B. Galbardi, M. Mariani, M. Piras, I. Persano, G. Notini, M. M. Naldini, C. Bosi, A. Rognone, S. Zambelli, L. Sica, D. Aldrighetti, P. Zucchinelli, G. Bianchini. Real-world patterns of trastuzumab deruxtecan discontinuation in metastatic breast cancer: insights from a single-center experience 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 PS5-04-18.