Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate that has demonstrated significant clinical benefit in patients with HER2-positive breast cancer and, more recently, in HER2-low and hormone receptor-positive (HR+), HER2 ultra-low metastatic breast cancer (MBC), thereby expanding the spectrum of targeted therapies. However, treatment-related interstitial lung disease (ILD) remains a clinically significant and potentially fatal adverse event. Real-world data on the incidence, clinical course, and risk factors associated with pneumonitis in patients receiving T-DXd remain limited. Methods: We conducted a real world (RW) single-institution, multi-site at Cleveland Clinic review of patients with MBC treated with T-DXd from December 2019 to December 2023. Demographic, clinical, and treatment-related variables were collected, including tumor characteristics, prior therapies, and outcomes. The primary endpoint was the incidence of pneumonitis, identified through clinical and radiographic assessments. Descriptive statistics were used to summarize patient characteristics and outcomes. Results: Among 76 patients, most were female (98.7%) and White (86.8%). Over half of patients had de novo metastatic disease (51.3%) and positive HR receptor status (52.6%). Prior treatments included chemotherapy, novel targeted therapies, and immunotherapy. At the time of data cutoff, 36.8% remained on T-DXd, while 42.1% had progressed. The majority (61.8%) were alive at last follow-up, with minimal loss to follow-up (2.6%).Treatment-related all-grade ILD occurred in 6 patients (7.9%). Management and outcomes varied by grade (Table 1). Additionally, 2 patients developed suspected pneumonitis, characterized by inflammatory changes on imaging after initiating T-DXd. Both cases were resolved without treatment with steroids and T-DXd was resumed. Conclusion: In this RW cohort of MBC treated with T-DXd, all-grade ILD occurred in 7.9% of patients, which is lower than the rates noted in all DESTINY trials (10-17.4%). Rate of Grade 3 or higher ILD in our study was 5.2% which is higher than reported in DESTINY trials (2.4-2.7%). 1 ILD-related death was observed in our study. Of all the 6 patients with confirmed ILD, none of the patients obtained a bronchoscopy before start of steroids. These findings underscore the importance of screening, early detection, and the need for individualized management strategies. The low rate of bronchoscopy diagnosis also highlights opportunities to engage pulmonary medicine teams in a timely manner. Further research is needed to identify predictive factors and optimize risk mitigation in patients receiving T-DXd. Citation Format: J. Hundal, N. Rehman, A. Abushamma, S. Haddad, M. Velimirovic, W. Wei, B. Honnekeri, X. Chen, M. Smith, M. Kruse, A. Ali. Real-world incidence and management of trastuzumab deruxtecan-associated interstitial lung disease 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 PS5-04-11.
Hundal et al. (Tue,) studied this question.