Abstract Background Trastuzumab deruxtecan (T-DXd) is a highly effective antibody-drug conjugate (ADC) indicated for the treatment for metastatic, HER2-positive or HER2-low/ultra-low, breast cancer (MBC) with objective response rates between 50-80% as reported within DESTINY-BREAST01, -03, -04, and -06. Despite its efficacy, T-DXd carries a black box warning for interstitial lung disease (ILD)/pneumonitis with approximately 10-15% risk of ILD development including some grade (G) 5 events. Given G2-4 ILD result in permanent discontinuation of T-DXd, identifying ILD earlier at G1 is essential to maintain therapy; however, monitoring guidance remains limited and variable amongst individual practice. The tumor microenvironment (TME) plays an important role in CNS tumor growth as cancerous cells create complex relationships that reorganize the local TME and reprogram CNS cells, including lymphocytes. It is not yet known if an association exists between patients (pts) with brain metastases (BrM) and decreased total lymphocyte counts and an increased risk of developing opportunistic infections (OI) and/or T-DXd-related ILD. However, the DESTINY-Breast12 study suggested potentially higher rates of ILD in pts with BrM than in pts without and 5 pts in the BrM group concurrently developed an OI. As T-DXd use continues to extend across other tumor types, identifying risk factors (RF) that may increase ILD risk as well as improved monitoring strategies is essential. This retrospective study aims to assess the incidence of ILD and OI, associated RF, monitoring strategies, and management of T-DXd-related ILD in MBC with BrM or leptomeningeal diseases (LMD) as well as assess any correlation with lymphocyte depletion. Methods This is a single-center, retrospective, cohort study in pts with MBC with BrM and/or LMD at the Duke Cancer Institute (DCI) Center from 12/2019 to 9/2024. Eligible pts were ≥18 years of age with a diagnosis of HER2 ultra-low/low/positive MBC with BrM and/or LMD receiving T-DXd, with or without additional ILD monitoring to include CT-ILD or standard restaging (PET or CT). Results A total of 36 pts with HER2-ultra low, low or positive MBC who had received T-DXd were included. A total of 23 pts had HR+ MBC, and 6 pts with TNBC. Approximately 36 pts and 6 pts had BrM and LMD, respectively. In the study cohort, 7 pts (19.4%; 95% CI 8.2%, 36%) developed ILD. One pt had G1 ILD, 5 pts had G2 ILD, and 1 pt had G3 ILD. Among pts who developed ILD, the average time from start of T-DXd treatment to ILD onset was 7.3 (range: 0.3-15.4) months. All 7 pts with confirmed ILD were treated with corticosteroids. Of pts who had a decreased lymphocyte count at the time of cycle 1 day 1 of T-DXd treatment, 4/15 (26.7%) developed ILD. Among pts with a history of smoking tobacco and pts with no history of smoking tobacco, 3/12 (25.0%) and 4/24 (16.7%) developed ILD, respectively. Among pts 60 yo and pts ≥60 yo, 4/20 (20.0%) and 3/16 (18.8%) developed ILD, respectively. No pts in the study cohort had a history of COPD, ILD, or CKD. Two pts developed an OI while on treatment with T-DXd (5.6%). One pt who developed an OI did not develop ILD while one pt did develop ILD. Additional results to be presented with increased sample size and ILD monitoring strategy. Conclusion A numerically higher rate of ILD was observed in pts with BrM and/or LMD compared to rates previously reported. The results of this study do not suggest an association between the RF assessed and T-DXd-related ILD, however, this may be due to the small sample size. Further investigation is needed to determine if pts with BrM and/or LMD may be at an increased risk of OI or ILD, however, 26.7% of pts with a decreased lymphocyte count at T-DXd initiation developed ILD, suggesting a potential correlation. Citation Format: H. Moore, A. Kupper, R. Bansal, C. Anders, J. Burrows, P. Alice, A. Erkanli. Assessment of risk factors, monitoring strategies, incidence, and management of trastuzumab deruxtecan (T-DXd)-related interstitial lung disease (ILD) in metastatic breast cancer with brain metastases 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 PS1-03-30.
Moore et al. (Tue,) studied this question.