Comparison of T-DXd-associated pulmonary toxicity in real-world settings and clinical trials

Interstitial lung disease (ILD) is a common and potentially life-threatening adverse event associated with trastuzumab deruxtecan (T-DXd). In the pivotal T-DXd clinical trials, 10-15% of patients developed ILD, with stringent mitigation strategies aimed at the early detection of low-grade cases. Real-world data are urgently needed to assess ILD incidence and outcomes outside controlled trial settings. This retrospective analysis included 190 patients treated with T-DXd at the Vienna Healthcare Group between August 2020 and December 2023. Among them, 17 (8.9%) developed any-grade ILD, with 8 cases (4.2% of the total cohort; 47.1% of ILD cases) classified as grade ≥3. The median time to ILD onset was 86 days, with a significantly shorter onset for high-grade compared to low-grade ILD (44.5 vs. 119 days, p = 0.01). A pooled real-world analysis (n = 1255, including patients from this study) demonstrated a higher incidence of high-grade ILD in real-world settings compared to phase III trials (2.9% vs. 1.4%, p = 0.014), despite no significant difference in overall ILD incidence (10.4% vs. 11.1%, p = 0.62). However, high-grade ILD rates in the real-world cohort were comparable to those reported in early phase I/II trials (2.9% vs. 3.5%, p = 0.41). These findings suggest a greater risk of high-grade ILD in real-world settings and underscore the need for rigorous patient selection, screening, and management strategies in clinical practice. Furthermore, the shorter onset of high-grade ILD suggests distinct pathophysiological mechanisms that warrant further investigation.