Trastuzumab Deruxtecan (T-DXd)-associated interstitial lung disease (ILD) in a large real-world French cohort of patients with HER2-driven breast cancer and other malignancies.

<bold>Background:</bold> The high incidence of potentially fatal ILD during T-DXd's clinical development prompted investigation in a real-world setting. <bold>Methods:</bold> This retrospective multicenter study enrolled all patients exposed to T-DXd in 11 French centers from April 18, 2019, to November 26, 2023. CT scans from T-DXd-ILD cases were centrally reviewed. <bold>Results:</bold> 600 patients (pts) were included during the study period. The majority were female (95%), and 77% non-smokers with a median age of 60 years old (IQR 55-73). 78% received prior chest radiotherapy and 54% prior HER-targeted therapy. 93% pts had a HER-driven breast cancer (HER2-high, 54%; HER2-low, 39%) and 3.8% a lung cancer. 67 pts (11.2%) developed a T-DXd-ILD with a median onset of 82 days (IQR 49-192). In 80% of cases, the primary cancer was controlled and 55% had lung metastatis. 51% had no respiratory symptoms. Radiological findings were ground glass opacities (87%) and consolidations (61%), with organizing pneumonia (52%) as the most common pattern and diffuse alveolar damage (DAD) being observed in 9%. ILD severity was grade 1-2: 81%, grade 3-4: 10%, and 9% (6/67) were fatal ILD, among whom 4 had a DAD pattern. T-DXd was withdrawn in 50 pts (75%) among whom 30 (60%) received corticosteroids and 18 (60%) improved. Interestingly, previous ILD was identified in 16 of the 67 pts who developed T-DXd-ILD and in 6 of the 533 pts without ILD (p<0.001). <bold>Conclusion:</bold> This first large non-Asian real-world cohort highlights the need for a vigilant monitoring and effective management of T-DXd-ILD, particularly those with a DAD pattern. Further analyses are forthcoming.