Trastuzumab Deruxtecan-Associated Pneumonitis in Non-Breast Solid Tumors: A Retrospective Cohort Study.

Introduction: Trastuzumab deruxtecan (T-DXd) has transformed treatment for HER2-expressing malignancies, yet pneumonitis remains a potentially fatal toxicity. Most pneumonitis data derive from breast cancer cohorts, but risk factors and outcomes in non-breast solid organ tumors are poorly characterized. Materials and Methods: We conducted a retrospective, single-center cohort study of adults with advanced non-breast solid organ tumors receiving T-DXd in routine clinical practice at a comprehensive cancer center (January 2019-May 2025). Pneumonitis was defined as new or worsening radiographic infiltrates not developing due to infection, disease progression, or an alternative etiology. Cumulative incidence was estimated using competing-risk methods. Fine-Gray subdistribution hazard regression identified risk factors, and extended Cox proportional hazards regression assessed the association between pneumonitis and overall survival. Results: Among 99 patients (median age, 65 years; 61% female), primary tumor sites included lung (43%), gynecologic (28%), gastrointestinal or esophageal (15%), and other (14%). Pneumonitis occurred in 11 patients (11.1%), predominantly among those with lung cancer (20.9% vs 3.6% non-lung; Conclusion: T-DXd-associated pneumonitis disproportionately affects patients with lung cancer and confers substantial mortality risk. A higher T-DXd dose and a short interval from prior therapy may increase pneumonitis risk but require validation in larger cohorts.