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

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Abstract 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; p = 0.009). Median time to onset was 144 days. Grade 5 pneumonitis occurred in three patients. In univariable competing-risk analysis, a higher T-DXd dose (subdistribution hazard ratio [sHR], 2.43; p = 0.001) and a short washout from prior therapy (≤14 days; sHR, 4.62; p = 0.01) were associated with pneumonitis. In the lung cancer subgroup, current smoking was associated with pneumonitis in an exploratory adjusted model (sHR, 3.55; p = 0.002). Pneumonitis was associated with a 3-fold increased mortality risk in adjusted time-varying Cox analysis (HR, 3.26; p = 0.003). 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.