Trastuzumab Deruxtecan-Associated Pneumonitis in Non-Breast Solid Tumors: A Retrospective Cohort Study
Abdelrahman M Attia1, Jose Carlos Tuesta Delgado2, Alexia Dayan Lecaros Zavalla2
1Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
