Risk factors for drug-induced pneumonitis from trastuzumab deruxtecan in patients with advanced HER2-positive solid malignancies.

e24153 Background: Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate that has demonstrated significant efficacy in treating multiple types of advanced HER2-positive solid malignancies. However, drug-induced pneumonitis is a known toxicity of T-DXd (incidence of up to 15%) and can have severe consequences. This study investigated potential risk factors for developing T-DXd-induced pneumonitis. Methods: We conducted a single center retrospective chart review of 235 patients with advanced HER2-positive solid malignancies (breast, lung, gastrointestinal, uterine, ovarian, bladder, salivary gland) who received at least one dose of T-DXd between December 2019 to March 2025. Variables including demographics (age, sex, race/ethnicity), smoking status, functional status, lung conditions (asthma, COPD, prior drug-induced or radiation pneumonitis, lung metastases, malignant pleural effusion), cancer type, prior immunotherapy, and T-DXd dose were collected. Severity of drug-induced pneumonitis was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Univariate and multivariate logistic regression analysis was used to evaluate potential risk factors for T-DXd-induced pneumonitis. Results: Of the 235 patients who received T-DXd, 33 patients (14%) developed T-DXd-induced pneumonitis. 12 (36%) had grade 1, 13 (39%) had grade 2, 5 (15%) had grade 3, 1 (3%) had grade 4, and 2 (6%) had grade 5 drug-induced pneumonitis, respectively. Multivariate logistic regression analysis identified significant risk factors for T-DXd-induced pneumonitis including prior drug-induced pneumonitis from previous cancer therapies (OR 5.76, 95% CI 1.64-20.26, p = 0.006), prior radiation pneumonitis (OR 7.60, 95% CI 2.20-26.29, p = 0.001), lung cancer (OR 3.71, 95% CI 1.08-12.68, p = 0.037), and malignant pleural effusion (OR 2.50, 95% CI 1.16-5.37, p = 0.019). In addition, malignant pleural effusion was associated with a higher incidence of high-grade (grades 3-5) compared to low-grade (grades 1-2) T-DXd-induced pneumonitis (OR 18.00, 95% CI 1.86-174.21, p = 0.013). No significant association was found with other variables evaluated. Conclusions: In this study, underlying lung conditions including prior drug-induced pneumonitis, prior radiation pneumonitis, lung cancer, and malignant pleural effusion were associated with a higher risk of developing T-DXd-induced pneumonitis. These findings suggest that patients with pre-existing lung conditions and thus compromised lung reserve may be more susceptible to potential off-target pulmonary toxicity effects of T-DXd and could warrant closer monitoring during the treatment course.