Real-world risk of interstitial lung disease and pneumonitis with trastuzumab deruxtecan vs trastuzumab in HER2-positive metastatic breast cancer: A propensity score–matched analysis.

Abstract

e13030 Background: HER2-targeted antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have substantially improved clinical outcomes in patients with HER2-positive metastatic breast cancer. However, these clinical benefits must be balanced with notable safety concerns, especially pulmonary toxicities such as interstitial lung disease (ILD) and pneumonitis. This study aimed to evaluate and quantify the risk of ILD and pneumonitis associated with T-DXd in comparison to trastuzumab using real-world data. Methods: The data used in this retrospective observational study was collected on 22 January 2026 from the TriNetX Dataworks – USA network, which provided access to electronic medical records from more than 120 million patients across 69 healthcare organizations. Adult patients with malignant breast neoplasms treated with T-DXd or trastuzumab were included. Propensity score matching was applied to balance baseline characteristics. Patients with prior ILD or pneumonitis were excluded. Outcomes assessed within one year of treatment initiation included newly diagnosed ILD and pneumonitis. Risk estimates were calculated as risk differences, risk ratios (RR), and odds ratios (OR) with 95% confidence intervals (CI). Results: In a real-world cohort of HER2-positive metastatic breast cancer patients from the TriNetX Dataworks–USA network, 1,908 patients treated with trastuzumab deruxtecan (T-DXd) and 1,986 with trastuzumab were analyzed after propensity score matching. Within one year of treatment initiation, ILD incidence was significantly higher in the T-DXd group (5.7%) compared to trastuzumab (2.3%) [RR: 2.47, 95% CI: 1.76–3.46; OR: 2.56, 95% CI: 1.80–3.63; p < 0.001]. Pneumonitis incidence was also elevated with T-DXd (11.1% vs 6.8%) [RR: 1.63, 95% CI: 1.31–2.01; OR: 1.70, 95% CI: 1.35–2.15; p < 0.001]. Conclusions: In this large, propensity-matched real-world study, T-DXd is associated with a significantly increased real-world risk of ILD and pneumonitis compared to trastuzumab. Our findings underscore the need for heightened clinical vigilance when using T-DXd, including early recognition and management of respiratory symptoms. Further studies – ideally prospective cohorts or registry-based analyses – are recommended to refine risk stratification for T-DXd–associated pulmonary toxicity. Comparison of ILD & pneumonitis risk between T-DXd and trastuzumab treatment groups. Outcome T-DXd (n=1,908) Trastuzumab (n=1,986) Risk Difference (95% CI) RR (95% CI) OR (95% CI) p-value ILD 5.7% 2.3% 3.4% (2.2–4.6) 2.47 (1.76–3.46) 2.56 (1.80–3.63) <0.001 Pneumonitis 11.1% 6.8% 4.3% (2.4–6.1) 1.63 (1.31–2.01) 1.70 (1.35–2.15) <0.001