Abstract Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2, conjugated with deruxtecan, a cytotoxic topoisomerase I inhibitor. While pneumonitis and interstitial lung disease are well-established complications of T-DXd therapy, little is known about their infection risks. We used trastuzumab emtansine (T-DM1), with an identical monoclonal antibody, to assess infection risk of T-DXd. We retrospectively analyzed infectious complications in patients with breast cancer who received at least one dose of T-DXd or T-DM1 at The Ohio State University between 2019 and 2024. Only the initial treatment for each patient was included in the statistical analysis. Multivariable logistic regression was used to evaluate the association between treatment group and infection, adjusting for clinical risk factors (lymphopenia, neutropenia, line of therapy, key demographics). 126 patients were treated with T-DXd, 196 with T-DM1, and 53 with both. Of patients treated with both, 5 received T-DXd first and 48 received T-DM1 first. There was no significant difference in selected demographics and medical history between treatment groups. 34 patients developed infections on T-DM1 treatment and 33 on T-DXd. Treatment duration was similar. T-DXd patients had lower lymphocyte counts at time of infection compared to T-DM1 (745 cells/μL 350, 1100 vs 1295 cells/μL 840, 1975, p = 0.002). There was no significant difference in time from treatment initiation to first infection, concurrent steroid administration, or lymphocyte or neutrophil counts at treatment initiation. Patients treated with T-DXd had higher incidence of total infections (25.2% vs 13.9%, p = 0.007), infection-related mortality (18% vs 0%, p = 0.01), and bloodstream infections (27.3% vs 2.9%, p = 0.006). In the T-DXd group, two patients developed PJP and one developed both PJP and CMV, all were on corticosteroid treatment preceding infection. No T-DM1 patients developed opportunistic infections. After adjusting for confounding variables, there was no difference in infection risk between T-DXd and T-DM1 (OR 1.84, 95% CI 0.86-3.98, p = 0.12). While unadjusted infection incidence was higher for the T-DXd group, the adjusted model showed no statistically significant association between infection risk and T-DXd compared to T-DM1. This suggests that the observed increased incidence of infections with T-DXd may reflect concurrent comorbidities rather than the drug itself. Opportunistic infections were rare, however concurrent treatment with steroids was present in all cases. As T-DXd is increasingly utilized in various malignancies, pulmonologists and intensivists need to be hypervigilant of the risk of opportunistic infections in patients on concurrent T-DXd and steroids. This abstract is funded by: None
Gayfield et al. (Fri,) studied this question.