Abstract Background: Trastuzumab-deruxtecan (T-DXd) is approved for advanced HER2+, low, and ultra-low advanced breast cancer, and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) after resolution of imaging findings. Limited data exist on T-DXd related ILD imaging findings and clinical outcomes after RC in patients (pts) treated in the real-world setting. Methods: We analyzed all pts treated with T-DXd at our institution from Sept 2018-June 2024. We identified pts with radiographic evidence of ILD by chart review. Adjudication of T-DXd related ILD was by treating provider and graded via CTCAE v5. A chest radiologist conducted a blinded review of baseline and follow-up chest CTs (up to 4 mos post T-DXd) for all pts treated with T-DXd, to identify possible cases of drug-related ILD and assess imaging improvement over time. Results: Of 214 pts treated with T-DXd, 44 (21%) developed ILD (27-G1, 8-G2, 4-G3, 3-G4, 2-G5). Median (med) ILD onset was 116 days (d) after 1st dose range (r:) 9-833. Among pts with ILD, 37 had breast, 5 had GI, 1 had lung, and 1 had head and neck cancer, with a med age of 59 yrs (r: 36-78), med 3 prior therapy lines for advanced disease (r: 0-13); 8/44 pts (18%) had renal impairment (CrCl60mL/min). Among pts with G1 ILD, 21/27 (78%) received steroids for a med of 49d (r: 15-149). Radiographic improvement was seen at a med of 23d (r: 9-79) for pts treated with steroids vs 66d (r: 28-82) without steroids. Of 27 pts with G1 ILD, 22 (81%) were RC with T-DXd; 4 had PD at ILD diagnosis, 1 was not RC due to persistent CT findings. Med time to RC was 42d (r: 20-236); 2 pts received intervening therapy before RC. After RC, 15 pts remained on T-DXd without recurrent ILD for a med of 95d (r: 20-365); 1 pt remained on T-DXd at data lock (6/26/25); 7 pts (32%) had recurrent ILD at a med of 47d after RC (r: 20-331; 5-G1, 2-G2). Four pts with recurrent G1 ILD were RC a 2nd time (2 dose reduced) and remained on T-DXd for a med of 152d (r: 92-370); 1 pt with recurrent G1 ILD, 3 with PD, 1 remained on T-DXd at data lock. Imaging review showed complete resolution of ILD in 4 of 27 pts with G1 ILD, partial response in 15, stable disease in 2, worsening ILD in 1, and 4 were unevaluable due to missing follow-up imaging. Med time from initial ILD diagnosis to complete or partial response was 32d (r: 9-209). All 7 pts with recurrent ILD after RC had partial imaging responses before RC. 22 pts had imaging findings consistent with possible ILD but were not diagnosed with or treated for T-DXd associated ILD. Per clinician assessment, imaging findings were attributed to PD (n=7), viral infection (n=5), aspiration/infection (n=4), radiation changes (n=2), and in 4 cases, ILD findings were not documented in the official report. These 22 pts remained on T-DXd for a med of 152d (r: 20-949) and were never clinically diagnosed or treated for ILD; 21pts stopped T-DXd for PD and 1 remained on T-DXd at data lock. Conclusions: In this real-world, single institution cohort, high rates of T-DXd RC after G1 ILD were reported with long duration of clinical benefit. After RC, low rates of low grade recurrent ILD were seen with no G5 events. Four pts with recurrent G1 ILD were RC a 2nd time with only 1 case of recurrent G1 ILD. Most pts with G1 ILD did not have complete resolution of ILD findings on CT. By imaging review, some patients had CT findings possibly concerning for ILD; however, providers identified alternative causes—underscoring the challenge of diagnosing T-DXd related ILD. This cohort provides clinically important information on RC safety and imaging characteristics associated with T-DXd related ILD. Citation Format: K. H. Natsuhara, M. Vella, S. C. Behr, N. Reddy, A. J. Chien, M. E. Melisko, M. Majure, G. C. Buckle, E. J. Walker, L. Al Rabadi, A. Ko, M. L. Cheng, A. Algazi, H. Batra-Sharma, L. N. Quintal, L. A. Huppert, H. S. Rugo. A real-world experience of treatment rechallenge after grade 1 trastuzumab-deruxtecan related interstitial lung disease: clinical outcomes and blinded imaging review abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-15.
Natsuhara et al. (Tue,) studied this question.