A comprehensive real-world analysis presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrates that rechallenging patients with trastuzumab deruxtecan (T-DXd, Enhertu) after grade 1 interstitial lung disease (ILD) is safe and provides sustained clinical benefit. The multi-institutional study offers critical guidance for managing one of the most concerning adverse events associated with this pivotal HER2-targeted therapy.
Study Design and Patient Population
The retrospective cohort study analyzed data from 1,476 patients treated with T-DXd across five US institutions between 2017 and 2024. Among these patients, 143 (9.7%) developed any-grade ILD, with 59 patients experiencing grade 1 ILD and being eligible for rechallenge consideration.
Of the 59 patients with grade 1 ILD, 44 patients (75%) were rechallenged with T-DXd. The remaining 15 patients were not rechallenged due to disease progression at ILD diagnosis (n=6), provider discretion (n=8), or intolerable adverse effects (n=1).
Rechallenge Outcomes and Safety Profile
Patients who were rechallenged remained on T-DXd for a median of 215 days, demonstrating substantial clinical benefit. The median time to rechallenge was 42 days following the last dose prior to ILD diagnosis. Notably, 61% of rechallenged patients received a dose reduction, while 38% were rechallenged during completion of a steroid taper.
Recurrent ILD occurred in 27% of rechallenged patients, with most cases being grade 1 (n=9), and fewer experiencing grade 2 (n=2) or grade 3 (n=1). The median time to ILD recurrence was 211 days. Importantly, no patients died from ILD after rechallenge, with the overall ILD mortality rate being 0.5%.
Impact of Steroid Treatment
The study revealed a significant benefit of steroid treatment for grade 1 ILD management. Patients treated with steroids showed radiographic improvement in a median of 29 days, compared to 82 days for those without steroids—a statistically significant difference. Among the 44 rechallenged patients, 66% were treated with steroids for a median of 36 days.
"I routinely treat with 0.5 mg/kg of steroids to promote faster recovery," said Hope Rugo, MD, professor in the Department of Medical Oncology & Therapeutics Research and division chief of Breast Medical Oncology at City of Hope, who presented the findings.
Clinical Practice Implications
The data provide reassurance for clinicians managing patients who develop grade 1 ILD on T-DXd therapy. For patients with grade 1, asymptomatic ILD—characterized by ground glass opacities on diagnostic chest CT imaging without symptoms—the recommendation is to hold the drug, monitor for recovery through radiographic changes, and resume therapy once ILD has resolved completely.
The study also examined outcomes in 19 patients with grade 2 ILD who were rechallenged outside current guidelines. These patients remained on T-DXd for a median of 91 days, with 16% developing recurrent ILD. While the numbers are small, this suggests potentially higher risk when rechallenging after grade 2 events.
Monitoring Recommendations
Based on the findings, Rugo recommends diagnostic CT scans at 9 weeks, then again at 12 weeks, continuing this pattern for the first year since 89% of ILD cases occur within the first year. For higher-risk patients—including older individuals, those heavily pretreated, those with prior ILD from other drugs, or with renal insufficiency—an initial CT at 6 weeks is recommended to catch early changes.
Multiple Rechallenge Experience
Three patients with grade 1 ILD who were rechallenged experienced recurrent grade 1 ILD and were subsequently rechallenged a second time. Two patients remained on treatment for 63 and 211 days respectively before disease progression, while the third patient remained on treatment as of the May 2025 data cutoff.
The study's findings support the safety and efficacy of T-DXd rechallenge after grade 1 ILD in real-world practice, potentially maximizing the therapeutic benefit of this important HER2-targeted therapy while maintaining patient safety. The data demonstrate that with appropriate monitoring and steroid management, patients can safely continue to benefit from T-DXd therapy even after experiencing grade 1 ILD.
