Rechallenge with the HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) after grade 1 interstitial lung disease (ILD) appeared to be safe in a diverse real-world population, including many patients with breast cancer, as presented during the 2025 ASCO Annual Meeting.1 The retrospective multicenter cohort study also demonstrated sustained clinical benefit.
“Treatment with steroids resulted in faster radiographic improvement of ILD, and the rates of recurrent ILD in those rechallenged were low and mostly grade 1,” added Hope S. Rugo, MD, FASCO, Professor Emeritus at the University of California San Francisco (UCSF) and currently Director of the Women’s Cancers Program, Division Chief of Breast Medical Oncology and Professor, Department of Medical Oncology & Therapeutics Research at the City of Hope Comprehensive Cancer Center. “A small number of patients with grade 2 ILD were rechallenged, with a similar rate of recurrent ILD but higher grade overall, but these data must be interpreted with caution….”
Background
Treatment with T-DXd has been approved by the U.S. Food and Drug Administration (FDA) for advanced HER2-positive and HER2-low/ultralow breast cancers, as well as for other HER2-positive or mutated solid tumors. According to Dr. Rugo, T-DXd carries a 12% to 15% risk of any-grade interstitial lung disease, with 1% to 2% of these cases being fatal. She highlighted the following points from a set of guidelines for the use of T-DXd in breast cancer, with a focus on managing interstitial lung disease:
- Grade 1 interstitial lung disease (asymptomatic; imaging findings only): T-DXd should be held; consider treatment with steroids; and T-DXd rechallenge is an option after imaging findings have resolved;
- Grade 2 or higher interstitial lung disease (symptomatic): T-DXd should be permanently discontinued; and steroids should be administered immediately.2
Dr. Rugo and colleagues previously conducted a pooled analysis of nine T-DXd trials, finding that approximately 23% of patients with grade 1 interstitial lung disease were retreated; about 18% of those were treated for more than 1 year, with one-third experiencing low-grade recurrent interstitial lung disease.3,4 However, a question remained: In real-world settings, how frequently is rechallenge attempted after T-DXd–related interstitial lung disease, and what are the associated patient outcomes?
Study Design
Dr. Kelsey Natsuhara (medical oncology fellow at UCSF and now Assistant Professor at UCSF), Dr. Rugo, and colleagues identified 1,476 patients from five U.S. institutions (UCSF, City of Hope, University of Minnesota, Baptist Health Miami Cancer Institute, and Mayo Clinic) who were treated with T-DXd for any cancer type between 2017 and 2024. Diagnostic code and chart reviews were performed to isolate those with any-grade interstitial lung disease (n = 143; 9.7%). The treating provider adjudicated T-DXd–related interstitial lung disease events and provided grading.
Rechallenge was attempted in 44 of the 59 eligible patients with grade 1 interstitial lung disease (75%). Of this population, 18 and 26 were rechallenged before and after CT improvement, respectively. A total of 19 patients with grade 2 interstitial lung disease were rechallenged outside the guidelines.
Rechallenge After Grade 1 Interstitial Lung Disease
In the 44 patients with grade 1 interstitial lung disease who were rechallenged, the onset of interstitial lung disease was documented at a median of 144 days after the first T-DXd dose. Most had breast cancer (n = 38; other [gastrointestinal, gynecologic, lung]: n = 6) and received three lines of prior therapy in the advanced or metastatic setting. Renal impairment was seen in approximately one-fifth of the population. More patients who did vs did not undergo rechallenge were treated with steroids (29 vs 6), and they were found to experience a shorter time to radiographic improvement of interstitial lung disease. The median time to radiographic improvement of interstitial lung disease appeared to be shorter in patients treated with steroids than in those who were not (29 vs 82 days; P < .001).
Rechallenge occurred at a median of 42 days from the last dose before the onset of interstitial lung disease. A total of 3 patients (7%) received intervening therapy before the rechallenge; 27 patients (61%) were rechallenged with a dose reduction; and 17 patients (38%) were rechallenged while completing steroid taper. According to Dr. Rugo, after the rechallenge, patients continued T-DXd therapy for a “remarkable” median of 215 days.
A total of 12 patients (27%) developed recurrent interstitial lung disease, and 9 cases were grade 1. The median time to recurrence was 211 days, and according to Dr. Rugo, “there were no known factors that predicted recurrence.”
“The three patients who were rechallenged a second time did very well,” she stated, also noting that two of them were rechallenged without a dose reduction. “They stayed on T-DXd for 63 and 211 days, with the third patient remaining on T-DXd as of May of this year.”
Rechallenge After Grade 2 Interstitial Lung Disease
In the 19 patients with grade 2 interstitial lung disease who were rechallenged outside the guidelines, the median time to rechallenge was 49 days. Patients continued T-DXd therapy for a median of 91 days after rechallenge. “Three of these patients developed recurrent interstitial lung disease,” noted Dr. Rugo, “and they were of higher grade, with one grade 3 and one grade 4; however, there were no grade 5 cases of recurrent interstitial lung disease seen after rechallenge in any patient.”
“Our large cohort data further support the safety of T-DXd rechallenge in diverse real-world settings,” the investigators concluded.
DISCLOSURE: Dr. Rugo has received honoraria and served as a consultant or advisor to Napo Pharmaceuticals, Bristol Myers Squibb, Helsinn Therapeutics, and BioNTech; and has received research funding to her prior institution (UCSF) from AstraZeneca, Gilead Sciences, Lilly, Merck & Co., Daiichi Sankyo, Novartis Pharmaceuticals, Pfizer, F. Hoffmann–La Roche/AG/Genentech, Stemline Therapeutics, and Ambrx. For full disclosures of the other study authors, visit coi.asco.org.
REFERENCES
- Natsuhara KH, Blum K, LeVee AA, et al: Treatment rechallenge after trastuzumab-deruxtecan–related interstitial lung disease: A multi-institution cohort study. 2025 ASCO Annual Meeting. Abstract 1015. Presented May 30, 2025.
- Rugo HS, Bianchini G, Cortes J, et al: Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open 7:100553, 2022.
- Rugo HS, Tokunaga E, Iwata H, et al: 267MO Pooled analysis of trastuzumab deruxtecan retreatment after recovery from grade 1 interstitial lung disease/pneumonitis. ESMO Open 9:103326, 2024.
- Rugo HS, Tokunaga E, Iwata H, et al: Pooled analysis of trastuzumab deruxtecan retreatment after recovery from grade 1 interstitial lung disease/pneumonitis. Ann Oncol. August 4, 2025 (early release online).
