Safety Observed With T-DXd Rechallenge After ILD Instance in Breast/Solid Tumors

T-DXd rechallenge occurred after grade 1 ILD, and was proven safe for patients with breast cancer/solid tumors.

Results from a multi-institutional retrospective cohort study found fam-trastuzumab deruxtecan-nxki (T-DXD; Enhertu) rechallenge was safe after grade 1 interstitial lung disease (ILD) instance during initial treatment for patients with breast cancer and solid tumors, according to results presented at the 2025 American Society of Clinical Oncology Annual Meeting.

Findings showed that among the 59 patients who experienced grade 1 ILD and were eligible for rechallenge with T-DXd, 75% (n = 44) were rechallenged. Reasons for patients not being rechallenged (n = 15) included disease progression at the time of ILD diagnosis (n = 6), provider discretion (n = 8), and intolerable adverse effects (AEs; n = 1).

The median time to rechallenge was 42 days (IQR, 34-64) following the last dose of T-DXd prior to ILD diagnosis. In patients who were rechallenged, 7% received intervening therapy prior to rechallenge, 61% were rechallenged with a dose reduction, and 38% were rechallenged during the completion of a steroid taper.

Rechallenged patients remained on T-DXd for a median of 215 days (IQR, 74-319). Recurrent ILD was reported in 27% of patients at grade 1 (n = 9), grade 2 (n = 2), and grade 3 (n = 1); the median time to ILD recurrence was 211 days (IQR, 72-295).

“Rechallenge with T-DXd after grade 1 ILD was safe. Patients in a diverse real-world population had ongoing clinical benefit from T-DXd, with long-term benefit in the majority of patients,” presenting study author Hope S. Rugo, MD, said during the presentation. Rugo is a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women's Cancers Program at City of Hope in Duarte, California.

Since its initial approval from the FDA in 2019, T-DXd has been approved across multiple solid tumors.² One indication includes the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

Within the breast cancer realm, T-DXd is approved in the following indications:

• For adult patients with unresectable or metastatic HER2-positive (IHC 3+ or in situ hybridization [ISH]+) breast cancer who have received a prior anti-HER2–based regimen either in the metastatic setting; or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy
• For adult patients with unresectable or metastatic hormone receptor (HR)–positive, HER2-low (IHC 1+ or IHC 2+/ISH–) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on 1 or more endocrine therapies in the metastatic setting
• For adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH–) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting; or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

T-DXd and ILD

During her presentation, Rugo explained that the risk of any-grade ILD associated with T-DXd is approximately 12% to 15%, and the risk of grade 5 ILD is approximately 1% to 2%.¹ This AE has prompted close monitoring for symptoms of ILD and imaging for patients receiving T-DXd.

Guidelines developed for managing ILD call for holding T-DXd in patients who experience a grade 1 AE, which comprises findings of ILD on imaging without symptoms. For these patients, the guidelines call for steroids to be considered, and T-DXd can be rechallenged once ILD resolves. In patients with grade 2 or higher ILD, which all include symptoms, the guidelines call for T-DXd to be permanently discontinued, and patients should immediately receive steroids.

Despite the guidelines, Rugo said that limited data are available regarding the real-world rechallenge of T-DXd in patients who develop grade 1 ILD.

To further assess real-world outcomes when rechallenging with T-DXd, Rugo and colleagues conducted a retrospective study that included patients treated with T-DXd for any cancer type at 1 of 5 institutions between 2017 and 2024. Patients who experienced ILD were identified by chart and ICD code reviews; T-DXd–related ILD instances were adjudicated based on the assessment of the treatment physician and graded based on CTCAE v5 criteria.

Patient Identification

Among the 1476 evaluable patients who received T-DXd between 2017 and 2014, 9.7% (n = 143) experienced any-grade ILD, including the 59 patients who had grade 1 ILD.Among the 44 patients with grade 1 ILD who were rechallenged, 26 were rechallenged after CT scans showed improvement of ILD, and 18 were rechallenged prior to CT scan findings. Among the 143 patients who had any-grade ILD, 45% (n = 65) permanently discontinued T-DXd due to grade 2 ILD (n = 35), grade 3 ILD (n = 16), grade 4 ILD (n = 6), or grade 5 ILD (n = 8). The mortality rate due to ILD was 0.5%.

In the 44 patients with grade 1 ILD who were rechallenged with T-DXd, the median age at the first dose of treatment was 60 years (IQR, 52-68), and the median time to onset of ILD from the first dose of the antibody-drug conjugate was 144 days (IQR, 77-216). Most patients in this group had breast cancer (86%), and the remaining patients (14%) comprised gastrointestinal, gynecologic, or lung tumors. Patients received a median of 3 (IQR, 1-4) lines of therapy prior to T-DXd. Twenty-three percent of patients had renal impairment. Additionally, 66% were treated with steroids for a median of 36 days (IQR, 21-76). The median time to radiographic ILD improvement was 39 days (IQR, 22-84).

In the 15 patients with grade 1 ILD who were not rechallenged, the median age at the start of treatment with T-DXd was 63 years (IQR, 48-72), and the median time to onset of ILD was 198 days (IQR, 123-334). Ninety-three percent of patients in this group had breast cancer, and 1 patient (7%) had another tumor type. Patients received a median of 2 (IQR, 2-5) prior lines of therapy. Twenty percent of patients had renal impairment, and 40% were treated with steroids for a median of 35 days (IQR, 25-49). The median time to radiographic ILD improvement was 80 days (IQR, 64-99).

Additional Data

Three patients with grade 1 ILD who were rechallenged with T-DXd were subsequently rechallenged a second time following a recurrence of grade 1 ILD. One of these patients was rechallenged a second time at a reduced dose. Two of these patients remained on treatment for 63 and 211 days, respectively, prior to disease progression; as of the May 8, 2025, data cutoff, the third patient remained on treatment.

Notably, 19 patients who experienced grade 2 ILD were rechallenged outside of the ILD management guidelines. The median time to rechallenge was 49 days (IQR, 42-126), and patients received T-DXd for a median of 91 days (IQR, 27-162) after being rechallenged. Recurrent ILD was reported in 16% of patients at grade 2 (n = 1), grade 3 (n = 1), and grade 4 (n = 1).

Notably, no grade 5 ILD occurred in any patients who were rechallenged across the study.

References

1. Natsuhara KH, Blum K, LeVee AA, et al. Treatment rechallenge after trastuzumab-deruxtecan–related interstitial lung disease: a multi-institution cohort study. J Clin Oncol. 2025;43(suppl 16):1015. doi:10.1200/JCO.2025.43.16_suppl.1015
2. Enhertu. Prescribing information. January 2025. Accessed May 30, 2025. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true