T-DXd Rechallenge After Grade 1 ILD Appears Safe, Study Finds

In an abstract presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Kelsey Natsuhara, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, and colleagues presented findings from a multicenter center study which revealed that high rechallenge (RC) success rates with trastuzumab-deruxtecan(T-DXd) were observed after grade 1 (G1) interstitial lung disease (ILD), with a prolonged duration of clinical benefit.

Dr. Natsuhara and colleagues wrote, “T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low 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 greater than grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, the drug is held with the option for RC if imaging findings resolve.”

The authors also noted that limited data are available on outcomes of RC after ILD in diverse real-world patients.

This retrospective, multi-center study examined patients with ILD related to T-DXd from 2017 to 2024. ILD cases were identified through chart reviews and ICD code assessments. T-DXd-related ILD was determined by evaluation from treating clinicians, with grading based on Common Terminology Criteria for Adverse Events v5 standards. Researchers collected data on demographics, T-DXd and steroid dosages, imaging results, and outcomes after rechallenge (RC). Statistical analysis used the Wilcoxon rank sum and Fisher’s exact tests.

Results revealed that four centers administered T-DXd to 712 patients, reporting an ILD rate of any grade of 9.1% (n=65). One center provided RC data for 18 patients with ILD; 47 patients achieved RC; 38 after G1 ILD (81%) and nine after G2. The median time to initial ILD was 145 days post-first dose.

Among 50 patients with G1 ILD, 28 (56%) received steroids for a median of 36 days. Median radiographic improvement was noted after 24 days for steroid-treated patients compared to 82 days for those without. Radiographic improvement was observed for RC patients at 35 days versus 81 days for non-RC patients. Among patients with G1 ILD, 38 of 50 (76%) achieved RC within a median of 42 days after the last dose; of these, 23 (61%) had a dose reduction. After RC, patients continued T-DXd for a median of 215 days, with 10 (26%) experiencing recurrent ILD (7-G1, 2-G2, 1-G3) at a median of 211 days after RC.

No meaningful variances were observed in ILD onset, time to RC, or demographics between patients with and without recurrent ILD. Among nine patients who achieved RC after G2 ILD, T-DXd was continued for a median of 129 days, with two (22%) developing recurrent ILD (1-G2, 1-G3), and no G5 toxicity cases were observed with RC.

“In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Patients treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously,” concluded the authors.

Finally, the authors noted that the data obtained from this large cohort further substantiate the safety of T-DXd RC in various real-world settings.