Pooled analysis of trastuzumab deruxtecan retreatment after recovery from grade 1 interstitial lung disease/pneumonitis

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate treatment for multiple solid tumors, carries risk of interstitial lung disease/pneumonitis (ILD). Management guidelines generally mandate interrupting T-DXd treatment for grade 1 ILD, with possible retreatment following resolution of imaging findings. This pooled analysis examined T-DXd retreatment duration and ILD recurrence following recovery from grade 1 ILD. Data were pooled from 9 clinical trials of patients with various HER2-positive, HER2-low, or HER2 (ERBB2)-mutant solid tumors treated with T-DXd (5.4-8.0 mg/kg). ILD events were reported and graded by investigators and confirmed as drug-related by an independent ILD adjudication committee. Patients who recovered from a first investigator-assessed grade 1 and adjudication committee-confirmed drug-related ILD event (ILD1) could receive T-DXd retreatment. Patients were evaluated until disease progression or data cutoff. Among 2145 pooled patients, 9% (193/2145) had grade 1 ILD1, of which 23.3% (45/193) were retreated with T-DXd. Median retreatment duration was 85 days (range, 1-848); 17.8% (8/45) of patients received T-DXd retreatment for ≥1 year. ILD recurrence (ILD2) occurred in 33.3% (15/45) of retreated patients; median time to ILD2 from T-DXd retreatment was 64 days (range, 22-391) and were low-grade events (grade 1, n=6; grade 2, n=9; no grade ≥3 or fatal events). Reasons for T-DXd retreatment discontinuation were disease progression (33.3% 15/45); ILD recurrence (20% 9/45); non-ILD adverse events (17.8% 8/45); physician's decision (4.4% 2/45). At the analysis cutoff, 24.4% (11/45) of retreated patients were still receiving treatment, and most patients with ILD2 (60% 9/15) had recovered with/without sequelae. This first large-scale pooled analysis demonstrates the safety of T-DXd retreatment after recovery from grade 1 ILD. ILD recurred in one-third of patients; all recurrence events were grade 1/2 and manageable using existing treatment guidelines. T-DXd retreatment following resolution of grade 1 drug-related ILD has potential to maximize therapeutic benefit.