267MO Pooled analysis of trastuzumab deruxtecan (T-DXd) retreatment (RTx) after recovery from grade (Gr) 1 interstitial lung disease/pneumonitis (ILD)

T-DXd, an approved therapy for multiple cancers, carries a risk of interstitial lung disease/pneumonitis (ILD) which may have fatal outcomes if not appropriately identified and managed. Management guidelines require interrupting T-DXd for all ILD grades, even if asymptomatic, but patients (pts) with Gr 1 ILD may be retreated upon complete radiographic recovery. In this retrospective analysis of T-DXd trials, we examined RTx duration and recurrence of ILD (rILD). Data were pooled from 9 clinical trials of pts with HER2-altered breast, gastric, colorectal, and non-small cell lung cancer who received ≥1 dose of T-DXd (5.4-8.0 mg/kg) monotherapy. T-DXd RTx duration and rILD were assessed in pts following Gr 1 first ILD (fILD); defined as complete recovery from investigator (inv)-assessed Gr 1 drug-related ILD, confirmed by an independent adjudication committee (AC). Overall, 9.0% (193/2145) of pooled pts had Gr 1 fILD, 50.3% (97/193) of whom received steroids. Per inv assessment or treatment dose discontinuation requirements (per protocol/label), 76.7% (148/193) of Gr 1 fILD pts were not eligible for T-DXd RTx. Following Gr 1 fILD, 23.3% (45/193) of pts were retreated with T-DXd. Median RTx duration was 85 d (range, 1-848 d); 31.1% (14/45) of pts were retreated with a 1-level reduced dose vs their original T-DXd dose; 17.8% (8/45) received T-DXd RTx for ≥1 year. Of those retreated: 2 pts (4.4% 2/45) had RTx before Gr 1 fILD was confirmed resolved, per AC, and events progressed to Gr 2 and Gr 3 (1 each), and 33.3% (15/45) had rILD (median time to rILD was 64 d range, 22-391 d). All pts with rILD received the same T-DXd dose level as their original dose: 40.0% (6/15) of rILD events were AC-assessed ILD Gr 1; 60.0% (9/15) Gr 2; no Gr ≥3 events. At the data cutoff from each trial, per inv assessment, 20.0% (3/15) of rILD cases were ongoing; 53.3% (8/15) of pts recovered without sequalae; 6.7% (1/15) recovered with sequalae; 20.0% (3/15) did not recover. This is the first pooled analysis of T-DXd RTx data after Gr 1 fILD recovery which shows clinically meaningful extension of treatment duration with RTx. All rILD events were of low grade and generally manageable using existing treatment guidelines.