Secondary safety analysis of trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in DESTINY-Breast05: Clinical and demographic risk factors of interstitial lung disease (ILD) and radiation pneumonitis (RP).

516 Background: In DESTINY-Breast05 (NCT04622319), T-DXd showed superior efficacy vs T-DM1 in patients (pts) with human epidermal growth factor receptor 2-postive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant therapy (NAT) and high risk of recurrence—a population in which radiotherapy (RT) is broadly used. Safety was consistent with the established T-DXd profile; ILD remained an important risk, although most cases were low grade. Previous T-DXd pooled analyses suggested potential associations between ILD and clinical and demographic factors. We report additional safety outcomes stratified by these risk factors. Methods: Pts with residual invasive HER2+ eBC and at high risk of recurrence after NAT were randomized 1:1 to receive T-DXd 5.4 mg/kg (n = 818) or T-DM1 3.6 mg/kg (n = 817) once every 3 weeks for 14 cycles. All pts underwent low-dose non-contrast chest computed tomography (CT) at screening. Pts who received adjuvant RT (aRT; either concurrently with or sequentially before study therapy) underwent additional low-dose CT during and after treatment completion. CT scans showing ILD or RP underwent blinded central adjudication. Results: At data cutoff (July 2, 2025), 806 pts in the T-DXd arm and 801 pts in the T-DM1 arm received ≥1 dose of treatment; no pts were ongoing study treatment. In the T-DXd arm, 93.9% of pts received aRT vs 93.6% in the T-DM1 arm. Adjudicated drug-related (adj DR) ILD rates were generally consistent across global regions (Asia, Europe, North America [NA] + Australia, and Rest of World), though numerically lower in NA + Australia for T-DXd. In both arms, adj DR ILD rates were higher in pts from Japan (n = 147) vs outside Japan (n = 1460; T-DXd: 14.9% vs 8.9%; T-DM1: 6.7% vs 1.2%), Japan vs other Asian countries (T-DXd: 14.9% vs 9.6%; T-DM1: 6.7% vs 2.1%), and in pts with baseline moderate vs normal renal impairment (T-DXd: 14.3% vs 9.7%; T-DM1: 5.0% vs 1.0%). Adj DR ILD incidence was comparable across racial subgroups. In both arms, investigator-reported RP rates were higher in pts from Japan vs outside Japan (T-DXd: 47.1% vs 27.4%; T-DM1: 45.0% vs 27.3%). Most ILD/RP events recovered or were recovering with protocol-specific management. Recovery/resolution was observed in 64.5% vs 75.0% of adj DR ILD events and 38.2% vs 43.2% of RP events in the T-DXd and T-DM1 arms, respectively. Conclusions: Adj DR ILD and RP events were mostly low grade and reversible with protocol-specific management guidelines. Adj DR ILD rates were higher with T-DXd than T-DM1 and were influenced by country and baseline renal function, consistent with prior pooled analysis. These findings are consistent with, and further characterize, the safety profile of T-DXd in post-NAT HER2+ eBC. Clinical trial information: NCT04622319 .