Phase 3 DESTINY-Lung04: first-line T-DXd extends PFS in HER2-mutant NSCLC, with no overall survival benefit so far

In the open-label phase 3 DESTINY-Lung04 trial (454 patients, 227 per arm), first-line trastuzumab deruxtecan extended median progression-free survival to 14.3 months (95% CI 12.4-16.5) versus 8.3 months (95% CI 7.0-9.9) with pembrolizumab plus platinum chemotherapy (HR 0.63; 95% CI 0.50-0.79; p<0.0001). Overall survival data were 46.9% mature with no formal hypothesis testing and showed no benefit (median 29.3 vs 33.1 months; HR 1.15; 95% CI 0.88-1.52), which the sponsor attributes in part to imbalanced subsequent therapies. Interstitial lung disease was reported in 20.8% of patients given T-DXd, including grade 5 (fatal) events in 1.8% (4 patients). The results were presented at the IASLC World Conference on Lung Cancer 2026 and have not yet appeared in a peer-reviewed journal.