Enhertu outperforms standard first-line therapy in HER2-mutant NSCLC

Topline results from the phase 3 DESTINY-Lung04 trial showed that Enhertu (trastuzumab deruxtecan) significantly and clinically meaningfully improved progression-free survival (PFS) compared with the current global standard of care—platinum-pemetrexed chemotherapy plus pembrolizumab—as first-line treatment for unresectable, locally advanced, or metastatic HER2-mutant nonsquamous non-small cell lung cancer (NSCLC).

The finding could be practice-impacting because HER2 mutations occur in approximately 2%-4% of NSCLC, yet patients with HER2-mutant disease currently lack a HER2-directed first-line standard and are generally treated with chemoimmunotherapy. Enhertu is already approved for previously treated HER2-mutant metastatic NSCLC; a positive phase 3 comparison against first-line standard therapy raises the possibility of moving HER2-targeted treatment earlier in the disease course.

DESTINY-Lung04 enrolled 454 patients with HER2 exon 19 or 20 mutations. The trial’s safety findings were generally consistent with Enhertu’s known profile, with no new safety concerns identified. Overall survival and other secondary endpoints remain under evaluation, and numerical PFS results have not yet been disclosed. Full data are planned for presentation at a future medical meeting and submission to regulatory authorities.

Source: AstraZeneca. (2026 Aug 17). Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival as 1st-line treatment of patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 Phase III trial