AstraZeneca (AZ) and partner Daiichi Sankyo have announced that the Phase III DESTINY-Lung04 trial met its primary endpoint, with Enhertu (trastuzumab deruxtecan) delivering statistically significant and clinically meaningful progression-free survival (PFS) improvement versus standard-of-care pembrolizumab plus platinum-doublet chemotherapy as first-line therapy in unresectable, locally advanced, or metastatic non-squamous non-small cell lung cancer (NSCLC) harbouring HER2 exon 19 or exon 20 mutations (n=454).

Enhertu becomes the first antibody-drug conjugate (ADC) to demonstrate single-agent superiority over a PD-1-based chemo-immunotherapy backbone in a first-line NSCLC Phase III, with overall survival and secondary endpoints still maturing.

Enhertu, first approved in the US in December 2019 and in China in 2023, already spans HER2-positive breast cancer, HER2-low and ultra-low breast cancer, gastric and gastro-oesophageal junction (GEJ) cancer, HER2-activated mutant NSCLC (second-line), and HER2-positive solid tumours.

The DESTINY-Lung04 result extends the franchise upstream into treatment-naive HER2-mutant NSCLC, a genomically defined subset historically forced into chemo-IO regimens despite low response durability. A first-line win reframes Enhertu from a later-line salvage option into a potential default initiation therapy in HER2-mutant lung cancer.