Roche reported first-line efficacy for trastuzumab deruxtecan in HER2-mutant non-small cell lung cancer from the Phase 3 DESTINY-Lung04 trial. The study compared single-agent trastuzumab deruxtecan against pembrolizumab plus chemotherapy, delivering improved progression-free survival and response rates, while overall survival interpretation was complicated by imbalanced subsequent therapies. The trial’s design matters for competitors because it tests the antibody-drug conjugate in the earliest treatment setting, where treatment sequencing influences both durability and future lines of therapy. If subsequent analyses support OS benefit, the regimen could reshape first-line standard-of-care decisions in this molecularly defined subgroup. For payer and guideline discussions, the key near-term question will be durability and safety in routine practice, alongside how quickly clinicians can implement HER2 mutation testing at scale.