 In the Phase III Aura III study, NCT02151981, the third-generation epidermal growth factor receptor tyrosine kinase inhibitor osomertanib prolonged progression-free survival versus platinum doublet chemotherapy in patients with EGFRT790M advanced NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to osomertanib in patients from the Aura III trial. This article was authored by Julian Kamelechi, Tony Mock, Yilong Wu, and others.