AbstractBackgroundPatterns of treatment failure and subsequent treatment in non‐small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies.MethodsWe identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)‐tyrosine‐kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed.ResultsEighty‐four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo‐progressive disease (PD) and central nervous system (CNS)‐sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM‐free (46/49, 93.9%), and 60% of patients (21/35) with pre‐existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M‐loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M‐loss (progression‐free survival, 5.4 vs. 16.5 months,p= 0.02; overall survival, not reached,p= 0.03).ConclusionPD during osimertinib treatment occurred preferentially in the thorax and pre‐existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies forEGFR‐mutated NSCLC with BM.