Up to 40% of patients with non-small cell lung cancer (NSCLC) and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nerve system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80mg), a third generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of 160mg osimertinib in BM or LM is unclear.This prospective single-arm two cohort study evaluated the efficacy of 160 mg osimertinib in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary endpoints were overall response rate (ORR) (H1=30%) for the BM cohort and overall survival (OS) (H1=5 months) for the LM cohort.The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate (DCR) were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months (95% confidential interval [CI] 5.0-16.6); the median OS was 16.9 months (95% CI 7.9-not reached [NR]). In the LM cohort, intracranial DCR was 92.5% and complete response (CR) rate was 12.5%. The median OS was 13.3 months (95%CI 9.1-NR); the median PFS was 8.0 months (95%CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including 80 mg osimertinib or other third generation EGFR TKIs, showed no difference in PFS in both the BM (n=18, P=0.39) and LM (n=17, P=0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P=0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2.Thus, 160 mg osimertinib demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.