Background: The management of brain metastases in lung cancer was always a global challenge. Studies have shown that erlotinib combined with bevacizumab could bring progression-free survival benefit for NSCLC. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor with higher CNS penetration. This study was to evaluate the safety and efficacy of osimertinib plus bevacizumab as the first-line treatment for patients with EGFR-positive NSCLC and brain metatases, and reveal the molecular characteristics of intracranial progression by matching plasma and CSF ctDNA. Methods: Patients with EGFR-positive NSCLC and brain metatases were treated with osimertinib (80mg, daily) plus bevacizumab (5mg/kg, every 4 week) as the first-line treatment. CSF and paird plasma ctDNA were collected before osimertinib and at the time of disease stable, intracranial progression and systematic progression, using the next-generation sequencing (NGS) to explore the dynamic changes between them. The primary end point was median CNS progression-free survival (PFS), CNS objective response rate (ORR). The second end point was to explore the molecular mechanism of CNS progression. Results: As the time of data cutoff (Jan 31, 2023), 15 patients were enrolled. 3 patients (20%) progressed in lung, 2 patients (13.3%) progressed in brain, and 1 patient (6.7%) progressed in leptomeningeal and bone, 2 of them still received oral osimertinib (80mg, daily). 9 patients (60%) were in partial or complete reponse and 8 of them continued to receive the original treatment. The median osimertinib exposure time was 16.8 months. The median bevacizumab exposure time was 9.1 months. The median CNS progression-free survival was 15.5 months (6.8 months to not reached). The CNS objective response rate was 93.33%. Six patients received gamma knife radiotherapy before Osimertinib, the median CNS progression-free survival was 14 months (6.8 months to not reached), the CNS objective response rate was 100%. After progression on Osimertinib, paired CSF and plasma ctDNA were analyzed and EGFR C797S, TP53, CDKN2A and etc could be found as resistanct mechanism. Adverse events of grade 3 or worse were observed in 1 patients (6.7%): severe ulcerative colitis, leading to the suspension of osimertinib. 2 patients (13.3%) stopped bevacizumab because of bleeding. Conclusions: This is a mid-term report with immature data. By the end of follow-up, we expected that osimertinib plus bevacizumab could better reduce the risk of intracranial progression and prolong the progression-free survival compared with osimertinib monotherapy. Clinical trial information: KY2021-155-02.