Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutant NSCLC with brain metastases: A dynamic ctDNA-guided study.

e20606 Background: Non-small cell lung cancer (NSCLC) patients with positive driver genes had a higher incidence of brain metastasis. This study evaluates the efficacy and safety of Osimertinib combined with Bevacizumab as first line treatment in EGFR-mutant NSCLC with brain metastases, utilizing liquid biopsy and dynamic molecular detection to guide treatment strategies. This approach is anticipated to bring progression-free survival (PFS) benefits and shows different resistant mechanisms. Methods: We enrolled EGFR-mutant NSCLC patients with brain metastases receiving Osimertinib and Bevacizumab as first-line therapy. Paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline, during stable disease, and at disease progression for Next-Generation Sequencing (NGS) analysis. The study's primary endpoints were central nervous system (CNS) PFS and objective response rate (ORR). Secondary endpoints included overall PFS, ORR, disease control rate (DCR), and safety. We also investigated resistance mechanisms to the combination therapy. Results: A total of 28 patients from Beijing TianTan Hospital (May 2020 - July 2023) were retrospectively enrolled. The average Bevacizumab treatment duration was 8.21 months (range: 1-27 months). CNS PFS was 26.73 months (95% CI, not reached), and overall PFS was 21.93 months (95% CI, 18.84-25.02 months). The CNS PFS for patients with 19del and L858R mutations were not reached and 26.73 months (95% CI, 15.11-38.35 months), respectively (p = 0.25). Patients undergoing intracranial local treatment showed a CNS PFS not reached, compared to 23.33 months (95% CI, 16.21-30.45 months) for those who did not (p = 0.417). The CNS ORR was 88%, ORR was 76%, and DCR was 100%. At the time of data cutoff (Dec 15th, 2023), 1 patient progressed in both lung and CNS metastases, 8 patients only progressed in lung, 8 patients only progressed in CNS metastases .EGFR C797S mutation was detected in 2 plasma sample, Met amplification in 1 tumor tissue, EGFR C719S mutation in 1 paired plasma-tumor tissue and PIK3CA in 2 plasma sample. Increasing abundance in TP53 and CDKN2A were detected in 2 paired plasma-tumor tissue. Adverse events of grade 3 or higher included one case (3.6%) of severe ulcerative colitis leading to Osimertinib discontinuation and two cases (7.1%) of bevacizumab discontinuation due to bleeding events. Conclusions: Osimertinib combined with Bevacizumab as a first-line treatment significantly prolonged CNS PFS in EGFR-mutant NSCLC patients with brain metastases, offering superior control over intracranial lesions compared to Osimertinib monotherapy (15.2 months, FLAURA study). This study underscores the potential of dynamic ctDNA monitoring in guiding effective treatment strategies for this patient population. Further research is warranted to explore the broader clinical implications of these findings.