Osimertinib plus Bevacizumab Improve the Outcome of Leptomeningeal Metastasis Patients with EGFR Mutant Non-Small-Cell Lung Cancer

Abstract Background EGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant lung cancer. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. Methods We retrospectively reviewed data from 27 LM patients with EGFR-mutant lung cancer who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood-brain barrier (BBB) and explored the potential mechanism. Results Our retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib (n=11) was 18.0 months versus 13.7 months (log-rank test, p=0.046, HR=2.867, 95%CI:1.007-8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p=0.037, HR=3.401, 95%CI:1.079-10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab play a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. Conclusions Our findings indicate that osimertinib plus bevacizumab tend to improve the outcome of LM patients with EGFR-mutant NSCLC than osimertinib.