The Efficacy And Mechanism Of Osimertinib Plus Bevacizumab In Leptomeningeal Metastasis With EGFR Mutant Non-Small Cell Lung Cancer

Objective:EGFR-mutant non-small cell lung cancer(NSCLC)is prone to leptomeningeal metastasis(LM)after Tyrosine kinase inhibitors(TKIs)treatment.The clinical data of27 patients with Non-small cell lung cancer(NSCLC)leptomeningeal metastasis(LM)were retrospectively analyzed,and the efficacy of osimertinib combined with or without bevacizumab in LM patients with EGFR-mutant NSCLC was compared.LM with EGFR-mutant NSCLC xenograft tumor model was established to compare the anti-tumor effects of osimertinib combined with or without bevacizumab,and the possible mechanism of action is explored.Method:We retrospectively reviewed data from 27 LM patients with EGFR-mutant NSCLC who were treated with osimertinib with or without bevacizumab,compared the Overall survival(OS)and intracranial Progression-free survival(i PFS).Then we examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood-brain barrier(BBB),and investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975(L858R/with or without T790 M second mutation)cell line.Results:Our retrospective study found that osimertinib plus bevacizumab group improved the outcomes of the LM patients with EGFR mutant NSCLC compared with osimertinib group.The median OS of the patients who received osimertinib and bevacizumab(n = 16)compared with osimertinib(n=11)was 18.0 months versus13.7 months((p =0.046,HR=2.867,95%CI:1.007-8.162)),The median i PFS was10.6 months versus 5.5 months(p=0.037,HR=3.401,95%CI:1.079-10.720).In the leptomeningeal metastasis xenograft model with H1975 cells,combined treatment with osimertinib and bevacizumab improved the blood-brain barrier permeability of osimertinib and successfully controlled the progression of LM at a tolerated dose.The potential mechanism was the reduction of Tumor microvessel density(TMD) and downregulation of EGFR and phosphorylation level of its downstream signaling pathways including p-AKT which possibly through modulating the level of E-cadherin.Conclusions:Our findings indicate that osimertinib plus bevacizumab is more effective than osimertinib for the leptomeningeal metastasis of EGFR-mutant NSCLC.