Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis 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 NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. Methods We retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC 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 group (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 may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. Conclusions Our findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysis

“…13 of the publications were case series [ [143] , [144] , [145] , [146] , [147] , [148] , [149] , [150] , [151] , [152] , [153] , [154] , [155] ]. 7 of the publications were retrospective studies [ 13 , [25] , [26] , [27] , [28] , 156 , 157 ]. Finally, 2 of the publications were prospective studies [ 12 , 29 ].…”

“…Given that LM is a relatively uncommon presentation of NSCLC, most studies on EGFR-TKIs for NSCLC have focused on advanced primary disease and CNS parenchymal metastases [ [20] , [21] , [22] , 24 ]. There are limited studies specifically evaluating the efficacy of osimertinib for NSCLC LM, predominantly consisting of smaller-scale cohort studies [ [25] , [26] , [27] , [28] , [29] , [30] , [31] ]. Consequently, the efficacy of osimertinib for NSCLC LM compared to previous-generation EGFR-TKIs remains unclear, with no studies, to our knowledge, directly comparing first-, second-, and third-generation EGFR-TKIs.…”

Co-treatment with atorvastatin and bevacizumab improved antitumor efficacy and biochemical status in lung cancer in vivo

“…Moreover, mice administered with benzo(a)pyrene and Narengine showed a signi cant amelioration in the mRNA PCNA expression in the lung's parenchyma and adenoma indicating well-prognosis-after-treatment [32]. Furthermore, using bevacizumab plus osimertinib against leptomeningeal metastasis of EGFR mutant NSCLC exerts a signi cant decrease in PCNA levels [33]. It is noteworthy to mention that the combination treatment of ATOR and bevacizumab showed higher antiproliferative levels than the treatment with each drug alone.…”

Intrathecal chemotherapy combined with systemic therapy in patients with refractory leptomeningeal metastasis of non-small cell lung cancer: a retrospective study

“…As an angiogenesis inhibitor against VEGFR, bevacizumab reduces brain edema and improves the blood‒brain barrier in patients with brain metastases and LM [ 24 , 26 ]. We previously found that osimertinib combined with bevacizumab had a synergistic effect by modulating E-cadherin levels and increasing osimertinib levels in the brain, resulting in a significant difference in OS between LM patients treated with osimertinib combined with bevacizumab and osimertinib alone (p = 0.046) [ 27 ]. However, it is not clear whether bevacizumab has synergistic effects in patients with EGFR-TKI-resistant disease treated with IC.…”