Due to the unclear mechanism of LM and the existence of the blood-brain barrier, it is difficult for drugs to reach an effective intracranial concentration. The treatment of LM in lung cancer is still a complicated problem. This is the first study to compare the effects of osimertinib with or without bevacizumab in LM of EGFR-mutant NSCLC. The efficacy is compared through a combination of basic research and clinical analysis and its possible mechanism is explored.
Studies have shown that EGFR-TKIs (erlotinib) and angiogenesis inhibitors that target endothelial growth factor receptor (anti-VEGFR) (bevacizumab) (A+T) achieved superior PFS and acceptable safety in NSCLC patients with intracranial metastasis[22]. Our study retrospectively analyzed 27 LM patients with EGFR-mutant lung cancer who received osimertinib with or without bevacizumab, the median OS of osimertinib plus bevacizumab group (n=16) compared 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 iPFS is 10.6 months versus 5.5 months (log-rank test, p=0.037, HR=3.401, 95%CI:1.079-10.720). Then we investigated the antitumor effects of osimertinib and bevacizumab in an EGFR-mutant LM model. We found that osimertinib plus bevacizumab significantly improved the concentration of osimertinib in mouse brain tissue.
A series of studies have supported that A+ T therapy can result in improved survival benefits[23]. The JO25567 recommended combined erlotinib and bevacizumab as a first-line regimen in EGFR mutation-positive NSCLC[24, 25]. The NEJ026 also suggested that TKIs combined with bevacizumab extended PFS 3.6 months compared to erlotinib in EGFR-mutant NSCLC[11]. The PFS of NSCLC patients with pleural or pericardial effusion is expected to be prolonged with the combined use of osimertinib plus bevacizumab and to demonstrate their safety[26]. Consistent with the above studies, our preclinical experiments and retrospective analysis indicated that osimertinib and bevacizumab improve the survival of LM patients with EGFR mutant NSCLC. In contrast, some reports showed that TKIs combined with angiogenesis inhibitors did not improve PFS in EGFR-mutant NSCLC[27]. Although the overall response rate (ORR) was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months)[28]. Dr. Toi reported that compared with osimertinib alone (n=40), the combination of osimertinib and bevacizumab (n=41) did not increase the PFS of NSCLC patients. Although the ORR of the combined group was higher, there was no difference in OS between the two groups[28]. Recent studies have found that 160 mg of osimertinib could have better efficacy than 80 mg in controlling LM[8, 29, 30]. Further investigation to compare the efficacy of osimertinib 80 to 160 mg in patients with LM is warranted.
VEGF is a key regulator of angiogenesis and a validated target for NSCLC[31]. The biologically synergistic antitumor activity of EGFR inhibition in combination with VEGF/VEGFR pathway blockade have been demonstrated in preclinical studies[32]. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs) [33, 34], and EGFR, similar to VEGFR-2, can be expressed on tumor-associated endothelial cells[23, 32]. The inhibitory effects of afatinib on EMT and tumorigenesis may be associated with the ERK‑VEGF/MMP9 signaling pathway[35]. The TMD has been regarded as one important indicator for quantitatively analyzing tumor angiogenesis, which can clearly reflect the intra-tumoral blood vessels state and tumor-induced angiogenesis ability[36, 37]. Tumor vascularization is critical to the pathogenesis of solid tumors, and TMD is related to tumor invasiveness and metastasis formation which could be used as a potential predictive marker for bevacizumab benefit[38]. Bevacizumab prunes vessels while normalizing those remaining[39]. Osimertinib is a small molecule targeted drug, which is easier to penetrate the blood-brain barrier than the first and second-generation targeted drugs[17]. These studies suggest that dual blockade of the VEGF and EGFR pathways would be more effective. Our results showed that the combination group has a more significant reduction in TMD. Perhaps it is the reason that bevacizumab improved the concentrations of osimertinib in the mouse brain, which further indicated that osimertinib plus bevacizumab have a synergistic effect. The further mechanism still needs to be investigated. Considering, our study found that 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 TMD, indicated that combined osimertinib with bevacizumab could play a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. In preclinically, osimertinib combined with bevacizumab is a more ideal and optimized treatment plan for EGFR mutant NSCLC with LM.
Although our research is instructive for the clinical treatment of NSCLC patients with LM. Owing to the animal model and the small number of patients, this study may not be conclusive. First, strictly speaking, our LM model belongs to a local growth model not metastasis model. Currently, there is no stable disease model that metastasizes to the meninges via the primary tumor. Commonly used models including cisternal injection and lateral ventricle injection, both of which are spread to the meninges through the cerebrospinal fluid circulation route. They have not been metastasized from the primary focus; hence they are not suitable for the study of the mechanism of LM. However, due to their excellent performance stability, it is benefit for drug intervention experiments. Second, it is a small sample size retrospective study, and there are several patients on survival. It is difficult to assess the iPFS of LM, and it is currently believed that a comprehensive assessment should be based on patient neurological examination, C radiological evaluation, and cerebrospinal fluid cytology. The main challenge is to define measurable and non-measurable (target) damage, and allow assessment of response changes, perform cerebrospinal fluid cytology for assessment, due to lumbar puncture is an invasive test, most patients refuse to perform. Therefore, it is difficult and subjective to evaluate iPFS in patients with LM, and the present results must be interpreted cautiously. The data were obtained from medical files, and we cannot exclude the possibility of undefined biases and/or confounding factors. Third, the interaction mechanism of osimertinib and bevacizumab needed to be further explored. The next step of our research, the phase II study of osimertinib plus bevacizumab for LM is already ongoing (NCT04425681). We are collecting the CSF and blood of NSCLC patients with LM in osimertinib group and the combination with bevacizumab group to further explore the mechanism and find the biomarkers for prognostic.
In conclusion, the current findings demonstrated that osimertinib plus bevacizumab tend to improve the outcome than osimertinib for LM patients with EGFR-mutant NSCLC, suggesting osimertinib plus bevacizumab is an appropriate treatment option for patients with LM from EGFR mutant NSCLC.