**6. Epidermal Growth Factor Receptor (EGFR) inhibitors**

The EGFR pathway has been demonstrated to play a role in the tumorigenesis of a great proportion of meningioma cases. Torp et al. demonstrated that EGFR expression is not detectable in healthy and injured adult human meninges, but is expressed in cases of meningioma [90]. Arnli et al. also showed that EGFR was absent in healthy meninges but present in MN [91]. Narla et al. analyzed 79 samples of MN using immunohistochemistry, to detect EGFR expression. They found that EGFR was expressed in all different grades of MN, but its expression was considerably higher in grade I MN (82.93%), than grade II MN (35.71%) and grade III MN (20%) (*p* < 0.0001) [92]. When analyzed as a general population, the expression of EGFR in MN ranges between 50% and 89% [93]. Even though EGFR is a potentially targetable molecule, its significance in meningioma might not be prognostic [94]. Caltabiano et al. analyzed MN samples using immunohistochemistry and FISH. They found that the expression of EGFR was not associated with outcomes like OS and PFS. Interestingly, they also found that progression from low grade MN to higher grades was associated with an increase in the level of EGFR expression (not the proportion of expression) [95].

Similar results were published by Wernicke et al. who found in a cohort of 89 MN samples that EGFR expression was more common in grade I MN than in other grades. They also showed that the staining percentage (SP) of immunoreactive cells was associated with histopathologic subtypes (*p* = 0.029), with anaplastic MN having the highest average SP [96]. EGFR expression in MN is also accompanied by a demonstrated receptor activation [93]. In the cell line IOMM-Lee, EGFR was found to play a role in radiation-induced progression of MN. Furthermore, EGFR is involved in the regulation of certain intracellular pathways including the MAPK, the PI3K/Akt and phospholipase C pathways, which have been seen to be activated in meningioma [37, 97].

In 2010, results from a phase II trial of erlotinib and gefitinib for the treatment of MN were published. Erlotinib is an orally available, reversible TKI directed against EGFR. Its use has been approved in different neoplastic disorders including non-small cell lung cancer (NSCLC) and pancreatic cancer [98]. Gefitinib is a first-generation

EGFR-TKI also approved for the treatment of locally advanced and advanced NSCLC [99]. In 2010, a clinical trial enrolled patients with recurrent histologically confirmed MN that were treated with no more than 2 chemotherapy regimens.

The study evaluated 25 patients with a median age of 57 years. From this cohort, 16 patients received gefitinib and 9 received erlotinib. Nine patients had atypical MN and 8 had anaplastic MN. PFS and OS were assessed at 6 and 12 months. For patients with low-grade histology, PFS-6 was 25%, PFS12 was 13%, OS-6 was 63% and OS12 50%. In the other hand, high-grade meningiomas seemed to respond a little better with a PFS6 of 29%, PFS-12 18%, OS6 71% and OS-12 65%. When statistical analysis was done no significant difference between low-grade and highgrade MN was seen [100]. Survival outcomes were not significantly better than that of standard treatment.

In 2020 Ferluga et al. found that STAT1 is overexpressed and present a constitutive phosphorylation in MN. They also found that this overactivation was not associated with the JAK-STAT pathway but instead it was induced by the constitutive phosphorylation of EGFR. They even demonstrated that STAT1 knockdown models presented a significant reduction of cellular proliferation as well as a deactivation of AKT and ERK1/2. The most interesting finding of this study was that the researchers used BM-1 cells and exposed them to three different EGFR inhibitors, two from second generation (canertinib and afatinib) and one first generation (erlotinib). After exposure to canertinib and afatinib, a decrease in about 60% of STAT1 expression was seen as well as an almost complete elimination of phosphorylated forms of STAT1, this effect was not seen after exposure to erlotinib.

Lapatinib is a dual EGFR/ErbB2 inhibitor currently approved for the treatment of advanced breast cancer with ErbB2 (HER2) expression [101]. There is preclinical evidence of lapatinib efficacy in decreasing tumoral growth in NF2-related Schwannomas. Ammoun et al. demonstrated that when NF2 is mutated or lost, there is an upregulation of different RTKs in Schwannoma, with EGFR and HER2 being two of the highest expressed [102]. Similar results have been seen in NF2 related MN. When the researchers added lapatinib at 5 and 10 μM concentrations to cultures of Schwannoma cells derived from patients' samples, they found that lapatinib successfully induced inhibition of the intracellular pathways downstream HER2, including ERK 1/2 and Akt. They also showed that after 24 h of exposure to lapatinib, cell viability decreased in a dose-dependent manner, with statistically significant differences between both concentrations of lapatinib to baseline, and from lapatinib 5 μM to lapatinib 10 μM [102].

The same group of researchers also tested lapatinib during a phase II clinical trial, with good results in terms of volumetric response, progression-free survival and safety profile [103]. Six years after this trial, the authors did a retrospective analysis of patients presenting with NF2-related meningiomas from the same cohort of patients with Schwannoma. Eight patients fulfilled criteria for analysis. After two months under treatment with lapatinib, the best volumetric response achieved was 26.1%. It is important to mention that in the group that was receiving lapatinib, two tumors increased in volume by more than 20%. Results from this analysis were confusing, with no clear benefit of lapatinib, however, the sample was extremely small, and the analysis was retrospective. This study might influence the development of future, prospective, larger clinical trials specifically for patients with MN [104].

In 2001, Crombet et al. published their results on the efficacy of a mouse antihuman neutralizing monoclonal antibody against EGFR (ior egf/r3). They performed a phase I clinical trial using this antibody in 9 patients with high-grade brain tumors that persisted or relapased after surgery. Only one of the patients had MN (hemangiopericytic). The patient had 48 years old and a Karnofsky Performance

*High Grade Meningiomas: Current Therapy Based on Tumor Biology DOI: http://dx.doi.org/10.5772/intechopen.100432*

Score of 90. She received four doses of 160 mg of antibody. At the end of the study, no objective response was seen in any of the patients, however the remained with stable disease until 6 months after the last antibody dose [105]. Even though EGFR inhibition has revolutionized cancer care in neoplasms with high incidence like NSCLC and colorectal cancer, these effects have not been seen in brain tumors, even when EGFR upregulation has been proved. Further studies must be performed with newer and more effective EGFR inhibitors, including monoclonal antibodies.
