The Role of Pharmacotherapy in Treatment of Meningioma: A Systematic Review

Simple Summary For the last 35 years, various systemic therapies for recurrent or refractory meningiomas have been investigated. The present review aggregated the currently available evidence in the literature regarding the safety and efficacy of these treatments and assessed the ongoing trials of medical therapy for meningiomas. The findings of the present study would assist future research in seeing what therapeutic regimens have been investigated, which targets are promising candidates for interventions, and how the ongoing clinical trials are currently designed. Abstract The safety and efficacy of various pharmacotherapeutic regimens on refractory meningiomas have been the focus of investigations. We present a comprehensive review of the previous efforts and the current state of ongoing clinical trials. A PRISMA-compliant review of the MEDLINE and ClinicalTrial.gov databases of the National Library of Medicine were performed. The primary outcomes of interest for included articles were radiographic response, overall survival, progression-free survival, six-month progression-free survival, and adverse events. Overall, 34 completed trials and 27 ongoing clinical trials were eligible. Six-month progression-free survival was reported in 6–100% of patients in the completed studies. Hematological disorders were the most common adverse events. Of the ongoing clinical trials identified, nine studies are phase I clinical trials, eleven are phase II trials, two are phase I and II trials, one is phase II and III, and two trials do not have a designated phase. Currently, there is no effective chemotherapy for refractory or recurrent meningiomas. Several promising targeted agents have been developed and are currently being investigated in the hope of identifying novel therapeutic strategies for the treatment of this pathology.


Introduction
Meningiomas are the most common primary tumor of the central nervous system, accounting for 38% of all brain and spinal cord tumors. The five-year prevalence is approximately 159,038 cases and the incidence is 8.81 annual cases per 100,000 people. Histologically, 80.3% of these tumors are classified by the World Health Organization (WHO) as low-grade (grade I), but 19.5% are considered high-grade (grade II or III) [1]. Up to 20% of meningiomas are clinically aggressive, regardless of histologic grading [2]. Complete surgical resection or radiotherapy are effective treatments for WHO grade I meningiomas, with an excellent prognosis with complete resection [2,3]. In many cases, however, there is disparity between histologic features and clinical behavior, creating difficulty in counseling of interest. The main outcomes of interest were radiographic response, overall survival, progression-free survival, six-month progression-free survival, and adverse events. Frequencies and percentages were utilized to present categorical variables. Means and ranges were used to present the continuous variables. The median of the continuous variable was reported in cases where the mean was unavailable. Meta-analysis of outcomes was not considered because of the limited number of included studies and outcome measure variability.

Results
The initial PubMed search resulted in 320 studies for initial review (Figure 1). Of these, 272 studies were excluded during title and abstract screening because of ineligible study type (n = 180), population (n = 35), outcomes (n = 27), and intervention (n = 7), or being written in a non-English language (n = 23). The full text of 48 papers was assessed for eligibility. Twenty-five papers were excluded due to retrospective design (n = 17), being non-clinical (n = 5), and having ineligible intervention (n = 1), population (n = 1), or outcomes (n = 1). One clinical trial was excluded since only one of the 21 patients was diagnosed with meningioma [16]. Overall, 23 studies were identified via MEDLINE search and 11 were identified through hand-searching of the references (Tables 1 and 2). Initial search of the ClinicalTrials.gov portal yielded 78 trials for initial review. Of these, 51 studies were excluded because they did not involve therapeutic interventions (n = 25), were not drug-based interventions (n = 22), or did not include target patients with meningioma (n = 4). Ultimately, 27 ongoing clinical trials were identified as appropriate for inclusion in this study (Table 3).

Study Characteristics
Most of these clinical trials were performed in the USA (n = 22) over a 36-year span. The enrolled patients generally had meningiomas that were either unresectable, recurrent, or progressive despite all surgical and radiotherapeutic treatments based on clinical and neuroimaging evaluations. The patients were adults (>18) in all studies. The number of patients enrolled across all trials ranged from 4 to 164, with the median number of patients being 16. Most of the 740 trial participants were female (n = 474, 64.05%). Tumors were intracranial in all but two studies [24,30]. All but three were single-arm [42,43,46], and only one had a comparator group of standard care [42]. Only four studies focused on a particular meningioma grade [28,34,35,50], and all others included more than one grade. Hydroxyurea was the most frequently investigated chemotherapeutic agent, used in 12 studies (Table 4), followed by octreotide (n = 4), and mifepristone (n = 3).

Study Characteristics
Most of these clinical trials were performed in the USA (n = 22) over a 36-year span. The enrolled patients generally had meningiomas that were either unresectable, recurrent, or progressive despite all surgical and radiotherapeutic treatments based on clinical and neuroimaging evaluations. The patients were adults (>18) in all studies. The number of patients enrolled across all trials ranged from 4 to 164, with the median number of patients being 16. Most of the 740 trial participants were female (n = 474, 64.05%). Tumors were intracranial in all but two studies [24,30]. All but three were single-arm [42,43,46], and only one had a comparator group of standard care [42]. Only four studies focused on a particular meningioma grade [28,34,35,50], and all others included more than one grade. Hydroxyurea was the most frequently investigated chemotherapeutic agent, used in 12 studies (Table 4), followed by octreotide (n = 4), and mifepristone (n = 3).

Outcomes
Overall, eight studies reported partial radiographic responses to the treatment [17,[20][21][22]29,33,42,43]. No study reported a complete response. Administered regimens in these trials were: (1) oral tamoxifen, 30 mg divided by three doses a day [17]; (2) oral mifepristone, 200 mg in one daily dose [20,33,42]; (3) oral tamoxifen, 40 mg for four days and 10 mg thereafter divided by two doses per day [21]; (4) three or six one-month cycles of intravenous cyclophosphamide (500 mg/m 2 /day) and doxorubicin (15 mg/m 2 /day) on days 1-3 in addition to one dose of vincristine (mg/m 2 /day) within days 10-14 [22]; (5) oral hydroxyurea, 20 mg/kg/day [29]; and (6) 42-day cycles of oral sunitinib malate (50mg/day) on days 1-28 [43]. Notably, only one of these eight trials was a randomized clinical trial and this did not find the difference in partial radiographic response between the intervention and placebo groups to be significant [42]. All other trials were single-arm. Of the trials that reported partial radiological responses, two trials defined a partial radiographic response as any decrease in the largest diameter of the tumor [17,20] while the other six used MacDonald criteria (Table 5) [51] for radiographic response [21,22,29,33,42,43]. Time to tumor progression ranged from three to more than 957 weeks. Overall survival ranged from 22 days to more than nine years. When measured, six-month progression survival was 6-100%. Hematological disorders including leukopenia, anemia, and thrombocytopenia were the most common adverse events with more than 65 cases. Of the 18 pharmacotherapeutic regimens, only five had evidence of partial radiographic response (Table 4). Table 5. MacDonald criteria for assessment of brain tumor treatment response *.

Types of Response Definition
Complete Response (CR) Complete disappearance of all enhancing tumors on consecutive CT or MRI scans at least 1 month apart, off steroids, and neurologically stable or improved.

Status and Coordination
All ongoing clinical trials started between 2008 and 2022. Expected completion dates range from 2021 to 2029. Of the 27 included studies, 21 are occurring in the USA. The number of trial sites per study range from 1 to 705, with a median of one. Most trials are privately funded (16 of 27 or 59.2%). Four are funded privately and publicly through the National Institute of Health (NIH) or a foreign equivalent. Seven trials are completely publicly funded. Nineteen studies are currently recruiting patients, five are active but no longer recruiting, and three are not yet recruiting.

Trial Design
Eight studies are phase I clinical trials, fourteen are phase II trials, two are phase I and II trials, and one is a phase II and III trial. No phase IV trials were found in the database. Two studies did not designate a trial phase. The target number of enrollment across all ongoing clinical trials ranges from 9 to 180, with a median number of patients being 34. Seventeen trials focus only on meningioma, with ten focusing on the drug of interest's impact on other tumors as well. The most common primary outcome of interest is progression-free survival in eighteen trials, followed by toxicity in ten trials. Other primary outcomes of interest include drug pharmacokinetics, gene expression following drug administration, immunogenicity, changes in tumor size, and radiological response rates.

Discussion
Classically, most meningiomas are WHO grade I lesions that can be cured surgically. This is one reason that advancements in medical treatments for aggressive recurrent or unresectable meningiomas have lagged behind treatments for other neoplasms. Physi-cians and scientists have been working to develop non-surgical therapeutic approaches for meningiomas for more than 35 years, with no effective pharmacotherapeutic agents currently recognized as standard of care. Moreover, thus far, all drug-based trials targeting meningioma have shown negative results. We previously performed multi-platform profiling of meningiomas and proposed three molecular groups based on transcriptional profiles that allowed us to better classify and prognosticate these tumors [7]. We demonstrated that these three groups could be identified using cytogenetics, DNA methylation profiling or transcriptional profiling [6]. Recently, several other groups have started to converge on the same biological groups [8,9,52]. As the field moves towards crystallizing a molecular classification scheme, looking through the lens of molecular groups may allow for new insights when both evaluating new pharmacotherapies and re-evaluating previously studied pharmacotherapies.

Completed Clinical Trials
While no clinical trial of biological agents has yet yielded a radiographic response, there were several chemotherapy and hormonal therapy regimens that were associated with a radiographic response. Overall, five of eighteen pharmacotherapeutic regimens demonstrated evidence of radiographic response, which were: (1) hydroxyurea; (2) cyclophosphamide, doxorubicin, and vincristine; (3) sunitinib; (4) mifepristone; and (5) tamoxifen.
Hydroxyurea is a ribonucleotide inhibitor that induces apoptosis by stopping the cell cycle in the S phase [23]. While one clinical trial showed partial radiographic response following treatment with this drug, other trials did not find any radiographic response following the therapy. Thus, it is hard to justify this drug's limited efficacy in light of its more established hematological and dermatological side effects [23,24,26,27,[29][30][31]34,47]. Hydroxyurea was also used as an adjunct to treatment with imatinib in two trials. However, no significant radiographic response to treatment in the two aforementioned studies was observed [39,46]. The same concerns apply to the combinatorial cytotoxic chemotherapy of cyclophosphamide/doxorubicin/vincristine, whose modest evidence of partial radiographic response in 21% of the patients was outweighed by much more pronounced evidence of dermatological and hematological adverse effects, which occurred in 100% of the patients [22,43].
The hormonal agents mifepristone and tamoxifen have both been studied in meningiomas. Mifepristone is an anti-progesterone drug that was found to result in partial radiographic in two earlier single-arm clinical trials [20,33]. However, its efficacy was similar to placebo with regard to radiographic response, time to tumor progression, overall survival and six-month progression-free survival in a phase III placebo-controlled clinical trial [42]. Tamoxifen is an anti-estrogen agent that was also associated with a radiographic response [17,21]. However, both clinical trials looking at tamoxifen were single-arm, and its effectiveness was not compared to a proper comparator group, limiting the impact of these findings.
There are several limitations to the methodology of the eight studies reporting the five regimens that demonstrate a radiographic response. First, two studies defined any reduction in tumor size as a response to treatment [17,20], which may lead to an overestimated response. Next, while the other six studies [21,22,29,33,42,43] used the established Mac-Donald radiographic response criteria [51], their results should be interpreted cautiously. Many patients in these clinical trials had undergone prior surgical resection or radiotherapy, which may significantly confound the noted response. Moreover, prior studies have shown meningioma aggressiveness to be significantly correlated with irregular shape, which may make measuring an adequate response difficult in patients with recurrent disease [16,53]. Furthermore, most of these studies had small sample sizes with limited statistical power and were single-arm, which inevitably introduces selection bias. The clinical validity of the results of these trails is further questioned by the fact that the only randomized placebocontrolled clinical trial of the eight studies did not demonstrate any significant difference in response to treatment between the systemic therapy and placebo [42].

On-Going Clinical Trials
Over the past three decades, several studies have chronicled the genomic makeup and common mutations found in meningioma [52,[54][55][56][57][58][59][60]. Thus, there are several ongoing clinical trials of agents targeting molecular pathways known to contribute to the pathogenesis of meningiomas. For example, some meningiomas are found to have a highly expressed hedgehog signaling pathway, making somatic mutations of Smoothened (SMO) a potential target for chemotherapy [61][62][63]. Based on this, SMO inhibitors, sonidegib and vismodegib, are currently being investigated as a treatment for meningiomas (NCT03434262 and NCT02523014). Similarly, considerable activation of mutated AKTs in the PI3K/AKT/mTOR pathway is also reported in some meningiomas, and trials of inhibitors of these pathways (capivasertib, alpesilib, vistusertib) are also ongoing [61][62][63]. Another active signaling pathway in meningioma is the RAS/RAF/MEK/MAPK pathway, which transduces the VEGFR, EGFR and PDGFR's pro-mitotic signals [61,64]. This signaling mechanism is currently the target of two distinct trials, using either trametinib or selumetinib (NCT03631953, NCT03095248). In addition to studying the efficacy of pharmacotherapies that target SMO (vismodegib), the PI3K/AKT/mTOR pathway (capivasertib), and CD4 and CD6 (abemacicilib), the ongoing multi-center Alliance trial (NCT02523014) is also studying the efficacy of the GSK2256098 FAK inhibitor. FAK is a cytoplasmic tyrosine kinase which integrates signals from integrins and growth factors to regulate cell proliferation, migration, and survival. Preclinical data have suggested increased vulnerability to FAK inhibitors in merlin-deficient tumor cells [65,66].
While some clinical trials have focused on molecular signaling pathways, others have utilized inhibition of certain growth factor receptors as a point of intervention. More than half of meningiomas exhibit overexpression of EGFR [63]. While a previous trial of EGFR inhibitors, gefitinib and erlotinib, did not result in any radiographic response to treatment [37], two ongoing trials of EGFR inhibitors, afatinib and brigatinib, are designed to investigate the safety and efficacy of these agents. As next-generation tyrosine kinase inhibitors, afatinib and brigatinib are effective against targets of gefitinib and erlotinib as well as less common EGFR mutations that might be resistant to gefitinib and erlotinib's action (NCT02423525 and NCT04374305). Therefore, it is reasonable to evaluate whether these agents might be effective against meningiomas despite the failure of first-generation EGFR inhibitors. Another tyrosine kinase inhibitor of interest currently being investigated in two ongoing trials are VEGFR2 inhibitors, apatinib and carbozantinib (NCT04501705 and NCT05425004). Furthermore, a currently recruiting phase II trial (NCT02847559) and a recently completed phase II trial with pending results (NCT01125046) explored the impact of the VEGFR2 inhibitor bevacizumab in the treatment of patients with recurrent or progressive meningioma. While previous trials of VEGF receptor inhibitors sunitinib, vatalanib, and bevacizumab did not demonstrate any considerable radiographic response, they were efficacious in increasing six-month progression-free survival, showing that some benefit may be offered by antiangiogenic treatments in meningiomas [40,43,63,67,68]. Moreover, carbozantinib also inhibits receptor tyrosine kinases AXL and c-MET, which have both previously been shown to demonstrate elevated expression in recurrent meningiomas [69][70][71].
Targeting dysregulated cell growth is another strategy that is currently under investigation. It is known that the inactivation of cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDKN2B genes leads to activation of CDK4 and CDK6, which may contribute to poorer outcomes and higher recurrence rates [63,72]. Two ongoing trials investigating ribociclib and one investigating abemaciclib as selective inhibitors of CDK4 and CDK6 are investigating the role of CDK inhibitors in treating meningiomas (NCT02933736, NCT03220646, NCT02523014). DNA hyper-acetylation by histone deacetylase inhibitor AR-42 has also shown promising anti-proliferative activity in preclinical meningioma models [4,73], which is now being used in the first clinical trial for the treatment of meningiomas (NCT05130866) [72]. The third agent in this category is 9-ING-41, an inhibitor of glycogen synthase kinase-3β (GSK-3β), which upregulates NF-κB's transcriptional activity (NCT04239092) [63,74]. GSK-3β inhibition has shown promising results in the treatment of multiple malignancies, and is now being investigated for several refractory neoplasms, including meningiomas [75]. The last drug in this category is ONC206 (NCT04541082). This imipiridone small molecule increases the activity of TNF-related apoptosis-inducing ligand, which is a major contributor to the cytotoxicity of tumor cells [76]. Its safety and dose-escalation are currently being examined in a phase I trial on primary CNS neoplasms, including meningiomas (NCT04541082).
With regard to biologic agents, most ongoing clinical trials focus on immune checkpoint inhibition through PD-1 or PD-L1 inhibition. PD-L1-expressing tumor cells inhibit T-cell activation by binding to the PD-1 surface receptor on T-and B-cells [77] (Figure 3). In meningiomas, elevated expression of PD-L1 correlates with higher tumor grade and, subsequently, worse prognosis [78,79]. Moreover, tumors that have received prior radiation therapy also have significantly higher PD-L1 expression [78]. Given these findings, seven ongoing trials are exploring the effect of anti-PD1 or anti-PD-L1 therapy on patients with meningioma. A phase II trial is comparing the use of nivolumab PD-1 inhibitor alone to combination therapy with the anti-CTLA-4 antibody, ipilimumab (NCT02648997). A phase I trial is investigating the preoperative use of the PD-L1 inhibitor, avelumab, in combination with proton therapy for 3 months to evaluate its effect on the unresected tumor volume (NCT03267836). Other trials in this category target patients with high-grade meningioma who have failed surgical resection.
Hormone-based pharmacotherapy currently being explored in clinical trials centers around the somatostatin receptor-targeted radioactive drug, LUTATHERA (177 Lu-DOTATE). This drug binds to somatostatin receptors on tumor cells and delivers high doses of radiation. While a prior phase II clinical trial exploring the effects of this drug on patients with unresectable meningiomas did not demonstrate tumor regression with this treatment, it did find some efficacy when it came to slowing tumor progression [44]. A current phase I trial is investigating the safety and efficacy of a slightly modified drug, 177 Lu-DOTA-JR11, which has been shown to exert higher binding affinity for somatostatin receptors than 177 Lu-DOTATE and thus, postulated to have improved clinical efficacy and therapeutic index when treating advanced and recurrent meningiomas (NCT04997317) [80]. Two ongoing phase II trials are further elucidating the efficacy of LUTATHERA in treating high grade meningioma (NCT04082520 and NCT03971461). NCT04082520, in particular, is evaluating the efficacy of LUTATHERA in patients with progressive meningioma who have received external beam radiation therapy. One phase I and phase II trial is evaluating the safety and efficacy of LUTATHERA in pediatric (phase I) and young adult (phase 2) patients with progressive or recurrent high-grade CNS tumors including meningioma (NCT05278208).

Limitations
There are several limitations common to the studies presently available in the literature. All included studies had a small sample size, were underpowered, and had no "standard care" comparison group. When added with inadequate measures to mitigate the confounding factors, selection bias, information bias, or reporting bias, it is impossible to draw a robust conclusion from the current literature. Designing a medical therapy trial for meningiomas is a known challenge due to the scarcity of patients that do not respond to GTR and radiotherapy, the inevitably heterogeneous sample population with regard to the grade and natural history of the disease, difficulty in creating an acceptable set of outcomes in the short-term resulting in heterogeneity of outcome measures, and issues arising from long follow-up times because of the natural history of the disease [67,72]. Even when taking the results of these clinical trials into account, the evidence of effectiveness of these drugs on meningiomas is lacking. This is consistent with the findings of previous reviews on medical therapy and chemotherapy of meningiomas [23,67,68,72,81].
The present review is also limited by the following factors. Due to the heterogeneity of outcome measures and the scarcity of eligible trials, no meta-analysis could be conducted. Therefore, the risk of bias of these trials could not be quantitatively evaluated. Additionally, ClinicalTrials.gov, while a comprehensive database, is U.S.-based and thus, may not contain an exhaustive list of all clinical trials being conducted around the world. It is likely that some trials may not have been registered on this database.

Conclusions
While most meningiomas are relatively slow-growing and histologically benign, a subset of these tumors are aggressive and remain challenging to treat with the existing options of surgical resection and radiotherapy. No systemic therapeutics, thus far, have shown efficacy in the treatment of meningioma in the recurrent setting. Moreover, the heterogeneity of outcome measurements of existing clinical trials precludes a quantitative meta-analysis. Insights into the genomic and epigenomic make-up of meningiomas have provided new targets for potential systemic therapies. There are several ongoing clinical trials which act on molecular targets (SMO, AKT, FAK, etc.) previously studied in the preclinical setting. Furthermore, chemotherapies that dysregulate cell growth (CDK inhibitors and GSK-3β inhibitors) and induce apoptosis through caspase activity (DRD2 inhibtor) are also being studied in ongoing clinical trials. Finally, trials studying biologic therapies that prevent checkpoint inhibition (PD-1 inhibitors and PD-L1 inhibitors) and hormone therapy targeting somatostatin receptors with radioactive analogs also exhibit exciting potential as systemic pharmacotherapies for meningioma in the recurrent setting.