Zhang Nan
Journal of Neurooncology published online on October 1, 2022 Austrian and Maximilian J Mair, Anna S Berghoff, Priscilla K Brastianos, Matthias Preusser in the United States, a review of "HEmerging Systemic Treatment Options for Meningioma ". Emerging systemic treatment options in menuimingioma》(doi: 10.1007/s11060-022-04148-8.).
Purpose:
Meningioma is the most common intracranial tumor. Usually, their treatment aims to be surgically removed. Radiotherapy and stereotactic radiosurgery are commonly used for adjuvant treatment of newly diagnosed atypical (CNS WHO grade 2) and anaplastic (CNS WHO grade 3) meningiomas, especially in patients with infeasible complete resection and relapse. In contrast, there is little evidence for drug treatment of meningiomas.
Method:
Use PubMed to screen existing literature on systemic treatment of meningiomas and search for ongoing clinical trials on the ClinicalTrials.gov website.
Results:
Classic cytotoxic drugs, somatostatin analogs and antihormone treatments have only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those that target angiogenesis signals such as sunitinib and bevacizumab, showed promising antitumor activity in small phase 2 trials. In addition, recent landmark findings on (epi-)genetic alterations in meningioma reveal potential therapeutic targets currently under investigation. These include inhibitors of mammalian target rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling pathway and histone deacetylases. In addition, clinical trials to evaluate immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently underway, with early results indicating clinically significant responses in a number of patients.
Conclusion:
Systemic treatment regimen for meningioma lacks high-level evidence. However, in the past decade, interesting new therapeutic targets have been found. Positive signals of antiangiogenic drugs, genomic targeted drugs and immunotherapy in early trials should be confirmed in large prospective controlled trials.
Introduction
Meningioma is the most common primary central nervous system (CNS) tumor in adults. It accounts for 39% of , the incidence rate in the United States is about 9.1/100,000 people-years, mainly females of higher age. In the recently updated 2021 WHO central nervous tumor classification, meningiomas are classified into WHO1-3 CNS based on histopathological characteristics such as the number of mitotic maps, aggressive growth patterns, specific morphological subtypes and anaplastic features, as well as genetic characteristics such as telomerase reverse transcriptase (TERT) promoter mutations or CDKN2A/2B homozygous deletion. homozygous deletions of CDKN2A/2B]. CNS WHO grade 1 meningiomas grow slowly and have clear boundaries. Atypical (CNS WHO grade 2) or anaplastic (CNS WHO grade 3) meningiomas can show malignant characteristics: such as rapid growth or invasion of the brain. Although CNS WHO grade 2 and 3 meningiomas occur only in 4-28% and 1.3% of patients, they have high clinical needs after resection and may metastasis to the lung, liver, or bone outside the brain. According to current guidelines, asymptomatic meningiomas without mass placeholding effects can be observed-waiting methods using annual magnetic resonance imaging (MRI). However, the mass placeholding effect on growth-neutral and/or symptomatic meningioma should be treated with maximum safe resection.In fact, the degree of resection has been repeatedly proven to be a prognostic factor, with high-grade meningiomas having higher recurrence and poor survival. Therefore, radiotherapy or stereotactic radiosurgery should be considered for meningiomas and higher grade tumors. Due to lack of evidence, the role of systemic therapy is not yet known, and drug treatment for meningiomas is generally considered experimental. However, systemic treatment regimens are often used as salvage treatment in the absence of further local treatment regimens. Overall, cytotoxic drugs show limited activity, while targeted therapeutic approaches, especially antiangiogenic drugs, show some efficacy in rescue treatment of meningiomas. Here, we aim to summarize the existing evidence for systemic treatment options for meningioma and provide an overview of the medications of the current study and an overview of future prospects.
clinical trial endpoint and treatment effect evaluation of meningioma
meningioma is uneven in terms of growth rate, clinical course and prognosis. Therefore, the definition of appropriate clinical trial endpoints and response criteria remains challenging, and recommendations for response criteria and clinical trial endpoints were not released until recently. Although overall survival (OS) is generally considered the main benchmark for evaluating the efficacy of anticancer treatments, especially in relatively benign tumors, such as CNS WHO grade 1 meningioma, the use of this parameter is complicated due to the long follow-up time. Due to the lack of effective historical data, the use of OS as the endpoint of clinical trials is only reasonable in randomized trials with their respective control arms. Radioreaction parameters, such as objective response rate (ORR), are also used; however, meningiomas lack clear criteria for radioimaging evaluation. This also complicates the use of progression-free survival (PFS) and PFS rates, as experimental and historical controls may define progress differently. Furthermore, due to the slow growth of most meningiomas, progression is easily overlooked. Nevertheless, PFS and PFS rates remain a commonly used alternative parameter to evaluate the activity of treatment without regard to the potential impact of post-progressive treatment. Furthermore, no progression in meningioma may also best reflect clinical stability in neurological symptom load. In fact, most clinical trials reported 6 months of PFS (PFS-6), providing a large number of historical controls for meningiomas of all grades. The efficacy of cytotoxic drugs such as hydroxyurea, irinotecan, temozolomide, vincristine , doxorubicin and cyclophosphamide (VAC) has been evaluated, but the overall efficacy is limited (Table 1). However, DNA-intercalating agent trabectedin showed promising activity in vitro and in one heavily pretreated patient, and a prospective randomized phase 2 trial (EORTC 1320) failed to meet its primary endpoint in terms of antitumor activity but significantly higher toxicity [a prospective randomized phase 2 trial (EORTC 1320) failed to meet its primary endpoint, with no difference to physical’s choice in terms of antitumoral activity but significantly higher toxicity].
Table 1 Some evidence of systemic treatment regimen for meningioma.
Since many meningiomas show somatostatin receptor 2A overexpression, somatostatin analogs such as octreotide or pareotide and targeted radionucleotide therapy (radionucleotide therapy) have also been studied, but the efficacy is different. In addition, a phase 2 trial evaluating the combination of octreotide with the mammalian target of rapamycin (mTOR) everolimus showed that octreotide is clinically active in WHO grade 1-3 meningiomas and has a reduced growth rate.Similarly, despite no clinically significant activity evidence, due to the high expression of progesterone receptor on meningioma cells, the progesterone antagonist mifepristone has been considered among other hormone agents, although no clinically meaningful activity was demonstrated. More promising results have been observed for
tyrosine kinase inhibitors, especially those targeting angiogenesis pathways such as vascular endothelial growth factor (VEGF) signaling pathways. In fact, soluble isomers of VEGF have been detected in WHO grade 2 and 3 meningiomas, and they also show higher microvascular density compared to WHO grade 1 tumors. These results suggest that VEGF-targeted drugs may be reasonable drugs for the treatment of high-grade meningiomas. Consistent with this hypothesis, in 36 patients with atypical anaplastic meningioma, the phase 2 trial of sunitinib showed a 6-month progression-free survival rate (PFS) (PFS-6) of 42%, which is better than historical controls. Similar results were observed with the tyrosine kinase inhibitor vatalanib (PTK787), targeting VEGF signaling, platelet-derived growth factor receptor (PDGFR), and c-kit. 15 patients with atypical or anaplastic meningiomas found that the median PFS was 26 weeks and the PFS-6 was 43.8%. Another retrospective study showed that there was no significant improvement if cytotoxic chemotherapy was added to PFS-6 even at 86%. Similar results were seen in a small phase 2 trial of a combination of bevacizumab and the mTOR inhibitor everolimus. In longitudinal imaging analysis, bevacizumab was also associated with growth-inhibitory and anti-edematosus activity in longitudinal imaging analysis. Other drugs previously studied include imatinib , erlotinib and gefitinib, and have no relevant clinical activity. These results are mainly derived from retrospective studies or small prospective studies, and can be confirmed in the exploratory analysis of the EORTC 1320 study, where physician selection was included in the control group. Control treatments included the cytotoxic compounds hydroxyurea, vincristine, cyclophosphamide, cyclophosphamide, cyclophosphamide, cyclostatin analogs [including the cytotoxic compounds hydroxyurea, vincristine, cyclophosphamide, doxorubicin as well as bevacizumab and somatostatin analogs]. An unplanned post hoc analysis confirmed the relative advantage of bevacizumab (median PFS: 6 months, PFS-6: 44.4%) over hydroxyurea (median PFS: 2.4 months, PFS-6: 8.8%) and the experimental drug trabetidine (median PFS: 2.4 months, PFS-6: 24.4%). However, these are unmotivated analyses and further prospective trials are needed to elucidate the efficacy of bevacizumab and other antiangiogenic drugs in meningiomas.
Frequent genetic changes and potential therapeutic significance
Based on data from high-throughput landmark studies, the genetic characteristics and molecular pathogenesis of meningiomas at different levels and tumor sites have made significant progress. For an in-depth review of this topic, we refer to the review of Preusser et al. Here, we summarize existing knowledge about frequent changes and discuss their potential as new systemic therapy targets based on preclinical and planned early clinical findings (Figure 1, Table 2).
Figure 1 New targets and candidate drugs for systemic treatment of meningiomas.
Table 2 Selection of ongoing clinical trials for systemic treatment of meningiomas.
Neurofibromin 2/Merlin (Neurofibromin 2/Merlin)
Nearly half of sporadic meningiomas carry defunctional mutations in the tumor suppressor gene NF2 encoding the Merlin protein. In contrast, patients with neurofibromatosis type 2 carrying NF2 germline mutations have significantly higher risk of developing meningiomas during their lifetime and even during childhood.From a pathological perspective, the encoding protein Merlin has an inhibitory effect on the growth-promoting phosphinositide 3-kinase (PI3K)/AKT/mTOR pathway, providing a potential therapeutic target because the pathway may be constitutively activated in the presence of NF2 mutations. Although the efficacy data of everolimus have been published, the mTOR inhibitor vistusertib (AZD2014) has also been studied. A phase 2 trial evaluated the efficacy of vistusertib in 18 patients with WHO grade 2-3 meningioma (NCT02831257), with early data showing a promising PFS-6 reaching 88.9%. Another phase 2 trial of vistusertib in the treatment of WHO grade 2-3 meningioma is underway (NCT03071874). As another potential target, focal adhesion kinase (FAK) has been shown to inhibit the exertion of antitumor activity in an in vitro meningioma model with NF2 deletion. FAK inhibitor GSK2256098 is being evaluated in a phase 2 trial still recruiting for progressive meningioma, including the cyclin-dependent kinase 4/6 inhibitor abemaciclib, the AKT inhibitor capivasertib, and the sonic hedgehog (SHH) inhibitor vismodegib. Early results of FAK inhibition of recurrent or progressive meningiomas showed that WHO grade 1 meningioma had PFS-6 of 83.3% and median PFS was 12.8 months, while WHO2-3 meningioma had PFS-6 of 33.3% and median PFS was 3.7 months. GSK2256098 is generally well tolerated.
Tumor necrosis factor receptor-associated factor 7 (TRAF7) and Krupple-like factor 4 (KLF4)[Tumor necrosis factor receptor‑associated factor 7 (TRAF7) and Krupple‑like factor 4 (KLF4]
TRAF7 mutation occurs in approximately 25% of meningiomas. According to the genomic landmark study of 300 meningiomas, the TRAF7 mutation appears to be mutually exclusive to the NF2 mutation. Functionally, TRAF7 is a ubiquitin ligase that affects a variety of signaling pathways, including NF-κB, MAP kinase pathway, etc., and has physiological proapoptotic functions. Similarly, KLF4 mutations appear to occur only in NF 2 Intact meningiomas, and often coexist with changes in TRAF7. Physiologically, the encoding protein KLF4 is involved in the renewal and differentiation of stem cells . Both TRAF7 and KLF4 changes in meningiomas are both loss-of-function mutations and therefore cannot be directly targeted. Therefore, further studies need to clarify the pathological effects of these mutations and identify potential drugable downstream targets. It is worth noting that KLF4-mutated meningiomas show higher sensitivity to mTOR inhibitors such as sirolimus esterides (temsirolimus), highlighting the potential role of the PI3K/AKT/mTOR pathway as potential therapeutic targets for meningiomas.
AKT serine/threonine kinase 1 (AKT1) and phosphoinositide 3 kinase (PI3K) [AKT serine/threonine kinase 1 (AKT1) and phosphoinositide 3 kinase (PI3K)]
AKT1 The E17K mutation is a known oncogenic alteration, which is detected in about 8-13% of meningiomas, especially meningiomas located at the base of the skull, and 31% of tumors show the alteration. In fact, this specific mutation occurs in a small number of breast cancer , uterine cancer, ovarian cancer, cervical cancer , lung cancer, prostate cancer , and colorectal cancer, while a specific inhibitor , such as capivasertib, is under investigation. In the above-mentioned targeting progressive NF 2 In the multi-arm phase II trial (NCT02523014) of patients with mutant meningioma, capivasertib has been included in one of four trial treatment options for patients with AKT mutant meningioma.
smooth curl family receptor (SMO)
11% of meningiomas have SMO mutations, but NF2, AKT1 and KLF1 did not show any changes. The encoding protein is a receptor that activates the sound hedgehog signaling pathway (SHH), which is involved in a variety of cellular processes such as differentiation and proliferation. This change is found in many solid tumors, including breast cancer, pancreatic cancer , colorectal cancer, gastric cancer , hepatocellular carcinoma, cholangiocarcinoma, lung cancer and medulloblastoma. In addition, the SHH pathway is involved in the pathogenesis of basal cell carcinoma , and its specific inhibitor Vismodegib was approved in Europe and the United States. Vismodegib is assessing progressive meningiomas in the above multi-arm test (NCT02523014).However, a recent article suggests that SMO mutations may not be associated with activation of the SHH pathway in preclinical models of meningiomas, which may pose a challenge to the efficacy of vismodegib in these tumors.
Meningioma as a potential therapeutic target for epigenetics landscape?
DNA methyl group analysis is increasingly used as an additional tool for the diagnosis of central nervous system malignant tumors because it defines a biologically homogeneous subgroup. Among meningiomas, a large study based on 497 samples found six distinct methylation clusters (benign 1-3, intermediate A/B and malignant) ], which was also associated with clinical factors such as gender, tumor location and prognosis. Another paper defines a prognosis-related methylation feature, which shows a higher degree of methylation in patients with poor survival tumors. In addition, some meningiomas have mutations in KDM5C, KDM6A, SMARCB1 and SMARCE1 encoding histone demethylase (KDM5C, KDM6A) or proteins involved in transcription-related chromatin remodeling (SMARCB1, SMARCE1). Based on these results, epigenetic modification of may be a new treatment. In fact, based on DNA methylation analysis, RNA sequencing, whole exome sequencing and copy number alteration, the histone deacetylase (HDAC) inhibitor vorinostat showed activity in in vitro models of tumors with specific molecular patterns. Furthermore, in the NF2-altered preclinical meningioma model, the HDAC inhibitor AR-42 showed some antitumor activity. AR-42 evaluated these results in a Phase 1 trial of NF2-related vestibular schwannoma and meningioma, with mixed results, but further data are needed. In this regard, a phase I trial is currently evaluating the efficacy of the histone deacetylase inhibitor panobinostat with stereotactic radiation surgery in patients with high-grade meningiomas, recurrent gliomas and brain metastases (NCT01324635).
Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B)
With the latest update of WHO central nervous system tumor classification in 2021, regardless of histological grading, there is enough CDKN2A/B homozygous deletion to designate meningiomas as WHO grade 3 CNS tumors. Previously, CDKN2A/B alterations were mainly reported in anaplastic meningiomas. Meningiomas with CDKN2A/B homozygous deletion are characterized by high recurrence rates, independent of WHO classification, DNA methylation grade, gender, age, and tumor location. In addition, the loss of heterozygous , mutations and promoter methylation of CDKN2A, were also found to be closely related to recurrent meningiomas and high Ki-67 indexes. Physiologically, CDKN2A/B encoded proteins stop the cell cycle; therefore, homozygous deletion leads to disordered cell cycle progression and uncontrolled proliferation. Drug inhibition of the cyclin-dependent kinase CDK4/6 may be a particularly promising therapeutic strategy for high-grade mitotic active meningiomas independent of the CDKN2A/B status. CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib are approved for hormone receptor-positive breast cancer combined with endocrine therapy. In a preclinical model of meningioma, radiotherapy with palbociclib showed attenuated proliferation and reduced tumor size in vivo. However, data from clinical trials remains to be seen. Currently, the multi-arm trial NCT02523014 is evaluating the efficacy of abemaciclib in recurrent meningiomas with CDK pathway or NF2 alterations. In addition, abemaciclib is being evaluated in a Phase 2 tissue agnostic trial (NCT03220646) in patients with recurrent brain tumors.
Immunomodulation method
In the past few decades, cytokine interferon alpha (IFN-α) has been evaluated as a potential therapeutic option for meningiomas. In fact, both case reports and small clinical trials have shown that IFN-α has anti-tumor activity. IFN-α may have antiproliferative activity, but there are also hypotheses that anti- angiogenesis and immunomodulatory properties are anti-. However, another group of retrospective cases failed to show clinically significant efficacy in high-grade meningiomas.
immune checkpoint inhibitor (ICI) has revolutionized the treatment of solid tumor , because persistent responses can be observed in various histological metastatic diseases, which have poor prognosis before these metastatic diseases. ICI targeting the axes of programmed death receptor (ligand)1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are widely used in solid malignant tumors, such as melanoma, lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, etc. Although ICI shows activity in asymptomatic patients with brain metastases, clinical trials have failed to show overall benefit in primary and recurrent primary central nervous system malignancy such as glioblastoma . Expression of
PD-L1 is often used as the biomarker that predicts the response to ICI. However, previous studies on the expression of PD-L1 in meningiomas are contradictory. Membranous PD-L1 expression is found in about 5 to 80% of meningeal tumors, which is higher in higher grade tumors, mainly on myeloid cells in the tumor microenvironment. In anaplastic meningiomas, the FOXP3+ infiltrated lymphocytes is elevated, suggesting that regulatory T cells play a major role in the particular immunosuppressive microenvironment in higher grade meningiomas. In clinical trials, the results of a phase 2 trial evaluating pembrolizumab for relapsed or progressive WHO grade 2 and grade 3 meningiomas were recently published, indicating that the trial met its primary endpoint. PFS-6 reached 48%, while the median PFS was 7.6 months, 10 of 25 patients were still alive at the time of database lockdown. Furthermore, clinical responses have also been observed in metastatic or extracranial diseases. Biomarker studies were also included, and trends in correlation between clinical benefits and PD-L1 expression and the apparent diffusion coefficient (ADC) evaluated by magnetic resonance imaging were observed. Further prospective studies are needed to validate these results and identify predictable biomarkers in order to rationally select meningioma patients who may benefit from ICI. Other trials of ICI in meningeal tumors are underway. Two NCI-sponsored Phase 2 trials were designed to evaluate the efficacy of nivolumab ± ipilimumab with stereotactic radiosurgery or peripheral radiation therapy for relapse of WHO grade 2-3 meningiomas (NCT03604978, NCT02648997). Another study is evaluating the treatment of relapsed rare central nervous system malignancy tumors, including WHO grade 2-3 meningioma, ependymoma, ependymoma, choroidal plexus tumors (NCT03173950). Similar trials are evaluating ICIs pembrolizumab (NCT04659811, NCT03279692, NCT03016091) and avelumab (NCT03267836).
In addition, the myeloid cell component is increasingly considered an emerging therapeutic target because tumor-associated myeloid cells stimulate tumor growth by secreting growth promoter . Therefore, inhibiting chemotaxis signals is an interesting therapeutic strategy that is responsible for recruiting myeloid cells into the tumor microenvironment, especially in tumors such as meningiomas, where a large amount of myeloid cells infiltrates the anti-tumor immune response. One of the signals is the colony-stimulating factor 1 (CSF-1) axis. In fact, a recent study by Yeung et al. showed that high expression of CSF-1 receptor on in the meningioma microenvironment of macrophages, in a mouse model, monoclonal antibody treatment targeting this signaling pathway can reduce meningioma growth.
Conclusions and future prospects
Recurrent meningioma is not suitable for local treatment, such as surgery or radiotherapy, and remains a therapeutic challenge. Although systemic therapy is often considered in these cases, due to the limited historical benchmark data on high-grade meningioma results, evidence of systemic therapy is generally lacking. Traditional cytotoxic drugs are usually ineffective. However, preclinical data show that the anti-metabolites gemcitabine have anti-tumor activity, but clinical trials are yet to be conducted.Antiangiogenic therapies, such as polytyrosine kinase inhibitors or antibodies targeting the VEGF axis, show promising results in small phase II trials and retrospective case series. However, prospective controlled trials are urgently needed to validate these positive findings. In addition, the elucidation of glioma (episode) genetic maps through high-throughput landmark studies reveals further potential therapeutic targets currently under investigation. Recent genomic studies have identified new potential targets that are being evaluated in ongoing national studies. Immunotherapy methods, including ICI (immune checkpoint inhibitor), are also being evaluated, with early results showing good activity in some patients.
