How useful is chemotherapy for atypical and anaplastic meningiomas?

KEYWORDS:

• Anaplastic meningioma
• malignant meningioma
• chemotherapy
• targeted therapy
• genomic profiling
• atypical meningioma

1. Introduction

Meningiomas are the most commonly diagnosed primary intracranial tumor. Although the majority of meningiomas are benign, a subset of patients present with atypical (WHO grade 2), and malignant (WHO grade 3) meningiomas. Grading of meningiomas has traditionally depended on mitotic rate, brain invasion, and specific histological features. In contrast to prior classifications, the recently updated 2021 WHO classification [1] has introduced molecular markers TERT promoter mutation and/or CDKN2A/B homozygous deletion to assign WHO grade 3, irrespective of histological criteria of anaplasia. Atypical tumors make up approximately 18.3% of all meningiomas with a further 1.6% of meningiomas representing grade 3 or anaplastic/malignant tumors [2]. The most frequent alterations in meningiomas of all WHO grades are chromosome 22q deletions and NF2 mutations. The frequency of NF2 mutations increases with grade and reaches 60% and 69% in atypical and anaplastic meningioma [3]. With increasing WHO grade, NF2-mutant meningiomas accumulate copy number alterations including deletions of chromosomal arm 1p and chromosome 10 [4]. Aggressive biologic behavior is often associated with alterations in the cyclin-dependent kinase (CDK) inhibitor pathway, occurring in approximately 20% of NF2-mutant anaplastic meningiomas [3], representing a distinct genomic subclass. The second genomic subclass of high-grade meningiomas includes an NF2-agnostic group harboring frequent TERT promoter and TP53 mutations. A third group is characterized by BAP1/PBRM1 alterations [3]. Overall, this data has increased our knowledge of the biology of high-grade meningiomas and the design of genomically informed clinical trials.

Higher grade meningiomas can be aggressive neoplasms with a high rate of recurrence, even after gross total resection. Adjuvant radiation therapy (RT) is a standard initial treatment consideration for all malignant meningiomas, regardless of the extent of resection, in an attempt to improve local control and overall survival. Adjuvant RT has been shown to decrease the recurrence rate and to improve five-year survival to more than 50% [5]. There is a subset of patients in whom disease cannot be controlled with these approaches and for whom systemic therapies are being considered when re-operation or re-irradiation are no longer feasible.

This article provides a comprehensive review of synthetic agents (excluding immunotherapy) used in the treatment of recurrent atypical and anaplastic meningioma. The author provides his expert perspectives on the field and his opinions for the future.

2. Chemotherapy

The National Comprehensive Cancer Network (NCCN)-published guidelines suggest only four agents (sunitinib, bevacizumab, bevacizumab and everolimus, and somatostatin analogs) in the medical treatment of recurrent meningiomas [6]. These recommendations, however, are based on a small number of studies, each with significant limitations. Many trials evaluating other agents have produced negative results. The main limitations of these studies are the heterogeneity of meningiomas included in these studies, the shifting definitions of pathologic grading, and the lack of larger well-controlled and randomized trials.

2.1. Hormonal therapies

While progesterone receptors are expressed in more than 80% of meningiomas, a large placebo controlled phase III trial of the progesterone receptor inhibitor mifepristone demonstrated no improvement in progression or overall survival among 164 patients with recurrent or refractory meningioma randomly assigned to mifepristone or placebo. The authors concluded that hormonal modulation may not be the driving force of meningioma progression [7]. Similarly, two studies evaluating the estrogen receptor inhibitor tamoxifen have failed to demonstrate activity that may be due to the expression of estrogen receptors only in a small subset of meningiomas [8].

2.2. Cytotoxic agents

A variety of cytotoxic agents have been studied in small series such as dacarbazine and adriamycin, temozolomide, irinotecan, and combinations such as cyclophosphamide, doxorubicin, and vincristine, all of which failed to show any significant efficacy [9]. The most extensively studied agent is hydroxyurea. Although early studies reported preliminary efficacy, these results were not confirmed in subsequent studies [10]. Trabectedin, an antineoplastic drug with activity in some forms of sarcoma, has been evaluated in a multicenter phase II randomized EORTC demonstrating no improvement of progression-free or overall survival compared to local standard of care in patients with high-grade meningioma but substantial toxicity [11].

2.3. Somatostatin analogs

Although somatostatin receptors are highly expressed in approximately 90% of meningiomas and initial case reports suggested that somatostatin analogs might have therapeutic benefit [12], subsequent trials have not shown clear benefit. A prospective, phase II trial of octreotide in patients with recurrent high-grade meningioma was terminated due to lack of efficacy, after enrolling only nine patients [13]. Another somatostatin analog, pasireotide (SOM230C), failed to produce any responses in a phase II study and demonstrated 6 months progression-free survival (PFS6) of only 15% for grade 2 and 3 meningiomas [14]. Treatment was well tolerated. Somatostatin analogs remain a treatment consideration in NCCN CNS guidelines as agents ‘useful in certain circumstances.’ At this time, however, they are not included in EANO meningioma management guidelines [15]. Somatostatin receptor targeted radionuclide therapy has demonstrated preliminary efficacy in small trials and is under investigation in a larger phase II study (NCT03971461 and NCT04082520).

2.4. Targeted agents

2.4.1. PDGF and EGFR targeted agents

Imatinib, a PDGF receptor blocker, has been evaluated in phase II studies either alone or in combination with hydroxyurea, demonstrating no meaningful benefit. Similarly, EGFR tyrosine kinase inhibitors gefitinib and erlotinib failed to demonstrate objective responses or improvement in progression-free survival [16].

2.4.2. VEGF targeted agents

Malignant meningiomas are highly vascularized, suggesting that inhibition of angiogenesis might be beneficial. The existing evidence has thus far shown mixed results, yet VEGF targeted drugs are among the most widely used agents. In total, nine retrospective and prospective studies have evaluated the use of bevacizumab in progressive meningiomas demonstrating PFS6 between 43.8% and 74% in high-grade meningiomas often accompanied by reduction in peritumoral edema, and symptom improvement [11]. A phase II trial of sunitinib, a tyrosine kinase inhibitor with dual VEGF and PDGF inhibition, including 30 atypical and 6 malignant meningioma patients, demonstrated a PFS6 rate of 42% in grade 2 and 3 patients combined [17].

2.4.3. Targeting of intracellular signaling pathways

Most high-grade meningiomas show evidence of upregulation of the Pi3K-Akt-mTOR (mammalian target of rapamycin) pathway. In a phase II study of octreotide plus everolimus in 20 patients with recurrent or refractory meningiomas, the PFS6 was 55%. Everolimus has also been combined with bevacizumab in a small prospective trial, demonstrating similar efficacy to monotherapy with bevacizumab [11]. Alpelisib, a phosphoinositide 3-kinase α (Pi3Kα) specific inhibitor is currently under investigation in combination with the MEK inhibitor trametinib (NCT03631953).

3. Expert opinion

Meningioma that recurs following surgical resection and radiotherapy presents a significant unmet need where evidence in support of systemic therapy remains very limited. Most clinical trials evaluating systemic therapies have produced negative or conflicting results. Conventional chemotherapeutic agents have generally been ineffective in achieving objective responses or stabilization of disease. Previously conducted clinical trials are limited as patient samples were heterogeneous in terms of tumor histology and prior therapy and enrolled patients agnostic to molecular targets.

Anti-VEGF targeted approaches such as bevacizumab, either alone or in combination with everolimus and sunitinib have the highest probability of treatment success particularly in high-grade meningiomas and after radiation treatment failure. The molecular biomarkers established in the 2021 WHO classification have important implications for the design of clinical trials. There is considerable potential for novel treatment strategies guided by molecular profiling, i.e. stratifying patients to treatments that may be most effective based on their tumor’s molecular profile. The better understanding of the molecular alterations underlying higher grade meningiomas has informed several ongoing and planned trials. These include potential targeting of BAP-1/PBRM1 genes mutations utilizing the EZH2 inhibitor tazemetostat, as well as targeting of CDK2NA mutations with ribociclib and abemaciclib, both CDK 4/6 inhibitors (NCT02933736 and NCT02523014/Alliance A071401). As strong evidence in support of any systemic therapies is lacking, all patients with recurrent high-grade meningioma should be considered for trials whenever possible.

Declaration of interest

J Drappatz is a stockholder of Pfizer and GSK and has received research support from Servier and Agios. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.