Improved Understanding of Genomics Drives Excitement in High-Grade Meningiomas

At present, there are no FDA-approved systemic therapies for patients with high-grade meningiomas, a type of tumor that develops in the membrane surrounding the brain and spinal cord known as the meninges. However, there has been an increase in research surrounding the disease over the past decade, which is improving the prospect a targeted agent may become for this population.

“Since 2013, we have had a genomic revolution of meningiomas,” Priscilla Kaliopi Brastianos, MD, an associate professor of medicine with Harvard Medical School and physician-scientist at Massachusetts General Hospital Cancer Center, said in an interview with OncLive®. “Multiple studies came out demonstrating new molecular drivers for meningiomas. I do think that improved sequencing technologies have increased our understanding of what drives meningiomas, and this is helping us identify potential new therapies for this disease entity.”

Meningiomas are the most common type of brain cancer and approximately 80% of these tumors are benign or grade I, according to the World Health Organization.¹ The remaining 20% are grade II and called atypical because they have an increased risk of returning after treatment or grade III, which are malignant^.2

Grade II and III tumors usually appear as an enhancing mass on the outside lining of the brain tissue on MRI. Malignant meningiomas can also invade into the brain tissue.³

Both benign (incidence rate ratio [IRR] 2.33) and malignant (IRR, 1.12) meningiomas are more common in women. Furthermore, Black patients were also more likely to develop both benign (IRR, 1.18) and malignant (IRR, 1.52) tumors than White patients.¹

“Grade 2 tumors are a little bit more aggressive. They’re not considered malignant, quote unquote, but they are tumors that have a higher propensity for recurrence. And these are tumors where oftentimes surgery alone is not enough,” said Nader Sanai, MD, chief scientific officer and chief of neurosurgical oncology with the Ivy Brain Tumor Center at the Barrow Neurological Institute. “Grade 3 tumors are these frankly aggressive meningiomas that you can consider to be malignant. These are tumors where surgery alone certainly is not adequate; usually a combination of therapies is required.”

Meningiomas often present with nonspecific symptoms but, depending on the site of the tumor, can cause focal neurologic deficits including cranial nerve deficits. The most common symptoms include headache, focal cranial nerve deficit, and seizure. However, 9.4% of patients are asymptomatic. More than half (54%) of tumors in the cranial fossa interfere with vision.¹

Sanai said that meningiomas in the frontal lobe, for example, may present with headaches and personality changes. Tumors closer to the cerebellum may present with posterior fossa type syndromes such as nausea, vomiting, balance problems, or double vision. High-grade tumors, he said, typically present with progressive symptoms such as a new onset seizure, focal neurological deficits, significant headache or mass effect symptoms such as fatigue, vision problems, or nausea and vomiting.¹

“For intermediate and high-grade tumors like grade II and III meningiomas, the symptom onset is usually more rapid. Typically, meningiomas are tumors that are with patients for many years before they’re diagnosed, particularly grade I tumors. You can have them during the course of your lifetime and never know it,” he added. “Grade II or III tumors though, grow more rapidly. And as they grow, they cause more swelling in the brain tissue. And that’s what leads to the symptoms—seizures are a common side effect of that parenchymal swelling.”

Systemic Treatments Move Closer to Reality

At present, surgery, radiation, and/or observation are the only modalities available for patients with meningiomas. Sanai noted that for high-grade tumors, surgery alone is often inadequate and requires the use of radiotherapy. Physicians are still debating the best role for radiation in grade II tumors, but its use is common for grade III tumors.

“Unfortunately for most grade III meningiomas, radiation plus surgery alone is not curative,” he said. “There are consistent problems today in terms of controlling those tumors beyond those regimens.”

However, investigators have been successful at understanding the genomic and epigenomic data associated with meningiomas and, in turn, have been working to identify genetic biomarkers that may predict tumor behavior and prognosis. Chromosomal instability is a common molecular alteration for disease recurrence and prognosis.

Furthermore, investigators have found that accumulation of cytogenetic aberrations correlates with increasing tumor grades and aggressiveness, and cytogentic profiles are significantly more complex in high-grade meningiomas compared with benign tumors.¹

Sanai said investigators at the Ivy Brain Tumor Center have been exploring cell cycle inhibitors that target the cell cycle. “It’s a logical target for these tumors because they're constantly dividing and dividing at a voracious rate,” he said. “Within other cancers, like breast cancer, cell cycle inhibitors have recently become FDA approved and more part of the standard of care.”

The center conducts phase 0 trials, in which patients get brief exposure to the experimental drug prior to surgery. Once the tumor is removed, investigators perform a biopsy to determine whether the drug is adequately penetrating the tumor and hitting its molecular targets. If both things are true, the patient can continue on the drug.

Sanai said his institution had seen success with CDK4/6 inhibitors. The Ivy Center recently led a phase 0/2 study of the CDK4/6 inhibitor ribociclib (Kisqali) in patients with recurrent grade II and III meningiomas.

“We’ve had some patients with remarkably durable clinical results, even those with grade III tumors. Importantly, the tissue biology data form these patients is equally compelling,” he said. “This may be part of the strategy moving forward, which is why we are assembling a randomized phase 2 clinical trial with a CDK4/6 inhibitor.”

Brastianos is responsible for some of the improved understanding of meningioma genomics. Her lab discovered clinically significant genetic drivers in meningiomas including AKT1 and SMO that may be therapeutic targets.

“Both of these mutations are potentially actionable, meaning there are drugs that target them in other cancers either in clinical trials or in clinical use,” she said. “We’ve now translated these findings to a national genetically driven trial for patients with meningiomas, where we assigned targeted treatments based on molecular features.”

That is the multiarm, multi-institution, National Cancer Institute Cooperative Group phase 2 Alliance A071401 trial (NCT02523014). Investigators are assessing the safety and efficacy of vismodegib (Erivedge), the focal adhesion kinase (FAK) inhibitor GSK2256098, the investigational AKT inhibitor capivasertib, or abemaciclib (Verzenio) in patients with progressive meningioma.

One of the study arms, assessing the FAK inhibitor GSK2256098, just completed accrual. In an analysis of 36 patients with NF2 mutations, GSK2256098 induced a 6-month progression-free survival (PFS) rate of 83% (95% CI, 52%-98%) in grade I patients and 33% (95% CI, 16%-55%) in grade II/III patients, meeting the primary efficacy end point for the trial.⁴

Further, the agent was well tolerated. Seven patients had a maximum grade 3 adverse event (AE) that was at least possibly related to the study treatment. There were no grade 4/5 AEs.

“We looked at FAK inhibition because FAK inhibition has a synthetic lethal relationship with Merlin loss, which is the protein product of NF2,” Brastianos said. “Approximately 50% of meningiomas have NF2 alterations.”

In addition to targeted agents, immune checkpoint inhibitors may have a future in treating patients with meningiomas. Sanai noted that investigators have explored the anti-VEGF drug bevacizumab (Avastin) in this disease. Findings published in August 2022 showed that bevacizumab induced a 6-month PFS rate of 73% (95% CI, 54%-85%) with a median PFS of 14 months and a median overall survival (OS) of 24 months in patients with grade II/III tumors.⁵

Brastianos published data in March 2022 assessing pembrolizumab (Keytruda) for patients with recurrent/residual high-grade meningiomas. Previous results have shown that high-grade meningiomas may harbor an immunosuppressive tumor microenvironment, and that PD-L1 expression may contribute to the aggressiveness of these tumors.

In findings from a single-arm, open-label phase 2 analysis of 25 evaluable patients (NCT03279692), pembrolizumab induced a 6-month PFS rate of 48% (90% CI, 31%-66%), meeting the primary end point for the study. The median PFS was 7.6 months (90% CI, 3.4-12.9). Further, many responses were durable—the median PFS for patients who achieved the 6-month PFS rate was 17.3 months.⁶

Twenty percent of patients experienced at least 1 grade 3 or higher AE.

“These results do suggest that pembrolizumab does exert promising efficacy on a subset of these tumors,” Brastianos said. “Larger studies are needed to confirm these data, but also to identify what the right biomarkers of response are, and our lab is actively trying to do that right now.

“There are ongoing studies by several fantastic research groups throughout the world that are molecular characterizing meningiomas more comprehensively, including using methylation profiling and single-cell sequencing,” she added. “Also, a number of groups, including our lab, are investigating different targeted therapies in mouse models for meningiomas. I’m hopeful as a field, we'll together be able to make great strides to find better treatments for this disease entity in the near future.”

References

1. Ogasawara C, Philbrick BD, Adamson DC. Meningioma: a review of epidemiology, pathology, diagnosis, treatment, and future directions. Biomedicines. 2021;9(3):319. doi:10.3390/biomedicines9030319
2. Cancer.net. Meningioma. December 2021. Accessed March 24, 2023. https://www.cancer.net/cancer-types/meningioma/
3. National Cancer Institute. Meningioma diagnosis and treatment. July 21, 2021. Accessed March 24, 2023. https://www.cancer.gov/rare-brain-spine-tumor/tumors/meningioma
4. Brastianos PK, Twohy EL, Gerstner ER, et al. Alliance A071401: phase II trial of focal adhesion kinase inhibition in meningiomas with somatic NF2 mutations. J Clin Oncol. 2023;41(3):618-628. doi:10.1200/JCO.21.02371
5. Kumthekar P, Grimm SA, Aleman RT, et al. A multi-institutional phase II trial of bevacizumab for recurrent and refractory meningioma. Neurooncol Adv. 2022;4(1):vdac123. doi:10.1093/noajnl/vdac123
6. Brastianos, PK, Kim, AE, Giobbie-Hurder, A, et al. Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas. Nat Commun. 2022;13(1):1325. doi:10.1038/s41467-022-29052-7