Abstract
High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31–0.66) and a median PFS of 7.6 months (90% CI: 3.4–12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.
Highlights
High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments
As a direct translation of our genomic-4,5 and TME14-characterization efforts, we evaluated the efficacy of pembrolizumab in recurrent and progressive high-grade meningiomas
We chose PFS-6 to screen for treatment efficacy based on recommendations of a Response Assessment in Neuro-oncology (RANO) working-group effort to homogenize benchmarks for clinical trials in treatment-refractory meningiomas[3]
Summary
High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Others have identified that the presence of immunosuppressive myeloid cells in high-grade meningioma[11,12], linked PD-L1/PD-L2 expression with worse outcomes[10,12], and found enrichment of PD-1/PD-L1 signaling in malignant meningiomas by single-cell RNA sequencing[11] Based on these studies suggesting that high-grade meningiomas harbor an immunosuppressive TME, which may contribute to its aggressive phenotype, we hypothesize that pembrolizumab, a PD-1 inhibitor, would result in antitumor activity for highgrade meningiomas. Given that meningiomas grow outside the blood–brain barrier, coupled with extensive studies showing manageable adverse events in a number of solid tumors[15–18], we have designed a prospective phase-2 study evaluating pembrolizumab, using a dose schedule that has demonstrated efficacy in systemic tumors, in patients with progressive high-grade meningiomas. Our results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors and results in prolonged PFS compared with historical controls
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