Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas

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.

Conflict of interest statement

PKB has consulted for Tesaro, Angiochem, Genentech-Roche, ElevateBio, Eli Lilly, SK Life Sciences, Advise Connect Inspire (ACI), Pfizer, Voyager Therapeutics, Sintetica, and Dantari, received institutional research funding (to MGH) from Merck, Mirati, Eli Lilly, BMS, and Pfizer, and has received honoraria from Merck, Pfizer, and Genentech-Roche. DAF has Eli Lilly stock ownership. ICA has received institutional research support from Astex Pharmaceuticals and consulted for Boehringer Ingelheim, FORMA Therapeutics, and Agios. DPC has consulted for Lilly, GlaxoSmithKline, Boston Pharmaceuticals, and Iconovir, and serves on the advisory board of Pyramid Biosciences, which includes an equity interest, and has received honoraria and travel reimbursement from Merck for invited lectures, and funding from the US NIH and DOD for clinical trial and grant review. Finally, pembrolizumab is a drug that was developed based in part on scientific research from Dana-Farber Cancer Institute (DFCI), which was licensed to Merck US, the pharmaceutical company that manufactures and sells pembrolizumab. Through the licensing arrangement, DFCI may receive money from this company. Any research that might affect the sales or use of pembrolizumab could change the payments DFCI receives from this company. This is known as an institutional conflict of interest. The remaining authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Kaplan–Meier curve for progression-free survival.

Kaplan–Meier estimates of PFS are shown. There were 22 PFS events among 25 patients. The median PFS was 7.6 months (90% CI: 3.4–12.9).

Fig. 2. Clinical course of high-grade meningioma patients treated with pembrolizumab.

Time of best radiographic response (as defined by TIMC), death, and study-limiting toxicity for the patient population. The arrow at the end of the bar indicates the time at which the patient was last known to be alive at the time of data analysis. The dashed line at 6 months is the threshold of the primary endpoint (PFS-6). Patients marked in blue had extracranial or metastatic meningiomas. One patient (MEN_06) was excluded from this schematic, as they withdrew consent one week after enrollment before receiving pembrolizumab.