Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study

Giuseppe Lombardi, Valeria Barresi, Stefano Indraccolo, Michele Simbolo, Matteo Fassan, Susanna Mandruzzato, Matteo Simonelli, Mario Caccese, Marco Pizzi, Arianna Fassina, Marta Padovan, Elena Masetto, Marina Paola Gardiman, Maria Giuseppina Bonavina, Maria Caffo, Pasquale Persico, Franco Chioffi, Luca Denaro, Angelo Paolo Dei Tos, Aldo ScarpaVittorina Zagonel

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed.

METHODS: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages.

RESULTS: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity.

CONCLUSIONS: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.

Original languageEnglish
Article number2283
Number of pages14
JournalCancers
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 14 2020

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