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Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study
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 rel...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464918/ https://www.ncbi.nlm.nih.gov/pubmed/32823925 http://dx.doi.org/10.3390/cancers12082283 |
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author | Lombardi, Giuseppe Barresi, Valeria Indraccolo, Stefano Simbolo, Michele Fassan, Matteo Mandruzzato, Susanna Simonelli, Matteo Caccese, Mario Pizzi, Marco Fassina, Arianna Padovan, Marta Masetto, Elena Gardiman, Marina Paola Bonavina, Maria Giuseppina Caffo, Maria Persico, Pasquale Chioffi, Franco Denaro, Luca Dei Tos, Angelo Paolo Scarpa, Aldo Zagonel, Vittorina |
author_facet | Lombardi, Giuseppe Barresi, Valeria Indraccolo, Stefano Simbolo, Michele Fassan, Matteo Mandruzzato, Susanna Simonelli, Matteo Caccese, Mario Pizzi, Marco Fassina, Arianna Padovan, Marta Masetto, Elena Gardiman, Marina Paola Bonavina, Maria Giuseppina Caffo, Maria Persico, Pasquale Chioffi, Franco Denaro, Luca Dei Tos, Angelo Paolo Scarpa, Aldo Zagonel, Vittorina |
author_sort | Lombardi, Giuseppe |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7464918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74649182020-09-04 Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study Lombardi, Giuseppe Barresi, Valeria Indraccolo, Stefano Simbolo, Michele Fassan, Matteo Mandruzzato, Susanna Simonelli, Matteo Caccese, Mario Pizzi, Marco Fassina, Arianna Padovan, Marta Masetto, Elena Gardiman, Marina Paola Bonavina, Maria Giuseppina Caffo, Maria Persico, Pasquale Chioffi, Franco Denaro, Luca Dei Tos, Angelo Paolo Scarpa, Aldo Zagonel, Vittorina Cancers (Basel) Article 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. MDPI 2020-08-14 /pmc/articles/PMC7464918/ /pubmed/32823925 http://dx.doi.org/10.3390/cancers12082283 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lombardi, Giuseppe Barresi, Valeria Indraccolo, Stefano Simbolo, Michele Fassan, Matteo Mandruzzato, Susanna Simonelli, Matteo Caccese, Mario Pizzi, Marco Fassina, Arianna Padovan, Marta Masetto, Elena Gardiman, Marina Paola Bonavina, Maria Giuseppina Caffo, Maria Persico, Pasquale Chioffi, Franco Denaro, Luca Dei Tos, Angelo Paolo Scarpa, Aldo Zagonel, Vittorina Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title | Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title_full | Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title_fullStr | Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title_full_unstemmed | Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title_short | Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study |
title_sort | pembrolizumab activity in recurrent high-grade gliomas with partial or complete loss of mismatch repair protein expression: a monocentric, observational and prospective pilot study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464918/ https://www.ncbi.nlm.nih.gov/pubmed/32823925 http://dx.doi.org/10.3390/cancers12082283 |
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