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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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