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. 2020 Aug 14;12(8):2283.
doi: 10.3390/cancers12082283.

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  1 , Valeria Barresi  2 , Stefano Indraccolo  3 , Michele Simbolo  2 , Matteo Fassan  4 , Susanna Mandruzzato  5 , Matteo Simonelli  6 , Mario Caccese  1 , Marco Pizzi  4 , Arianna Fassina  3 , Marta Padovan  1 , Elena Masetto  3 , Marina Paola Gardiman  4 , Maria Giuseppina Bonavina  7 , Maria Caffo  8 , Pasquale Persico  6 , Franco Chioffi  9 , Luca Denaro  10 , Angelo Paolo Dei Tos  4 , Aldo Scarpa  2 , Vittorina Zagonel  1
Affiliations

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 et al. Cancers (Basel). .

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.

Keywords: TMB; glioblastoma; high grade glioma; mismatch repair; pembrolizumab.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative histological features of a MSH2/MSH6-negative glioblastoma. Immunohistochemical analysis highlighted negativity for MSH2 and MSH6 in neoplastic cells, with preserved expression of MLH1 and PMS2. Background inflammatory cells were used as positive internal controls. (Immunoperoxidase stain, original magnification 40×).
Figure 2
Figure 2
Kaplan–Meier survival analysis. Median overall survival for all patients (n = 13) was 5.6 months (95% CI 0.1–11.9) from start of pembrolizumab treatment.
Figure 3
Figure 3
Genomic and immunological characteristics of 12 high-grade gliomas. The matrix shows the characteristics of each patient and matched tumor sample. Gene mutations, immunohistochemical analysis of genes involved in mismatch repair (MMR IHC), are correlated to histology, treatment response, tumor mutational burden (TMB) and immunological characteristics.
Figure 4
Figure 4
Immune infiltrate analysis in a glioblastoma sample. Representative example of a Multispectral Imaging field obtained from a glioblastoma sample in which the markers GFAP (light blue), CD68 (orange) and CD8 (pink) are reported (20× zoom, lower right panel) and relative pseudo-immunohistochemistry representations of the single cell populations (40× zoom). DAPI (blue) was used as nuclear counterstain.
See this image and copyright information in PMC

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