Avelumab in newly diagnosed glioblastoma

Francois H Jacques, Garth Nicholas, Ian A J Lorimer, Victorine Sikati Foko, Jasmine Prevost, Nathalie Dumais, Katy Milne, Brad H Nelson, John Woulfe, Gerard Jansen, B Erik Apedaile, Francois H Jacques, Garth Nicholas, Ian A J Lorimer, Victorine Sikati Foko, Jasmine Prevost, Nathalie Dumais, Katy Milne, Brad H Nelson, John Woulfe, Gerard Jansen, B Erik Apedaile

Abstract

Background: Glioblastoma (GBM) is known to use both local and systemic immunosuppressive strategies. One such strategy is the expression of the immune checkpoint protein programmed cell death ligand-1 (PD-L1) by both tumor cells and tumor-associated immune cells. Recent phase III trials using IgG4 antibodies targeting PD-1, the ligand for PD-L1, failed to show any benefit. Avelumab is an IgG1 monoclonal antibody targeting PD-L1. In contrast to the previously tested immune checkpoint inhibitors, it can directly bind tumor cells and immune cells expressing PD-L1 and can induce antibody-dependent cellular cytotoxicity.

Methods: We conducted a single center, open label, phase II study where avelumab 10 mg/kg IV Q2W was added concurrently to the first monthly temozolomide cycle in patients with newly diagnosed GBM. Immunohistochemical analyses were performed on surgery samples. The primary objective was safety. Secondary objectives were efficacy outcomes according to the immunotherapy Response Assessment in Neuro Oncology criteria, progression free survival (PFS), and overall survival (OS). Exploratory objectives aimed at determining prognostic biomarkers.

Results: Thirty patients were started on therapy and two were lost to follow-up. Median follow-up time (reverse Kaplan-Meier) was 41.7 months (IQR: 28.3-43.4). Three (10.0%) patients had a related or possibly related treatment emergent adverse event that lead to transient or permanent discontinuation of avelumab. Eight (26.7%) patients had one or more immune-related adverse events, and 8 (26.7%) patients had an infusion-related reaction. The overall response rate was 23.3%, median PFS was 9.7 months, and the median OS was 15.3 months. No pretreatment biomarkers showed any predictive value.

Conclusions: The addition of avelumab to standard therapy in patients with GBM was not associated with any new safety signal. There was no apparent improvement in OS.

Trial registration: NCT03047473 Registered February 9, 2017.

Keywords: PD-L1; avelumab; glioblastoma; immune checkpoint inhibitor; phase II.

© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.
Figure 1.
Kaplan Meier plots for patients grouped according to steroid use. A. progression-free survival in patients who did not require the use of steroids at month 1 (red) and those who did (blue). B. Overall survival in patients who did not require the use of steroids at month 1 (red) and those who did (blue).
Figure 2.
Figure 2.
Biomarker analyses: A. Multicolour immunohistochemistry analyses of first surgery samples from trial patients. Top row of bar graphs show the results for the CD3/CD8/CD20 analysis. The bottom row of bar graphs show results for PD1/PDL1/CD68 analysis. Y axes show the number of positive cells per mm2 and x axes show results for individual patients. B. Single cell RNA-seq expression data from twenty-eight glioblastoma patients sequenced by Neftel et al. were analyzed for mRNA expression of immunohistochemistry markers used in this study, using Broad Institute Single Cell portal software https://singlecell.broadinstitute.org/single_cell. C. Comparison of immune status in first and second surgery samples from trial patients. Y axes show the number of positive cells per mm2 and x axes show paired bars for individual patient samples from first (grey bar) and second surgeries (black bar).

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