Pre-radiation Nivolumab plus ipilimumab in patients with newly diagnosed high-grade gliomas

Abstract

The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018.

Keywords: Glioblastoma; glioma; immune checkpoint blockade; neoadjuvant; pre-radiation.

Figure 1.

Kaplan–Meier curves of survival probability among patients treated with nivolumab and ipilimumab (N = 15). (a) progression-free survival in all patients. (b) overall survival in all patients. (c) progression free survival among patients with high-grade glioma containing a methylated MGMT promoter and an unmethylated MGMT promoter. (d) overall survival among patients with high-grade glioma containing a methylated MGMT promoter methylation and an unmethylated MGMT promoter. Censored patients are annotated by a small vertical line.

Figure 2.

Magnetic resonance imaging of patient 301.Brain MRI shows axial T1 post-gadolinium images (a-d) and corresponding T2-FLAIR images (e-h) of a left frontal residual tumor (arrows) before treatment with nivolumab and ipilimumab (a, e), and 1 month (b, f), 5 months (c, g), and 9 months (d, h) after treatment initiation. The images show improving enhancing disease for over 5 month before progression at 9 months.

Figure 3.

Gene expression profile of tumors from 6 patients pre- and post-treatment with nivolumab and ipilimumab. (a) heatmap of log counts per million (log-cpm) values for top 100 differentially expressed genes (DEGs) with a p-value <0.05 in tumor samples of 6 patients collected pre- and post- treatment with nivolumab and ipilimumab. Red coloration represents relatively high expression of a given gene and blue coloration represents relatively low expression. Lighter shades and white coloration represent genes with intermediate expression levels. Samples and genes were arranged by hierarchical clustering. A dendrogram is shown for the sample clustering. (b) graph representing the most significant canonical pathways from DEGs with a p-value <0.05 in pre- versus post-treatment samples. Orange-colored bars indicate predicted pathway activation; blue-colored bars indicate predicted inhibition. (c) pie plot showing the proportion of immune cell types in tumor samples pre- and post- treatment. Abundance of 8 immune cell types and infiltration levels in samples compared amongst, and within, patients were estimated by TIMER2.0 using CIBERSORT algorithm. (d and e) abundance, expressed as mcp-counter score in absolute value, of pre-treatment samples from patients with tumor shrinkage compared to patients with tumor growth of T cells (d) and CD8+ T cells (e). (f-h) gene expression (expressed as transcript per million (TPM)) in pre-treatment samples from patients with tumor shrinkage compared to patients with tumor growth of PDCD1 (PD-1) and CTLA4 (f), HAVCR2 (TIM-3) and LAG-3 (g), and costimulatory molecules CD40L, CD86 and CD80 (h). For graphs F-H, data are presented as means ± SEM and significance was determined with two-tailed Student’s t test, *p<.05 **p<.01. i) heatmap of log-cpm values for top 100 DEGs with a p-value <0.05 in pre-treatment samples from patients with tumor shrinkage and patients with tumor growth. High- and low- expression is marked in red and blue, respectively. Samples and genes were arranged by hierarchical clustering. A dendrogram is shown for the sample clustering. j) graph representing the most significant canonical pathways from DEGs with a p-value <0.05 in pre-treatment samples from patients with tumor shrinkage and patients with tumor growth. Orange-colored bars indicate predicted pathway activation; blue-colored bars indicate predicted inhibition.