Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis

Abstract

Purpose: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.Patients and Methods: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.Results: Between November 2015 and February 2017, 119 patients were enrolled (n ¼ 59 regorafenib and n ¼ 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P ¼ 0.0013; test for interaction ¼ 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.Conclusions: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.

Comprehensive Molecular Characterization of Chinese Patients with Glioma by Extensive Next-Generation Sequencing Panel Analysis

“…However, before using gene amplification results for clinical decision-making, it is best to use other molecular analyses for proper clinical validation to guide targeted therapy in glioblastoma. 52,53 Herein, we found that the frequency of CNV events in high-grade gliomas was significantly higher than in low-grade tumors, and the recurrence group had significantly more CNV events than the initial treatment group. Previous studies have found that the existence of EGFR amplification in CNV analysis was significantly associated with both worse disease-free survival (DFS) and overall survival (OS) in gliomas.…”

Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study

“…Unfortunately, we did not perform an exploratory analysis to study some predictors of efficacy; indeed, two prior studies have investigated the role of molecular predictors of regorafenib efficacy in the REGOMA trial: a mini-signature of 2 gene transcripts (HIF1A, CDKN1A), 3 miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) [ 26 ] and phosphorylated acetyl-CoA carboxylase [ 27 ] were associated with prolonged survival in recurrent glioblastoma patients treated with regorafenib.…”

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Based on these results, NCCN 2020 guidelines included regorafenib as a preferred regimen in rGBM patients and the Italian Agency of Medicine (AIFA) approved the use of this treatment for Italian patients. Two subsequent studies demonstrated a higher efficacy of regorafenib in selected patients with specific molecular alterations such as phosphorylated acetyl-CoA carboxylase [129,130]. Dovitinib, an oral FGFR, VEGFR and PDGFRβ inhibitor, was analyzed in another phase II study [87] where dovitinib was tested in two different populations of rGBM patients: anti-angiogenetic naive patients and anti-angiogenetic drug pretreated patients; however, results showed poor efficacy in terms of prolonging PFS (primary endpoint): mPFS was 2.0m (95% CI, 1.3-3.7) for anti-angiogenic naïve patients versus 1.8m (95% CI, 0.9-1.8) for anti-angiogenic pretreated patients (p = 0.03).…”