Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma

Abstract

Background Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 um 2/ms) or low (< 1.24 um 2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. Results Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P=0.0006), as well as BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P<0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. Conclusion Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

Texture Analysis of the Apparent Diffusion Coefficient Focused on Contrast-Enhancing Lesions in Predicting Survival for Bevacizumab-Treated Patients with Recurrent Glioblastoma

“…Ellingston et al [47] found an association between lower pretreatment ADC values and lower progression-free survival and overall survival in patients with recurrent glioblastoma treated with bevacizumab. Analyzing data from a randomized, controlled phase III trial comparing the efficacy of bevacizumab with and without VB-111, the same group [48] found that baseline tumor volume and data derived from ADC histogram analysis were predictive biomarkers of overall survival. As in our study, the histograms were generated from ADC values extracted from contrast-enhancing regions in T1-weighted images.…”

Clinically approved combination immunotherapy: Current status, limitations, and future perspective

“…In addition, higher baseline Ktrans and larger drop in extracellular volume fraction (EVF) was correlated with longer PFS (p < 0.05) ( Sahani et al, 2013 ). Interestingly, similar imaging biomarkers have also been investigated in patients with recurrent glioblastoma treated with cediranib, an inhibitor of VEGFRs ( Batchelor et al, 2007 ; Sorensen et al, 2009 , 2012 ) or bevacizumab and bevacizumab plus ofranergene obadenovec ( Ellingson et al, 2021 ). These studies demonstrated that increased tumor blood prefusion and vessel normalization were associated with longer PFS and OS.…”