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

Benjamin M Ellingson; Kunal Patel; Chencai Wang; Catalina Raymond; Andrew Brenner; John F de Groot; Nicholas A Butowski; Leor Zach; Jian L Campian; Jacob Schlossman; Shan Rizvi; Yael C Cohen; Noa Lowenton-Spier; Tamar Rachmilewitz Minei; Shifra Fain Shmueli; Patrick Y Wen; Timothy F Cloughesy

doi:10.1093/noajnl/vdab082

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

Neurooncol Adv. 2021 Jun 19;3(1):vdab082. doi: 10.1093/noajnl/vdab082. eCollection 2021 Jan-Dec.

Authors

Benjamin M Ellingson^{1

2

3}, Kunal Patel^{1

4}, Chencai Wang^{1

2}, Catalina Raymond¹, Andrew Brenner⁵, John F de Groot⁶, Nicholas A Butowski⁷, Leor Zach⁸, Jian L Campian⁹, Jacob Schlossman^{1

2}, Shan Rizvi^{1

2}, Yael C Cohen¹⁰, Noa Lowenton-Spier¹⁰, Tamar Rachmilewitz Minei¹⁰, Shifra Fain Shmueli¹⁰, Patrick Y Wen¹¹, Timothy F Cloughesy^{3

12}

Affiliations

¹ UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
² Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
³ UCLA Neuro Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁵ University of Texas Health San Antonio Cancer Center, San Antonio, Texas, USA.
⁶ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
⁸ Oncology Institute, Chaim Sheba Medical Center, Tel HaShomer, Israel.
⁹ Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁰ VBL Therapeutics, Modi'in, Israel.
¹¹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹² Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

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, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm²/ms) or low (<1.24 µm²/ms) ADC_L, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor.

Results: Baseline tumor volume (P = .3460) and ADC_L (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADC_L had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADC_L identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADC_L phenotypes (P = .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.

Keywords: VB-111; anti-VEGF therapy; bevacizumab; diffusion MRI; imaging biomarker; recurrent GBM.