Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial

PURPOSE: GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS: Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS: When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION: GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

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Publication Details

Journal
Journal of Clinical Oncology
Published
2026-04-14
DOI
https://doi.org/10.1200/jco-25-01137
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial

Omar H. Butt, Heather M. Kling, Mustafa Khasraw, Emma Maria Viktoria Hyddmark et al.
Journal of Clinical Oncology
Glioma Diagnosis and Treatment
article

Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial

Omar H. Butt, Heather M. Kling, Mustafa Khasraw, Emma Maria Viktoria Hyddmark, Lars Anker, Jethro Hu, Evanthia Galanis, Pierre Giglio, Ingo K. Mellinghoff, Kurt A. Jaeckle, Benjamin M. Ellingson, Tobias Walbert, Megan Mantica, Jerome Graber, Macarena I. de la Fuente, Howard Colman, Shiao‐Pei Weathers, Meredith Buxton, Erik P. Sulman, John de Groot, Andrew B. Lassman, Jeffrey J. Olson, Lyndon Kim, Timothy F. Cloughesy, Sarah Untch, Todd Graves, Michelle A. Detry, Webster K. Cavenee, Donald A. Berry, Nicholas Berry, Anna McGlothlin, Emma Wilcox, Joe Marion, M Weller, Eudocia Q. Lee, Jennifer Connelly, Marija Kalabic, Mark Anderson, Denise M. Damek, James Perry, Brian Alexander, Adam Johnson, James R Perry, W. K. Alfred Yung, Michael Lim, Mark Fitzgerald, Herbert B. Newton, for the GBM AGILE Regorafenib Study Group, Patrick Y. Wen, Christina T. Saunders, Nicholas A. Blondin, Fabio Iwamoto, Emma Viktoria Hyddmark, Ashley Powell, Burt Nabors, Scott Owen, Glenn J. Lesser, David Schiff, Gary Gordon, Katherine B. Peters, Tim Cloughesy, Kirk Tanner, Jan Drappatz, Tom Mikkelsen, Erin Dunbar
article en

Abstract

PURPOSE: GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS: Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS: When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION: GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Journal of Clinical Oncology
Sunnybrook Health Science Centre (CA), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of Miami (US), Emory University (US), Henry Ford Health System (US), University of California, Los Angeles (US), Palo Alto University (US), University of California, San Francisco (US), University of Toronto (CA), Wayne State University (US), University of Zurich (CH), Washington University in St. Louis (US), University of Utah (US), Columbia University Irving Medical Center (US), Huntsman Cancer Institute (US), Jacksonville College (US), Health Sciences Centre (CA), WinnMed (US), The Ohio State University Wexner Medical Center (US), University of Alabama at Birmingham (US), Yale University (US), Berry & Associates (United States) (US), Piedmont Cancer Institute (US), University Hospital of Zurich (CH), Dana-Farber Cancer Institute (US), University Hospitals Seidman Cancer Center (US), University of Pittsburgh Medical Center (US), Mayo Clinic in Florida (US), Sylvester Comprehensive Cancer Center (US), University of Virginia (US), Columbia University (US), University of Colorado Denver (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 20%
Glioma Diagnosis and Treatment
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