Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial. J Clin Oncol 2026 Jun 20;44(18):1676-1686
Date
04/14/2026Pubmed ID
41980234DOI
10.1200/JCO-25-01137Scopus ID
2-s2.0-105037061447 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
Wen PY, Berry DA, Buxton MB, Colman H, de Groot J, Lim M, Mellinghoff I, Perry JR, Weller M, Blondin NA, Butt OH, Damek DM, de la Fuente MI, Drappatz J, Dunbar E, Giglio P, Hyddmark EV, Iwamoto F, Jaeckle KA, Kim L, Kling HM, Lee EQ, Mantica M, Mikkelsen T, Nabors B, Newton HB, Olson JJ, Schiff D, Walbert T, Weathers SP, Cloughesy T, Lassman AB, GBM AGILE Regorafenib Study GroupAuthor
Jennifer M. Connelly MD Professor in the Neurology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Bayes Theorem
Brain Neoplasms
Female
Glioblastoma
Humans
Lomustine
Male
Middle Aged
Neoplasm Recurrence, Local
Phenylurea Compounds
Pyridines
