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