Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial
Michael Weller, Nicholas Butowski, David D Tran, Lawrence D Recht, Michael Lim, Hal Hirte, Lynn Ashby, Laszlo Mechtler, Samuel A Goldlust, Fabio Iwamoto, Jan Drappatz, Donald M O'Rourke, Mark Wong, Mark G Hamilton, Gaetano Finocchiaro, James Perry, Wolfgang Wick, Jennifer Green, Yi He, Christopher D Turner, Michael J Yellin, Tibor Keler, Thomas A Davis, Roger Stupp, John H Sampson, ACT IV trial investigators, Nicholas Butowski, Jian Campian, Lawrence Recht, Michael Lim, Lynn Ashby, Jan Drappatz, Hal Hirte, Fabio Iwamoto, Laszlo Mechtler, Samuel Goldlust, Kevin Becker, Gene Barnett, Garth Nicholas, Annick Desjardins, Tara Benkers, Naveed Wagle, Morris Groves, Santosh Kesari, Zsolt Horvath, Ryan Merrell, Richard Curry, James O'Rourke, David Schuster, Mark Wong, Maciej Mrugala, Randy Jensen, John Trusheim, Glenn Lesser, Karl Belanger, Andrew Sloan, Benjamin Purow, Karen Fink, Jeffrey Raizer, Michael Schulder, Suresh Nair, Scott Peak, James Perry, Alba Brandes, Michael Weller, Nimish Mohile, Joseph Landolfi, Jon Olson, Gaetano Finocchiaro, Ross Jennens, Paul DeSouza, Bridget Robinson, Marka Crittenden, Kent Shih, Alexandra Flowers, Shirley Ong, Jennifer Connelly, Costas Hadjipanayis, Pierre Giglio, Frank Mott, David Mathieu, Nathalie Lessard, Sanchez Juan Sepulveda, József Lövey, Helen Wheeler, Po-Ling Inglis, Claire Hardie, Daniela Bota, Maciej Lesniak, Jana Portnow, Bruce Frankel, Larry Junck, Reid Thompson, Lawrence Berk, John McGhie, David Macdonald, Frank Saran, Riccardo Soffietti, Deborah Blumenthal, Sá Barreto Costa Marcos André de, Anna Nowak, Nimit Singhal, Andreas Hottinger, Andrea Schmid, Gordan Srkalovic, David Baskin, Camilo Fadul, Louis Nabors, Renato LaRocca, John Villano, Nina Paleologos, Petr Kavan, Marshall Pitz, Brian Thiessen, Ahmed Idbaih, Jean Sébastien Frenel, Julien Domont, Oliver Grauer, Peter Hau, Christine Marosi, Jan Sroubek, Elizabeth Hovey, P S Sridhar, Lawrence Cher, Erin Dunbar, Thomas Coyle, Jane Raymond, Kevin Barton, Michael Guarino, Sumul Raval, Baldassarre Stea, Jorge Dietrich, Kirsten Hopkins, Sara Erridge, Joachim-Peter Steinbach, Losada Estela Pineda, Quintero Carmen Balana, Barco Berron Sonia Del, Miklós Wenczl, Katalin Molnár, Katalin Hideghéty, Alexander Lossos, Linde Myra van, Ana Levy, Rosemary Harrup, William Patterson, Zarnie Lwin, Sith Sathornsumetee, E-Jian Lee, Jih-Tsun Ho, Steven Emmons, J Paul Duic, Spencer Shao, Hani Ashamalla, Michael Weaver, Jose Lutzky, Nicholas Avgeropoulos, Wahid Hanna, Mukund Nadipuram, Gary Cecchi, Robert O'Donnell, Susan Pannullo, Jennifer Carney, Mark Hamilton, Mary MacNeil, Ronald Beaney, Michel Fabbro, Oliver Schnell, Rainer Fietkau, Guenther Stockhammer, Bela Malinova, Karel Odrazka, Martin Sames, Gil Miguel Gil, Evangelia Razis, Konstantin Lavrenkov, Guillermo Castro, Francisco Ramirez, Clarissa Baldotto, Fabiana Viola, Suzana Malheiros, Jason Lickliter, Stanislaw Gauden, Arunee Dechaphunkul, Iyavut Thaipisuttikul, Ziad Thotathil, Hsin-I Ma, Wen-Yu Cheng, Chin-Hong Chang, Fernando Salas, Pierre-Yves Dietrich, Christoph Mamot, Lakshmi Nayak, Shona Nag, Michael Weller, Nicholas Butowski, David D Tran, Lawrence D Recht, Michael Lim, Hal Hirte, Lynn Ashby, Laszlo Mechtler, Samuel A Goldlust, Fabio Iwamoto, Jan Drappatz, Donald M O'Rourke, Mark Wong, Mark G Hamilton, Gaetano Finocchiaro, James Perry, Wolfgang Wick, Jennifer Green, Yi He, Christopher D Turner, Michael J Yellin, Tibor Keler, Thomas A Davis, Roger Stupp, John H Sampson, ACT IV trial investigators, Nicholas Butowski, Jian Campian, Lawrence Recht, Michael Lim, Lynn Ashby, Jan Drappatz, Hal Hirte, Fabio Iwamoto, Laszlo Mechtler, Samuel Goldlust, Kevin Becker, Gene Barnett, Garth Nicholas, Annick Desjardins, Tara Benkers, Naveed Wagle, Morris Groves, Santosh Kesari, Zsolt Horvath, Ryan Merrell, Richard Curry, James O'Rourke, David Schuster, Mark Wong, Maciej Mrugala, Randy Jensen, John Trusheim, Glenn Lesser, Karl Belanger, Andrew Sloan, Benjamin Purow, Karen Fink, Jeffrey Raizer, Michael Schulder, Suresh Nair, Scott Peak, James Perry, Alba Brandes, Michael Weller, Nimish Mohile, Joseph Landolfi, Jon Olson, Gaetano Finocchiaro, Ross Jennens, Paul DeSouza, Bridget Robinson, Marka Crittenden, Kent Shih, Alexandra Flowers, Shirley Ong, Jennifer Connelly, Costas Hadjipanayis, Pierre Giglio, Frank Mott, David Mathieu, Nathalie Lessard, Sanchez Juan Sepulveda, József Lövey, Helen Wheeler, Po-Ling Inglis, Claire Hardie, Daniela Bota, Maciej Lesniak, Jana Portnow, Bruce Frankel, Larry Junck, Reid Thompson, Lawrence Berk, John McGhie, David Macdonald, Frank Saran, Riccardo Soffietti, Deborah Blumenthal, Sá Barreto Costa Marcos André de, Anna Nowak, Nimit Singhal, Andreas Hottinger, Andrea Schmid, Gordan Srkalovic, David Baskin, Camilo Fadul, Louis Nabors, Renato LaRocca, John Villano, Nina Paleologos, Petr Kavan, Marshall Pitz, Brian Thiessen, Ahmed Idbaih, Jean Sébastien Frenel, Julien Domont, Oliver Grauer, Peter Hau, Christine Marosi, Jan Sroubek, Elizabeth Hovey, P S Sridhar, Lawrence Cher, Erin Dunbar, Thomas Coyle, Jane Raymond, Kevin Barton, Michael Guarino, Sumul Raval, Baldassarre Stea, Jorge Dietrich, Kirsten Hopkins, Sara Erridge, Joachim-Peter Steinbach, Losada Estela Pineda, Quintero Carmen Balana, Barco Berron Sonia Del, Miklós Wenczl, Katalin Molnár, Katalin Hideghéty, Alexander Lossos, Linde Myra van, Ana Levy, Rosemary Harrup, William Patterson, Zarnie Lwin, Sith Sathornsumetee, E-Jian Lee, Jih-Tsun Ho, Steven Emmons, J Paul Duic, Spencer Shao, Hani Ashamalla, Michael Weaver, Jose Lutzky, Nicholas Avgeropoulos, Wahid Hanna, Mukund Nadipuram, Gary Cecchi, Robert O'Donnell, Susan Pannullo, Jennifer Carney, Mark Hamilton, Mary MacNeil, Ronald Beaney, Michel Fabbro, Oliver Schnell, Rainer Fietkau, Guenther Stockhammer, Bela Malinova, Karel Odrazka, Martin Sames, Gil Miguel Gil, Evangelia Razis, Konstantin Lavrenkov, Guillermo Castro, Francisco Ramirez, Clarissa Baldotto, Fabiana Viola, Suzana Malheiros, Jason Lickliter, Stanislaw Gauden, Arunee Dechaphunkul, Iyavut Thaipisuttikul, Ziad Thotathil, Hsin-I Ma, Wen-Yu Cheng, Chin-Hong Chang, Fernando Salas, Pierre-Yves Dietrich, Christoph Mamot, Lakshmi Nayak, Shona Nag
Abstract
Background: Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.
Methods: In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479.
Findings: Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut.
Interpretation: Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.
Funding: Celldex Therapeutics, Inc.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Source: PubMed