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Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial

2017; Elsevier BV; Volume: 18; Issue: 10 Linguagem: Inglês

10.1016/s1470-2045(17)30517-x

1474-5488

Michael Weller, Nicholas Butowski, David Tran, Lawrence D. Recht, Michael Lim, Hal W. Hirte, Lynn S. Ashby, Laszlo Mechtler, Samuel Goldlust, Fábio M. 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 Yellin, Tibor Keler, Thomas A. Davis, Roger Stupp, John H. Sampson, Nicholas Butowski, Jian L. Campian, Lawrence D. Recht, Michael Lim, Lynn S. Ashby, Jan Drappatz, Hal W. Hirte, Fábio M. Iwamoto, Laszlo Mechtler, Samuel Goldlust, Kevin Becker, Gene H. Barnett, Garth Nicholas, Annick Desjardins, Tara Benkers, Naveed Wagle, Morris D. Groves, Santosh Kesari, Zsolt Horváth, Ryan Merrell, Richard Curry, James O’Rourke, David M. Schuster, Mark Wong, Maciej M. Mrugała, Randy Jensen, John Trusheim, Glenn J. Lesser, Karl Bélanger, Andrew E. Sloan, Benjamin Purow, Karen Fink, Jeffrey J. Raizer, Michael Schulder, Suresh Nair, Scott Peak, James Perry, Alba A. Brandes, Michael Weller, Nimish Mohile, Joseph Landolfi, Jon Olson, Gaetano Finocchiaro, Ross Jennens, Paul DeSouza, Bridget A. Robinson, Marka R. Crittenden, Kent C. Shih, Alexandra Flowers, Shirley Ong, Jennifer Connelly, Costas G. Hadjipanayis, Pierre Giglio, Frank E. Mott, David Mathieu, N. Lessard, Sanchez Juan Sepulveda, József Lövey, Helen Wheeler, Po-Ling Inglis, Claire Hardie, Daniela A. Bota, Maciej S. Lesniak, Jana Portnow, Bruce Frankel, Larry Junck, Reid C. Thompson, Lawrence Berk, John Paul McGhie, David Macdonald, Frank Saran, Riccardo Soffietti, Deborah T. Blumenthal, Sá Barreto Costa Marcos André de, Anna K. Nowak, Nimit Singhal, Andreas F. Hottinger, Andrea Schmid, Gordan Srkalović, David S. Baskin, Camilo E. Fadul, Burt Nabors, Renato V. LaRocca, John L. Villano, Nina A. Paleologos, Petr Kavan, Marshall Pitz, Brian Thiessen, Ahmed Idbaïh, Jean‐Sébastien Frénel, Julien Dômont, Oliver Grauer, Peter Hau, Christine Marosi, Jan Šroubek, Elizabeth Hovey, P.S. Sridhar, Lawrence Cher, Erin Dunbar, Thomas Coyle, Jane M. Raymond, Kevin Barton, Michael J. Guarino, Sumul Raval, Baldassarre Stea, J. Richard Dietrich, Kirsten Hopkins, Sara Erridge, Joachim-Peter Steinbach, Losada Estela Pineda, Carmen Balañá, Barco Berron Sonia del, M. Wenczl, Katalin Molnár, Katalin Hideghéty, Alexander Lossos, Linde Myra van, Ana Levy, Rosemary Harrup, William P. Patterson, Zarnie Lwin, Sith Sathornsumetee, E-Jian Lee, Jih-Tsun Ho, Steven Emmons, J. Paul Duic, Spencer H. Shao, Hani Ashamalla, Michael Weaver, Jose Lutzky, Nicholas G. Avgeropoulos, Wahid T. Hanna, Mukund Nadipuram, G Cecchi, Robert D. O’Donnell, Susan C. Pannullo, Jennifer Carney, Mark Hamilton, Mary MacNeil, R. P. Beaney, Michel Fabbro, Oliver Schnell, Rainer Fietkau, Guenther Stockhammer, Běla Malinová, Karel Odrážka, Martin Sameš, Gil Miguel Gil, E. Razis, Konstantin Lavrenkov, Guillermo Castro, Francisco Ramirez, Clarissa Baldotto, Fabiana Viola, Suzana Mária Fleury Malheiros, Jason D. Lickliter, Stanislaw J. Gauden, Arunee Dechaphunkul, Iyavut Thaipisuttikul, Ziad Thotathil, Hsin‐I Ma, Wen-Yu Cheng, Chin-Hong Chang, Fernando Palacios Salas, Pierre‐Yves Dietrich, Christoph Mamot, Lakshmi Nayak, Shona Nag,

Mathematical Biology Tumor Growth

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.