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Rindopepimut with temozolomide for patients with newly Articles

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, and John H Sampson, for the ACT IV trial
investigators*

Summary
Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, Lancet Oncol 2017; 18: 1373–85
consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed Published Online
to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients August 22, 2017
with EGFRvIII-positive glioblastoma. http://dx.doi.org/10.1016/
S1470-2045(17)30517-X
See Comment page 1294
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 *Investigators who participated
in this trial are listed in the
by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation appendix
without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive Department of Neurology
partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with (Prof M Weller MD) and
a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 µg admixed with 150 µg Department of Oncology
GM-CSF) or control (100 µg keyhole limpet haemocyanin) via monthly intradermal injection until progression or (Prof R Stupp MD), University
Hospital and University of
intolerance, concurrent with standard oral temozolomide (150–200 mg/m² for 5 of 28 days) for 6–12 cycles or longer. Zurich, Zurich, Switzerland;
Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall Department of Neurological
survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm² post-chemoradiation by central Surgery, University of
review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. California, San Francisco, CA,
USA (N Butowski MD);
Washington University,
Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant St Louis, MO, USA
residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or (D D Tran MD); Stanford
control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final University Medical Center, Palo
Alto, CA, USA (L D Recht MD);
analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was The Johns Hopkins Hospital,
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 Baltimore, MD, USA
(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 (M Lim MD); Juravinski Cancer
rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), Centre, Hamilton, ON, Canada
(H Hirte MD); Barrow
fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache Neurological Institute,
(six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] Phoenix, AZ, USA (L Ashby MD);
vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] DENT Neurologic Institute,
in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of Buffalo, NY, USA
(L Mechtler, MD); John Theurer
treatment—was assessed as potentially related to rindopepimut. Cancer Center, Hackensack, NJ,
USA (S A Goldlust MD);
Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination Columbia University Medical
approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Center, New York, NY, USA
(F Iwamoto MD); University of
Pittsburgh Medical Center,
Funding Celldex Therapeutics, Inc. Pittsburgh, PA, USA
(J Drappatz MD); Department
Introduction The tumour­treating fields device, recently reported to of Neurosurgery, Perelman
School of Medicine, University
Glioblastoma is the most common malignant primary extend survival to 20·5 months, represents an additional of Pennsylvania, Philadelphia,
brain tumour in adults. Its annual incidence is more treatment option for glioblastoma. Treatment at PA, USA (D M O’Rourke MD);
4
than three per 100 000 people worldwide without recurrence, which might include second surgery, re­ Westmead Hospital,
major regional variation, and men are affected more irradiation, alkylating chemotherapy using nitrosoureas Westmead, NSW, Australia
(M Wong MD); University of
1
frequently than women. The standard of care—maximum such as lomustine or temozolomide rechallenge, or Calgary, Department of Clinical
feasible surgical resection followed by radiotherapy with antiangiogenic therapy using bevacizumab, is less well Neurosciences, Division of
concomitant and maintenance temozolomide chemo­ standardised and has not shown a significant improvement Neurosurgery, Foothills
Hospital, Calgary, AB, Canada
therapy—generally leads to a median overall survival of in survival in a randomised trial. Poor prognostic factors (Prof M G Hamilton MD);
about 15 months. 2,3 include poor performance status, older age, incomplete Fondazione IRCCS Istituto

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