Rindopepimut With Temozolomide for Patients With Newly Diagnosed EGFRVIII-Expressing Glioblastoma (Act IV): A Randomised Double-Blind International Phase 3 Trial
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 Î¼g admixed with 150 Î¼g GM-CSF) or control (100 Î¼g keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150â€“200 mg/m2 for 5 of 28 days) for 6â€“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 20Â·1 months (95% CI 18Â·5â€“22Â·1) in the rindopepimut group versus 20Â·0 months (18Â·1â€“21Â·9) in the control group (HR 1Â·01, 95% CI 0Â·79â€“1Â·30; p=0Â·93). The most common grade 3â€“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 oneâ€”a pulmonary embolism in a 64-year-old male patient after 11 months of treatmentâ€”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.
Medical Subject Headings
The Lancet Oncology
Digital Object Identifier (DOI)
Weller, Michael; Butowski, Nicholas; Tran, David D.; Recht, Lawrence D.; Lim, Michael; Hirte, Hal; Ashby, Lynn S.; Mechtler, Laszlo; Goldlust, Samuel A.; Iwamoto, Fabio; Drappatz, Jan; O'Rourke, Donald M.; Wong, Mark; Hamilton, Mark G.; Finocchiaro, Gaetano; Perry, James; Wick, Wolfgang; Green, Jennifer; He, Yi; and al., et, "Rindopepimut With Temozolomide for Patients With Newly Diagnosed EGFRVIII-Expressing Glioblastoma (Act IV): A Randomised Double-Blind International Phase 3 Trial" (2017). Neurology. 12.