ATIM-03. ACT IV: AN INTERNATIONAL, DOUBLE-BLIND, PHASE 3 TRIAL OF RINDOPEPIMUT IN NEWLY DIAGNOSED, EGFRvIII-EXPRESSING GLIOBLASTOMA

The EGFR deletion mutation, EGFRvIII, is expressed in ~30% of glioblastomas (GBM). The EGFRvIII-targeted vaccine rindopepimut consists of EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH). A survival benefit was observed in a randomized phase 2 trial of recurrent GBM (ReACT; n=73). In three phase 2 studies of 105 total patients with newly diagnosed, EGFRvIII+ GBM and minimal residual disease (MRD), the median overall survival (mOS) was 20–22 months, as compared to ~16 months for two matched contemporary datasets (n=16, n=29). Patients with newly diagnosed, resected, EGFRvIII+ GBM were, after standard chemoradiation, stratified by RPA class, MGMT promoter methylation, and geographic region, and randomized (1:1) to double-blind rindopepimut or control (KLH) concurrent with standard maintenance temozolomide. Primary endpoint is OS for MRD patients (enhancing tumor <2 cm2 post-chemoradiation by central review) aiming to detect hazard ratio (HR) ≤0.71 with 80% power and alpha=0.05 (log-rank test). Interim analyses were preplanned at 50% and 75% of events. Secondary analyses included patients with ≥2 cm2 of residual tumor (non-MRD). 745 patients (405 MRD) were enrolled at 165 centers. The study was terminated for futility after the 2nd interim analysis (MRD OS HR=0.99). At final analysis, mOS for rindopepimut vs. control was 20.1 vs. 20.0 (HR=1.01; p=0.93) in the MRD cohort, and 14.8 vs. 14.1 (HR=0.79; p=0.066) with 2-year OS 30% vs. 19% in the non-MRD cohort. There were no substantial differences in progression-free survival. Rindopepimut was well tolerated (chief toxicity: injection site reaction) with robust anti-EGFRvIII immune response. The study failed to demonstrate a survival benefit for patients treated with rindopepimut and standard chemotherapy. Rindopepimut OS is comparable to prior studies, however, patients in the control arm fared better than historical controls. A trend for long-term survival benefit in non-MRD patients suggests a preferential effect in bulkier disease.