EGFR-targeted antibody-toxin conjugate in recurrent glioma: a phase 1 trial.

Abstract

D2C7-ATC is a recombinant antibody-toxin conjugate (ATC) targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII). We conducted a single-arm, single-site, open-label phase 1 trial evaluating a single infusion of D2C7-ATC via convection-enhanced delivery in the enhancing disease of 81 patients with biopsy-confirmed recurrent malignant glioma. The primary objective was to determine toxicity and the recommended phase 2 dose (RP2D) of D2C7-ATC. Secondary objectives included describing overall survival (OS) and assessing the association between EGFR expression and OS. The median overall survival (mOS) was 7.9 months among 72 patients with isocitrate dehydrogenase wild-type recurrent glioblastoma (IDHwt rGBM), including 35 patients in the dose-escalation stage (40 to 35,032 ng ml^-1) and 37 patients in the dose-expansion stage (RP2D of 6,920 ng ml^-1). D2C7-ATC was generally well tolerated, with mainly grade 1-2 treatment-related adverse events (67%). The maximum tolerated dose was exceeded at 35,032 ng ml^-1, where four patients experienced dose-limiting toxicities, including grade 4 (N = 2) and grade 3 (N = 2) events. Eight patients died on trial; all deaths were unrelated to D2C7-ATC. Univariate analyses identified survival-associated biomarkers, including tumor D2C7 antibody reactivity, circulating cytokines, a tumor inflammatory gene signature and neutrophils, monocytes and lymphocytes in blood. Notably, patients with IDHwt rGBM with a D2C7 antibody reactivity score of <1.5+ in pre-treatment tumor had an mOS of 17.38 months, whereas those with low IL-8 in post-treatment plasma had an mOS of 16.6 months. These findings indicate that EGFR-targeted D2C7-ATC therapy prolongs survival in a subset of patients with IDHwt rGBM via intratumoral and systemic immune activation. ClinicalTrials.gov identifier: NCT02303678 .