Depatux-M and temozolomide in advanced high-grade glioma

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. Brief Communication

The treatment for multiple progressing high-grade gliomas remains challenging. Amplifications of the epidermal growth factor receptor (EGFR) are frequent events in high-grade glioma. Targeting strategies involving amplified EGFR are therefore considered promising. We present a single-center cohort of 9 advanced EGFR-amplified high-grade gliomas treated with the antibody-drug conjugate (ADC), Depatuxizumab Mafodotin (Depatux-M, ABT-414). Depatux-M acts by an EGFR-antibody-guided delivery of monomethyl auristatin F to molecular-defined target cells. The antitumoral activity will only occur in EGFR-amplified cells but not in the cells of normal tissue without EGFR amplification. 1 The main adverse event in our cohort was corneal epitheliopathy.
The results of the INTELLANCE 2/EORTC 1410 phase II study of Depatux-M alone and with temozolomide versus temozolomide or lomustine in progressive EGFR-amplified glioblastoma have been recently published. 1 This trial enrolled patients with the first progression of glioblastoma.
The treatment durations were 1 cycle (2 infusions) through 8 cycles (15 infusions) ( Figure 1B). The first MRI, 1.5-3 months after Depatux-M initiation, showed a partial response according to RANO criteria in 1 patient, stable disease in 2 patients, and progressive disease in 4 patients ( Figure 1C). Two patients had clinical deterioration and were not suitable for further MRI follow-up. The median overall survival after initiation of Depatux-M was 4 months (mean 5.1 months, range 1.7-10.9 months). One patient is alive, and another one was lost to follow-up.
We used eye cool packs during infusions for all patients. Corneal epitheliopathy occurred after 2-3 Depatux-M infusions in 7 of 9 patients ( Figure 1D). These patients used eye drops containing glucocorticoids 3 times a day and hyaluronic acid-containing liquids every hour. If ocular toxicity ≥ CTC AE grade II occurred, Depatux-M dose was reduced to 1.0 mg/kg. Patient 14 had a cornea crack after 3 infusions, and we stopped therapy. In patient 5, an acute vision decline to 0.25 occurred after 4 infusions, and we stopped the therapy for 5 weeks.
Of note, the INTELLANCE 1 phase III trial using Depatux-M in EGFR-amplified newly diagnosed glioblastoma was discontinued for futility (NCT02573324). The INTELLANCE 2 phase II trial did not detect any significant activity of Depatux M monotherapy at the first progression of glioblastoma, but the Depatux-M/TMZ combination arm became significant with a two 2-year OS analysis of 19.8% (95% confidence interval [CI]: 12.2, 28.8) and 5.2% (95% CI: 1.7, 11.7) in the control arm. 2 Our observations demonstrate the feasibility of Depatux-M/ TMZ in multiple progressing high-grade gliomas but with rather limited activity. A precise refinement of the molecular profile for patient stratification, for example, the threshold for copy numbers or companion molecular alterations, and identification of molecular mechanisms leading to acquired resistance might be further important steps for optimizing clinical development programs of EGFR-targeting ADCs.