Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study

Abstract

PurposePatients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM.MethodsM12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible.ResultsAmong 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%.ConclusionDepatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

“…However, the majority resolved or improved upon administration of steroid eye drops or when patients entirely stopped taking the mafodotin‐conjugated ADCs 12. Resolution and/or improvement of ocular AEs were observed in this and other depatux‐m trials 21, 22, 23, 24. However, calculating the median time to resolution has been unreliable because of limited patient numbers in this first‐in‐human study.…”

“…This encouraging result provided evidence that depatux‐m may be highly specific for tumor types with EGFR amplification, leading to further study of depatux‐m in glioblastoma, in which nearly 50% of patients have EGFR amplification 13. Encouraging efficacy of depatux‐m has been observed in a phase 1 trial of patients with newly diagnosed and recurrent glioblastoma 21, 22, 23, 24. In addition, preliminary efficacy results from a large phase 2 trial of patients with recurrent glioblastoma (http://clinicaltrials.gov identifier NCT02343406) further support its development as a novel, targeted therapy that may improve outcomes for patients with EGFR amplification in a disease with very few treatment options 25.…”

An Integrated Population Pharmacokinetic Model Versus Individual Models of Depatuxizumab Mafodotin, an Anti‐EGFR Antibody Drug Conjugate, in Patients With Solid Tumors Likely to Overexpress EGFR

“…The PK was characterized by measuring the serum or plasma concentrations of ADC (depatux‐m), the total antibody (conjugated and unconjugated depatuxizumab), and the payload (cys‐mafodotin, cys‐mcMMAF). Depatux‐m showed linear PK with no evidence of target‐mediated drug disposition at the doses tested (0.5 to 4 mg/kg) in the clinical trials . Plasma concentrations of cys‐mafodotin were orders of magnitude lower when compared with ADC or total antibody.…”

“…The pharmacokinetics (PK) of depatux‐m from 2 phase 1 studies has been published previously . The PK was characterized by measuring the serum or plasma concentrations of ADC (depatux‐m), the total antibody (conjugated and unconjugated depatuxizumab), and the payload (cys‐mafodotin, cys‐mcMMAF).…”

“…Plasma concentrations of cys‐mafodotin were orders of magnitude lower when compared with ADC or total antibody. Depatux‐m has shown efficacy in clinical studies when administered as monotherapy and in combination (radiation plus temozolomide, temozolomide) in glioblastoma multiforme (GBM) patients with EGFR amplification . It is currently in phase 2/3 clinical trials evaluating its efficacy in subjects with EGFR‐amplified glioblastoma (NCT02343406, NCT02573324).…”