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

Abstract

Background: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific.

Methods: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD.

Results: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional.

Conclusions: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Trial registration: ClinicalTrials.gov NCT01800695.

Keywords: ABT-414; antibody-drug conjugate; depatuxizumab mafodotin (depatux-m); epidermal growth factor receptor (EGFR).

Figure 1

The study schema is illustrated. EGFR indicates epidermal growth factor receptor; MTD, maximum tolerated dose; Q3W, once every 3 weeks; RPTD, recommended phase 2 dose.

Figure 2

The pharmacokinetics of depatuxizumab mafodotin (depatux‐m), total depatux, and Cys‐mafodotin are illustrated. (A) Concentration‐time profiles are illustrated for each analyte after the first intravenous infusion of depatux‐m at 2 mg/kg. Mean ± standard deviation values are shown for the depatux‐m (B) maximum serum concentration (C_max) and (C) area under the curve on day 21 (AUC_{day 21}) versus the depatux‐m dose.

Figure 3

Best response and time on therapy are illustrated. The best responses, as determined by the investigator, and the time on depatuxizumab mafodotin (depatux‐m) therapy are shown for 52 of 56 patients who had data available. EGFR indicates epidermal growth factor receptor.