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Cancer Chemother Pharmacol. 2019 Aug;84(2):327-336. doi: 10.1007/s00280-019-03879-2. Epub 2019 Jun 1.

Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII.

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Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
TriHealth Physician Partners, Cincinnati, OH, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Amgen Inc., Thousand Oaks, CA, USA.
Clinical Pharmacology Modeling and Simulation, Amgen Inc., South San Francisco, CA, USA.
Department of Early Oncology Development and Clinical Research, Pfizer Inc., San Diego, CA, USA.
The Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.



Epidermal growth factor receptor variant III (EGFRvIII) is expressed in a significant percentage of primary and recurrent glioblastoma (GBM), a common malignant primary brain tumor in adults. AMG 595 is an antibody-drug conjugate comprising a fully human, anti-EGFRvIII monoclonal antibody linked to DM1. The study goals were to assess safety, tolerability, and pharmacokinetics of AMG 595 in GBM.


In this phase 1, first-in-human, open-label, sequential-dose, exploration study, adults with recurrent GBM received AMG 595 once every 3 weeks (Q3W) according to incremental dosing cohorts (0.5-3.0 mg/kg). Primary endpoints were to assess safety, the incidence of dose-limiting toxicities (DLTs), objective response (per Macdonald criteria), evaluate pharmacokinetics, and estimate the maximum tolerated dose (MTD).


Of 382 patients screened, 32 were enrolled and received ≥ 1 dose of AMG 595. Ten patients experienced 18 DLTs (all grade 4 thrombocytopenia), and the MTD was 2.0 mg/kg. Twenty-eight patients (88%) experienced ≥ 1 treatment-related adverse event (AE); the most common AEs were thrombocytopenia (50%) and fatigue (25%). Grade ≥ 3 treatment-related AEs occurred in 17 patients (53%); 11 (34%) had serious treatment-emergent AEs, and none were considered treatment related. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and cytotoxin, dose-proportional increases in plasma exposures for the conjugated antibody over the studied range, and less than twofold accumulation following multiple Q3W dosing. Two patients (6%) had partial responses; 15 (47%) had stable disease.


AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeutic options.


AMG 595; Antibody–drug conjugate; DM1; EGFRvIII; Glioblastoma


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