The glycoprotein NMB or gpNMB, a novel transmembrane protein which is overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients.

The antibody-drug conjugate glembatumumab vedotin, also known as CDX-011, which is being developed by Celldex Therapeutics, consists of a fully human anti-gpNMB monoclonal antibody, conjugated linked via a cleavable linker to the synthetic antineoplastic agent monomethyl auristatin E (MMAE). Ongoing clinical trials have shown that glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma and metastatic breast cancer, particularly in patients with tumors that over-express GPNMB (defined as expression in > 25% of tumor cells).


The mechanism of action of calicheamicin, a DNA-damaging agent that, following intracellular activation, binds to DNA in the minor groove and introduces double-strand DNA breaks, leading to G2/M arrest and subsequent cell death, is fundamentally different from the tubulin-binding class of cytotoxics targeting the mitotic spindle, which represent the most common class of payloads for antibody-drug conjugates (ADCs) currently undergoing clinical development.


Trial Design
In a clinical trial researchers at Weill Cornell Medical College, New York, NY enrolled eligible patients with advanced/metastatic breast cancer. These patients had received at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue.

MabPlex
 

Trial Results
Forty-two patients were enrolled. The dose-limiting toxicity consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no dose-limiting toxicity occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC.

Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.

Published in: Journal of Clinical Oncology


Last editorial update: September 28, 2014

Copyright © 2014 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

Add to Flipboard Magazine.