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.
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.
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
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