Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer.

Abstract

PURPOSE:

Glycoprotein NMB (gpNMB), a novel transmembrane protein 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 consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer.

PATIENTS AND METHODS:

Eligible patients had advanced/metastatic breast cancer with 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.

RESULTS:

Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT 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.

CONCLUSION:

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.

• Authors: Johanna Bendell, Mansoor Saleh, April A N Rose, Peter M Siegel, Lowell Hart, Surendra Sirpal, Suzanne Jones, Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, Thomas Davis, Linda Vahdat
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 32 Issue 32 Pg. 3619-25 (Nov 10 2014) ISSN: 1527-7755 [Electronic] United States
• PMID: 25267761 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by American Society of Clinical Oncology.

Chemical References

• Antibodies, Monoclonal
• GPNMB protein, human
• Immunoconjugates
• Membrane Glycoproteins
• glembatumumab vedotin

Topics

• Adult
• Aged
• Alopecia (chemically induced)
• Anemia (chemically induced)
• Antibodies, Monoclonal (adverse effects, immunology, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Therapy (methods)
• Fatigue (chemically induced)
• Female
• Humans
• Immunoconjugates (adverse effects, immunology, therapeutic use)
• Immunohistochemistry
• Membrane Glycoproteins (immunology, metabolism)
• Middle Aged
• Nausea (chemically induced)
• Neoplasm Metastasis
• Neutropenia (chemically induced)
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)