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

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.

[1]  A. Stopeck,et al.  Abstract P6-10-01: A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study , 2012 .

[2]  C. Keir,et al.  The use of an antibody drug conjugate, glembatumumab vedotin (CDX-011), for the treatment of breast cancer , 2012, Expert opinion on biological therapy.

[3]  Chris Twelves,et al.  Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study , 2011, The Lancet.

[4]  John P Leonard,et al.  Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. , 2010, The New England journal of medicine.

[5]  F. Pépin,et al.  ADAM10 Releases a Soluble Form of the GPNMB/Osteoactivin Extracellular Domain with Angiogenic Properties , 2010, PloS one.

[6]  P. Hwu,et al.  Frequent dosing and GPNMB expression with CDX-011 (CR011-vcMMAE), an antibody-drug conjugate (ADC), in patients with advanced melanoma. , 2010 .

[7]  L. Naumovski,et al.  Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. , 2010, Current opinion in molecular therapeutics.

[8]  M. Hallett,et al.  Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer , 2010, Clinical Cancer Research.

[9]  D. Benjamin,et al.  Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate , 2010, Clinical Cancer Research.

[10]  N Harbeck,et al.  Triple-negative breast cancer--current status and future directions. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  A. Selim.  Osteoactivin bioinformatic analysis: prediction of novel functions, structural features, and modes of action. , 2009, Medical science monitor : international medical journal of experimental and clinical research.

[12]  Michael G. Anderson,et al.  Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. , 2008, Experimental cell research.

[13]  F. Pépin,et al.  Osteoactivin Promotes Breast Cancer Metastasis to Bone , 2007, Molecular Cancer Research.

[14]  E. Perez,et al.  Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  M. Jeffers,et al.  Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB , 2007, Cancer Chemotherapy and Pharmacology.

[16]  D. Hume,et al.  Gpnmb Is Induced in Macrophages by IFN-γ and Lipopolysaccharide and Acts as a Feedback Regulator of Proinflammatory Responses1 , 2007, The Journal of Immunology.

[17]  Damon L. Meyer,et al.  Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-specific Cytotoxicity by Peptide-linked Anti-CD30-Auristatin Conjugates* , 2006, Journal of Biological Chemistry.

[18]  G. Riggins,et al.  Glycoprotein Nonmetastatic Melanoma Protein B, a Potential Molecular Therapeutic Target in Patients with Glioblastoma Multiforme , 2006, Clinical Cancer Research.

[19]  T. Chittenden,et al.  Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. , 2006, Cancer research.

[20]  Damon L. Meyer,et al.  CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  K. Nagata,et al.  Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells. , 2003, Journal of hepatology.

[22]  D. Bigner,et al.  Bone-related Genes Expressed in Advanced Malignancies Induce Invasion and Metastasis in a Genetically Defined Human Cancer Model* , 2003, The Journal of Biological Chemistry.

[23]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[24]  Jun Yu Li,et al.  Gpnmb/osteoactivin, an attractive target in cancer immunotherapy. , 2012, Neoplasma.

[25]  C. Hudis,et al.  Triple-negative breast cancer: an unmet medical need. , 2011, The oncologist.

[26]  S. Popoff,et al.  Functional roles of osteoactivin in normal and disease processes. , 2010, Critical reviews in eukaryotic gene expression.

[27]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.