title: Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Johanna
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Saleh
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: April A N
authors.initials: AA
authors.lastname: Rose
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Lowell
authors.initials: L
authors.lastname: Hart
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Surendra
authors.initials: S
authors.lastname: Sirpal
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Green
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crowley
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Tibor
authors.initials: T
authors.lastname: Keler
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY.
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.affiliation: Johanna Bendell and Suzanne Jones, Sarah Cannon Research Institute, Nashville, TN; Mansoor Saleh, Georgia Cancer Specialists, Atlanta, GA; April A.N. Rose and Peter M. Siegel, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Lowell Hart, Florida Cancer Specialists, Fort Myers; Surendra Sirpal, Hematology Oncology Associates, Lake Worth, FL; Jennifer Green, Elizabeth Crowley, Ronit Simantov, Tibor Keler, and Thomas Davis, Celldex Therapeutics; and Linda Vahdat, Weill Cornell Medical College, New York, NY. ltv2001@med.cornell.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Vahdat
mesh_terms: D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000740:Anemia / Q000139:chemically induced; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy / Q000379:methods; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; C551271:glembatumumab vedotin