Johanna Bendell1, Mansoor Saleh1, April A N Rose1, Peter M Siegel1, Lowell Hart1, Surendra Sirpal1, Suzanne Jones1, Jennifer Green1, Elizabeth Crowley1, Ronit Simantov1, Tibor Keler1, Thomas Davis1, Linda Vahdat2. 1. 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. 2. 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.
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.
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: G Maric; M G Annis; Z Dong; A A N Rose; S Ng; D Perkins; P A MacDonald; V Ouellet; C Russo; P M Siegel Journal: Oncogene Date: 2015-03-16 Impact factor: 9.867
Authors: Lisa M Kopp; Suman Malempati; Mark Krailo; Yun Gao; Allen Buxton; Brenda J Weigel; Thomas Hawthorne; Elizabeth Crowley; Jeffrey A Moscow; Joel M Reid; Victor Villalobos; R Lor Randall; Richard Gorlick; Katherine A Janeway Journal: Eur J Cancer Date: 2019-10-03 Impact factor: 9.162