Denise A Yardley1, Robert Weaver1, Michelle E Melisko1, Mansoor N Saleh1, Francis P Arena1, Andres Forero1, Tessa Cigler1, Alison Stopeck1, Dennis Citrin1, Ira Oliff1, Rebecca Bechhold1, Randa Loutfi1, Agustin A Garcia1, Scott Cruickshank1, Elizabeth Crowley1, Jennifer Green1, Thomas Hawthorne1, Michael J Yellin1, Thomas A Davis1, Linda T Vahdat2. 1. Denise A. Yardley, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Robert Weaver, Florida Cancer Specialists, Tampa, FL; Michelle E. Melisko, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Scott Cruickshank, Scott Cruickshank & Associates, Santa Barbara; Agustin A. Garcia, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; Mansoor N. Saleh, Georgia Cancer Specialists, Sandy Springs, GA; Francis P. Arena, New York University Langons Arena Oncology, Lake Success; Tessa Cigler and Linda T. Vahdat, Weill Cornell Medical College, New York, NY; Andres Forero, University of Alabama, Birmingham, AL; Alison Stopeck, University of Arizona Cancer Center, Tucson, AZ; Dennis Citrin, Cancer Treatment Centers of America/Midwestern Regional Medical Center, Zion; Ira Oliff, Orchard Healthcare Research, Skokie, IL; Rebecca Bechhold, Oncology Hematology Care, Cincinnati, OH; Randa Loutfi, Henry Ford Health System, Detroit, MI; and Elizabeth Crowley, Jennifer Green, Thomas Hawthorne, Michael J. Yellin, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ. 2. Denise A. Yardley, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Robert Weaver, Florida Cancer Specialists, Tampa, FL; Michelle E. Melisko, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Scott Cruickshank, Scott Cruickshank & Associates, Santa Barbara; Agustin A. Garcia, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; Mansoor N. Saleh, Georgia Cancer Specialists, Sandy Springs, GA; Francis P. Arena, New York University Langons Arena Oncology, Lake Success; Tessa Cigler and Linda T. Vahdat, Weill Cornell Medical College, New York, NY; Andres Forero, University of Alabama, Birmingham, AL; Alison Stopeck, University of Arizona Cancer Center, Tucson, AZ; Dennis Citrin, Cancer Treatment Centers of America/Midwestern Regional Medical Center, Zion; Ira Oliff, Orchard Healthcare Research, Skokie, IL; Rebecca Bechhold, Oncology Hematology Care, Cincinnati, OH; Randa Loutfi, Henry Ford Health System, Detroit, MI; and Elizabeth Crowley, Jennifer Green, Thomas Hawthorne, Michael J. Yellin, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ. ltv2001@med.cornell.edu.
Abstract
PURPOSE:Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS:Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION:Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.
RCT Entities:
PURPOSE:Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS:Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION:Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumorgpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.