EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB - Expressing breast cancer

Denise A. Yardley, Robert Weaver, Michelle E. Melisko, Mansoor N. Saleh, Francis P. Arena, Andres Forero, Tessa Cigler, Alison T Stopeck, Dennis Citrin, Ira Oliff, Rebecca Bechhold, Randa Loutfi, Agustin A. Garcia, Scott Cruickshank, Elizabeth Crowley, Jennifer Green, Thomas Hawthorne, Michael J. Yellin, Thomas A. Davis, Linda T. Vahdat

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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.

Original languageEnglish (US)
Pages (from-to)1609-1619
Number of pages11
JournalJournal of Clinical Oncology
Volume33
Issue number14
DOIs
StatePublished - May 10 2015

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Glycoproteins
Breast Neoplasms
Antibodies
Triple Negative Breast Neoplasms
Pharmaceutical Preparations
Research Personnel
Neoplasms
glembatumumab vedotin
Drug Therapy
Alopecia
Cytotoxins
Pruritus
Stromal Cells
Exanthema
Epithelial Cells
Immunohistochemistry
Monoclonal Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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EMERGE : A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB - Expressing breast cancer. / Yardley, Denise A.; Weaver, Robert; Melisko, Michelle E.; Saleh, Mansoor N.; Arena, Francis P.; Forero, Andres; Cigler, Tessa; Stopeck, Alison T; Citrin, Dennis; Oliff, Ira; Bechhold, Rebecca; Loutfi, Randa; Garcia, Agustin A.; Cruickshank, Scott; Crowley, Elizabeth; Green, Jennifer; Hawthorne, Thomas; Yellin, Michael J.; Davis, Thomas A.; Vahdat, Linda T.

In: Journal of Clinical Oncology, Vol. 33, No. 14, 10.05.2015, p. 1609-1619.

Research output: Contribution to journalArticle

Yardley, DA, Weaver, R, Melisko, ME, Saleh, MN, Arena, FP, Forero, A, Cigler, T, Stopeck, AT, Citrin, D, Oliff, I, Bechhold, R, Loutfi, R, Garcia, AA, Cruickshank, S, Crowley, E, Green, J, Hawthorne, T, Yellin, MJ, Davis, TA & Vahdat, LT 2015, 'EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB - Expressing breast cancer', Journal of Clinical Oncology, vol. 33, no. 14, pp. 1609-1619. https://doi.org/10.1200/JCO.2014.56.2959
Yardley, Denise A. ; Weaver, Robert ; Melisko, Michelle E. ; Saleh, Mansoor N. ; Arena, Francis P. ; Forero, Andres ; Cigler, Tessa ; Stopeck, Alison T ; Citrin, Dennis ; Oliff, Ira ; Bechhold, Rebecca ; Loutfi, Randa ; Garcia, Agustin A. ; Cruickshank, Scott ; Crowley, Elizabeth ; Green, Jennifer ; Hawthorne, Thomas ; Yellin, Michael J. ; Davis, Thomas A. ; Vahdat, Linda T. / EMERGE : A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB - Expressing breast cancer. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 14. pp. 1609-1619.
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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.",
author = "Yardley, {Denise A.} and Robert Weaver and Melisko, {Michelle E.} and Saleh, {Mansoor N.} and Arena, {Francis P.} and Andres Forero and Tessa Cigler and Stopeck, {Alison T} and Dennis Citrin and Ira Oliff and Rebecca Bechhold and Randa Loutfi and Garcia, {Agustin A.} and Scott Cruickshank and Elizabeth Crowley and Jennifer Green and Thomas Hawthorne and Yellin, {Michael J.} and Davis, {Thomas A.} and Vahdat, {Linda T.}",
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TY - JOUR

T1 - EMERGE

T2 - A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB - Expressing breast cancer

AU - Yardley, Denise A.

AU - Weaver, Robert

AU - Melisko, Michelle E.

AU - Saleh, Mansoor N.

AU - Arena, Francis P.

AU - Forero, Andres

AU - Cigler, Tessa

AU - Stopeck, Alison T

AU - Citrin, Dennis

AU - Oliff, Ira

AU - Bechhold, Rebecca

AU - Loutfi, Randa

AU - Garcia, Agustin A.

AU - Cruickshank, Scott

AU - Crowley, Elizabeth

AU - Green, Jennifer

AU - Hawthorne, Thomas

AU - Yellin, Michael J.

AU - Davis, Thomas A.

AU - Vahdat, Linda T.

PY - 2015/5/10

Y1 - 2015/5/10

N2 - 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.

AB - 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.

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