Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy

William J. Gradishar, Denise A. Yardley, Rachel Layman, Joseph A. Sparano, Ellen Chuang, Donald W Northfelt, Gary N. Schwartz, Hagop Youssoufian, Shande Tang, Ruslan Novosiadly, Amelie Forest, Tuan S. Nguyen, Jan Cosaert, Dmitri Grebennik, Paul Haluska

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human antiinsulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor positive breast cancer. Experimental Design: Patients with hormone receptorpositive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n62; arm B, n31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1Rtargeted therapies requires further validation.

Original languageEnglish (US)
Pages (from-to)301-309
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2016

Fingerprint

Insulin Receptor
Breast Neoplasms
Therapeutics
Disease-Free Survival
Estrogen Receptor Modulators
anti-IGF-1R antibody A12
Safety
Survival
Biomarkers
Hormones
Messenger RNA
Growth Factor Receptors
Random Allocation
Insulin-Like Growth Factor I
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy. / Gradishar, William J.; Yardley, Denise A.; Layman, Rachel; Sparano, Joseph A.; Chuang, Ellen; Northfelt, Donald W; Schwartz, Gary N.; Youssoufian, Hagop; Tang, Shande; Novosiadly, Ruslan; Forest, Amelie; Nguyen, Tuan S.; Cosaert, Jan; Grebennik, Dmitri; Haluska, Paul.

In: Clinical Cancer Research, Vol. 22, No. 2, 15.01.2016, p. 301-309.

Research output: Contribution to journalArticle

Gradishar, WJ, Yardley, DA, Layman, R, Sparano, JA, Chuang, E, Northfelt, DW, Schwartz, GN, Youssoufian, H, Tang, S, Novosiadly, R, Forest, A, Nguyen, TS, Cosaert, J, Grebennik, D & Haluska, P 2016, 'Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy', Clinical Cancer Research, vol. 22, no. 2, pp. 301-309. https://doi.org/10.1158/1078-0432.CCR-15-0588
Gradishar, William J. ; Yardley, Denise A. ; Layman, Rachel ; Sparano, Joseph A. ; Chuang, Ellen ; Northfelt, Donald W ; Schwartz, Gary N. ; Youssoufian, Hagop ; Tang, Shande ; Novosiadly, Ruslan ; Forest, Amelie ; Nguyen, Tuan S. ; Cosaert, Jan ; Grebennik, Dmitri ; Haluska, Paul. / Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 2. pp. 301-309.
@article{3e7c9d4d0afb47c7b44fe84df1a3a3d1,
title = "Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy",
abstract = "Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human antiinsulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor positive breast cancer. Experimental Design: Patients with hormone receptorpositive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n62; arm B, n31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1Rtargeted therapies requires further validation.",
author = "Gradishar, {William J.} and Yardley, {Denise A.} and Rachel Layman and Sparano, {Joseph A.} and Ellen Chuang and Northfelt, {Donald W} and Schwartz, {Gary N.} and Hagop Youssoufian and Shande Tang and Ruslan Novosiadly and Amelie Forest and Nguyen, {Tuan S.} and Jan Cosaert and Dmitri Grebennik and Paul Haluska",
year = "2016",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-15-0588",
language = "English (US)",
volume = "22",
pages = "301--309",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy

AU - Gradishar, William J.

AU - Yardley, Denise A.

AU - Layman, Rachel

AU - Sparano, Joseph A.

AU - Chuang, Ellen

AU - Northfelt, Donald W

AU - Schwartz, Gary N.

AU - Youssoufian, Hagop

AU - Tang, Shande

AU - Novosiadly, Ruslan

AU - Forest, Amelie

AU - Nguyen, Tuan S.

AU - Cosaert, Jan

AU - Grebennik, Dmitri

AU - Haluska, Paul

PY - 2016/1/15

Y1 - 2016/1/15

N2 - Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human antiinsulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor positive breast cancer. Experimental Design: Patients with hormone receptorpositive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n62; arm B, n31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1Rtargeted therapies requires further validation.

AB - Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human antiinsulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor positive breast cancer. Experimental Design: Patients with hormone receptorpositive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n62; arm B, n31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1Rtargeted therapies requires further validation.

UR - http://www.scopus.com/inward/record.url?scp=84958961569&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958961569&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-0588

DO - 10.1158/1078-0432.CCR-15-0588

M3 - Article

VL - 22

SP - 301

EP - 309

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -