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

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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

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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.
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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.",
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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.

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