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 journalArticlepeer-review

41 Scopus citations


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
Issue number2
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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