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Clinical Trial
. 2016 Jan 15;22(2):301-9.
doi: 10.1158/1078-0432.CCR-15-0588. Epub 2015 Aug 31.

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

William J Gradishar  1 , Denise A Yardley  2 , Rachel Layman  3 , Joseph A Sparano  4 , Ellen Chuang  5 , Donald W Northfelt  6 , Gary N Schwartz  7 , Hagop Youssoufian  8 , Shande Tang  9 , Ruslan Novosiadly  10 , Amelie Forest  10 , Tuan S Nguyen  11 , Jan Cosaert  9 , Dmitri Grebennik  9 , Paul Haluska  12
Affiliations
Clinical Trial

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

William J Gradishar et al. Clin Cancer Res. .

Abstract

Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti-insulin-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 receptor-positive 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, n = 62; arm B, n = 31). 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-1R-targeted therapies requires further validation.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

P. Haluska reports receiving speakers bureau honoraria from Boehringer Ingleheim, is a consultant/advisory board member for Boehringer Ingleheim, Bristol-Myers Squibb, and Medimmune, and reports receiving commercial research support from Bristol-Myers Squibb, ImClone, and Medimmune. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1
Figure 1
Patient disposition. aFourteen patients randomized to receive cixutumumab plus antiestrogen therapy received cixutumumab only, and 8 patients randomized to receive single-agent cixutumumab received cixutumumab plus antiestrogen therapy. bOne patient was still on treatment as of the study cutoff date of January 2, 2013.
Figure 2
Figure 2
Kaplan–Meier curves of PFS and OS from the ITT population. PFS (A) and OS (B) are shown for the ITT population in arm A (solid line) and arm B (dotted line). n, number of patients; NR, not reached.
Figure 3
Figure 3
Kaplan–Meier curves of PFS and OS from pooled group and arm A dichotomized by total insulin receptor (IR) expression (high vs. low) using the 75th percentile of marker distribution as cutoff point. PFS and OS curves are presented for the arms dichotomized for high (dotted line) or low (solid line) total IR expression on the pooled group (n = 59) and arm A population (n = 40). A, PFS: pooled group; B, PFS: arm A; C, OS: pooled group; D, OS: arm A. Arm A, cixutumumab + antiestrogen; n, number of patients; NR, not reached; Pooled group, cixutumumab + antiestrogen (arm A) + cixutumumab monotherapy (arm B); Q, quartile.
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