Clinical and Translational Results of a Phase 2, Randomized Trial of an Anti-IGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy
Mené sur 93 patientes atteintes d'un cancer du sein HR+ ayant progressé après une hormonothérapie, cet essai randomisé de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du cixutumumab, un anticorps monoclonal anti IGF-1R
Purpose: This phase 2 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 anti-estrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same anti-estrogen (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 treated (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 arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of 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 anti-estrogen 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 treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R-targeted therapies requires further validation.