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.
OBJECTIVE
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.


METHODS
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.
Northwestern University Feinberg School of Medicine, Chicago, Illinois. w-gradishar@northwestern.edu.
William J
WJ
Gradishar
Sarah Cannon Research Institute, Nashville, Tennessee. Tennessee Oncology, PLLC, Nashville, Tennessee.
Denise A
DA
Yardley
Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Rachel
R
Layman
Montefiore Medical Center, Bronx, New York.
Joseph A
JA
Sparano
Weill Cornell Medical College, New York, New York.
Ellen
E
Chuang
Mayo Clinic Cancer Center, Scottsdale, Arizona.
Donald W
DW
Northfelt
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
Gary N
GN
Schwartz
Progenics Pharmaceuticals, Tarrytown, New York.
Hagop
H
Youssoufian
Eli Lilly and Company, Bridgewater, New Jersey.
Shande
S
Tang
Eli Lilly and Company, New York, New York.
Ruslan
R
Novosiadly
Eli Lilly and Company, New York, New York.
Amelie
A
Forest
Eli Lilly and Company, Indianapolis, Indiana.
Tuan S
TS
Nguyen
Eli Lilly and Company, Bridgewater, New Jersey.
Jan
J
Cosaert
Eli Lilly and Company, Bridgewater, New Jersey.
Dmitri
D
Grebennik
Mayo Clinic Cancer Center, Rochester, Minnesota.
Paul
P
Haluska
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D020847:Estrogen Receptor Modulators; D012333:RNA, Messenger; C557414:cixutumumab; D017526:Receptor, IGF Type 1