Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor

This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreati...

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Bibliographic Details
Published in:	Clinical cancer research Vol. 19; no. 15; p. 4282
Main Authors:	McCaffery, Ian, Tudor, Yanyan, Deng, Hongjie, Tang, Rui, Suzuki, Samuel, Badola, Sunita, Kindler, Hedy L, Fuchs, Charles S, Loh, Elwyn, Patterson, Scott D, Chen, Li, Gansert, Jennifer L
Format:	Journal Article
Language:	English
Published:	United States 01.08.2013
Subjects:	Adenocarcinoma - blood Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - pathology Antibodies, Monoclonal - administration & dosage Biomarkers, Tumor - blood Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Humans Insulin-Like Growth Factor Binding Protein 2 - blood Insulin-Like Growth Factor Binding Protein 3 - blood Insulin-Like Growth Factor I - metabolism Neoplasm Metastasis - drug therapy Neoplasm Metastasis - genetics Neoplasm Metastasis - pathology Pancreatic Neoplasms - blood Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) PTEN Phosphohydrolase - genetics ras Proteins - genetics Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - immunology Survival Analysis
ISSN:	1078-0432, 1557-3265, 1557-3265
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Summary:	This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3
ISSN:	1078-0432 1557-3265 1557-3265
DOI:	10.1158/1078-0432.CCR-12-1840