Molecular bases for sensitivity to figitumumab (CP-751,871) in NSCLC

Abstract

8091 Background: Signaling of Insulin like Growth Factors (IGFs) through the IGF type 1 receptor (IGF-IR) induces tumor resistance to cancer therapy. Bioavailability of IGFs is regulated by IGF-binding proteins (IGFBP), of which IGFBP3 is the most abundant. Figitumumab (F) (CP-751,871), a specific IGF-IR inhibitor, has shown phase 2 activity in NSCLC in some histologies (i.e., squamous cell and adenocarcinoma) but not others (i.e, large cell or NOS tumors). Methods: Protein expression of members of the IGF-IR pathway, EGFR and differentiation markers was determined in core biopsies from 230 NSCLC pts, including 52 pts enrolled in F trials. Plasma concentration of IGF-1 and related proteins was determined in 159 NSCLC pts in F trials. Gene expression profiling was conducted in 35 NSCLC cell lines treated with F. Results: Squamous NSCLC had the highest IGF-IR expression (p=0.057). An association with better outcome was seen for E-cadherin expression (HR =0.62, 0.46–0.82 95% CI, p=0.005) and clustering by E-cadherin levels revealed a strong correlation between IGF-IR and EGFR expression in the high E-cadherin group (p<0.001). This subset included 73% of the squamous cell tumors investigated (N=44). Plasma levels of free IGF-1 (fIGF-1) were low and not predictive of response in squamous cell. In contrast, pts with adenocarcinoma had high plasma fIGF-1 levels (p=0.06) that correlated with vimentin expression (Rho=0.732, p=0.06), and both fIGF-1 and vimentin were predictive of F clinical benefit (p=0.03). Large cell/NOS NSCLC expressed the highest levels of vimentin (p<0.001) but had low E-cadherin and IGF-IR expression and low fIGF-1 plasma levels. Analysis of anchorage independent growth in NSCLC cell lines confirmed that F activity is independently associated to IGF-IR overexpression (p=0.02) and IGFBP3 under-expression (p=0.009). Conclusions: IGF-IR overexpression and increased free IGFs/low IGFBP are key independent mechanisms of sensitivity to F in NSCLC of squamous and adenocarcinoma cell histologies. [Table: see text] [Table: see text]