Characterization of NSCLC patients responding to anti-IGF-IR therapy

Abstract

8000 Background: CP-751,871, a fully human IgG2 subtype monoclonal antibody, is a potent and specific inhibitor of the insulin-like growth factor type I receptor (IGF-IR). Methods: A comprehensive evaluation of blood and tissue markers of the IGF-IR pathway was undertaken during the conduct of phase I/II studies to evaluate the safety and efficacy of the combination of paclitaxel (T), carboplatin (C) and CP-751,871 (I) as first line treatment of advanced non-small cell lung cancer (NSCLC) patients (pts). Expression of IGF- IR and its ligands was investigated further in archival samples using tissue arrays and AQUA technology. IGF1R gene scanning was also performed. Circulating Tumor Cells (CTCs) expressing the IGF-IR were enumerated using CellTracks. Serum markers investigated included cleaved circulating IGF-IR, total and free IGF-I, IGFBP-3 and ALS. Glycemia was evaluated using fasting glucose. hGH and insulin levels were determined in a cohort of pts treated with single agent CP-751,871. Results: Blood and/or tissue samples were obtained from 190 NSCLC pts. Tissue markers were further investigated in 178 archival NSCLC specimens. Tumor IGF-IR expression was most pronounced in squamous cell carcinoma in concert with a high objective response rate to TCI in that histology (72% response rate). Two somatic mutations were identified in the beta subunit of the IGF-IR tyrosine kinase domain. One of them translated into blockade of ligand-induced receptor autophosphorylation in functional studies. CTCs expressing the IGF-IR were cleared from blood upon TCI treatment and reappeared in some patients upon disease progression. Circulating IGF-IR decreased, and IGF-1, IGFBP3 and ALS levels accumulated in serum in response to I treatment in a dose dependent manner. Importantly, sustained IGF-1 levels were observed at higher I doses, consistent with systemic IGF-IR downregulation. Hyperglycemia (glucose >250 mg/dL) was seen in 11% of NSCLC pts receiving combination TCI. It was manageable, reversible and independent of glucose levels at enrollment. hGH and glucose oscillated in parallel suggesting that hGH may play a role in the pathogenesis of I induced hyperglycemia. Conclusions: Biomarkers of the IGF-IR pathway are key elements in the development and monitoring of anti-IGF-IR therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration HistoRx Inc, Immunicon, Pfizer Oncology Immunicon, Pfizer Inc, Pfizer Oncology Pfizer Oncology