Abstract #1741: Combination treatment strategy of an IGF-1R kinase inhibitor, OSI-906, in models of progressive disease following initial response to EGFR tyrosine kinase inhibitor therapy

Erlotinib is a small molecule tyrosine kinase inhibitor (TKI) of EGFR that is approved for use in non-small cell lung cancer (NSCLC) and pancreatic cancer. While this drug is highly efficacious for many patients, their disease often progresses after a period of time on erlotinib. While it is common practice to change therapies upon disease progression, recent clinical data may support a hypothesis that patients may continue to benefit from erlotinib therapy beyond disease progression. Here we report preclinical data that support maintaining erlotinib treatment in combination with another molecular targeted agent after initial response and then progression on erlotinib, which we term treatment beyond progression (TBP). We have identified two human tumor xenograft models, NCI-H292 (NSCLC) and GEO (colon) that initially respond to erlotinib but are characterized by renewed tumor growth upon prolonged and continuous treatment with erlotinib. Characterization of the tumors that acquired resistance to erlotinib revealed elevated phosphorylation of IGF-1R and downstream signaling mediators, AKT and ERK. We employed these xenograft models to evaluate the efficacy of erlotinib maintenance therapy with and without the addition of OSI-906, a potent and selective IGF-1R inhibitor, following response and then progression on erlotinib monotherapy. We observed a benefit with either continued erlotinib treatment or switching to OSI-906 treatment compared to no further treatment. However, the combination of adding OSI-906 to erlotinib treatment was significantly better than either single agent. This data provides preclinical proof of concept for the use of OSI-906 in the TBP setting and suggests that IGF-1R pathway activation may play an important role in erlotinib drug resistance. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1741.