Lung cancer is the leading cause of cancer death worldwide. In the USA, nearly 200,000 men and women are diagnosed with lung cancer every year and approximately 80% of them will die from the disease. More effective, and better tolerated, treatment regimens are needed. Histologically, approximately 85% of lung cancers are non-small cell lung cancer (NSCLC). Novel therapies targeting the epidermal growth factor receptor (EGFR) have recently shown a significant survival benefit in patients with advanced NSCLC, although only a relatively small percentage of patients manifest objective responses. Based on retrospective analyses it has already been shown that EGFR gene copy number and EGFR and ras mutations can usefully differentiate patients that are more/less likely to respond to EGFR inhibition. Multiple prospective trials are now in progress to verify these as pre-selection factors. Pre-clinically, the EGFR pathway has been shown to have extensive crosstalk with the insulin-like growth factor-1 receptor (IGF-1R) pathway and IGF-1R may play an important role in resistance mechanisms to EGFR-targeted agents, such as erlotinib. IMC-A12 is a fully human IgG1/? monoclonal antibody directed against the IGF-1R. This grant hypothesizes that the combination of IGF-1R blockade with IMC-A12 and anti-EGFR therapy with erlotinib will demonstrate greater activity in NSCLC patients than either agent alone and that combined inhibition may reverse mechanisms of resistance to anti-EGFR therapy. This grant also hypothesizes that biomarkers, such as gene copy number, that relate to both the EGFR and IGF-1R pathways may predict those most likely to benefit from the combination. The goal of this grant is to complete a randomized phase II clinical study of erlotinib with or without IMC-A12 in patients with advanced NSCLC, to confirm that the combination will be clinically tolerable and to assess whether the combination will demonstrate evidence of improved anti-tumor effects compared to erlotinib alone in the target population. Blood specimens and archived tumor specimens will be collected for analysis of suspected biomarkers of clinical benefit/treatment resistance. Additional blood specimens from the patients will be collected to explore aspects of drug-drug pharmacokinetic interactions between IMC-A12 and erlotinib, and inherited germline effects on outcomes relating to clinical activity, toxicity and erlotinib exposures. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death worldwide, and it has been the most common cause of death from malignancy in the USA in men since the mid-1950s and in women since the mid-1980s. Although recent advances in targeting treatment to key molecules that may drive lung cancer have improved the outlook for some patients, treatment resistance remains a major problem. This project is a clinical trial in patients and will test a rational combination of two novel targeted agents to overcome some of this treatment resistance in lung cancer (the new drugs target the communication that goes on between the EGFR and IGF-1R molecular pathways) and sets out to explore the factors that may predict those who will gain the most benefit from this combination in the future.

R21CA135595

2008-09-01

2012-08-31