Targeted COX-2 and EGFR TK inhibition in advanced non-small cell lung cancer

Abstract

7179 Background: Prostaglandin E2 (PGE2) activates Erk/MAPK signaling pathway in an epidermal growth factor receptor (EGFR) tyrosine kinase (TK)-resistant manner as a result of cyclooxygenase-2 (COX-2) overexpressed in lung cancer. Because 10% of patients respond to this class of drugs, evaluating agents that may overcome resistance and determining the population of patients most likely to respond is crucial. Imaging tumor metabolism by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) is an innovative approach for assessing the efficacy of targeted agents. We studied the combination of COX-2 inhibition (celecoxib) and EGFR inhibition (erlotinib) in a phase I trial in advanced non-small cell lung cancer (NSCLC) and added FDG-PET imaging as a potential method for evaluation of early response. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose (OBD) of the combination of celecoxib and erlotinib in pts with refractory stage IIIB/IV NSCLC. FDG-PET was evaluated in selected patients at baseline, week 2 and week 8 of study treatment. Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUV). Changes in SUV were compared to CT imaging at week 8 with response defined by RECIST criteria. Results: Twenty-two subjects were enrolled and 21 were evaluable for the determination of the OBD, toxicity assessment and response. Rash and skin-related effects were the most commonly reported toxicities. Seven patients demonstrated partial responses and five patients developed stable disease. Responses were seen in patients both with and without EGFR activating mutations. The duration of partial response was 24–93 wks. TTP was 83 weeks in one patient with stable disease. A patient evaluated by FDG-PET had a significant decrease in SUV (-45%) at week 2 which corresponded to partial responses by RECIST at week 8. Conclusions: FDG-PET as a measure of tumor glucose utilization appears to be a promising tool for assessing early response to targeted therapies. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, and evaluating FDG-PET response as a marker of early efficacy. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Award. [Table: see text]