A phase I trial of targeted COX-2 and EGFR TK inhibition in advanced NSCLC

Abstract

7112 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI) is a novel targeted therapy for selected pts with NSCLC. Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer and acts through PGE2 to promote tumor proliferation, invasion, angiogenesis, decreased anti-tumor immunity and resistance to apoptosis. Cross talk between EGFR and COX-2 signaling pathways results in regulation of tumorigenesis. Previously, we have described a mechanism in which signaling through the COX-2 pathway activates the Erk/MAPK pathway in an EGFR TKI-resistant manner. These findings have led to evaluations of the combination of COX-2 and EGFR inhibition in NSCLC. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose of the combination of COX-2 inhibition (celecoxib-C) and EGFR inhibition (erlotinib-E) in pts with refractory stage IIIB/IV NSCLC. Pts receive increasing doses of C (200mg, 300mg, 400mg, 600mg and 800mg BID) and a fixed dose of E (150mg QD). Primary endpoints include evaluation of toxicity and determination of the biologically active dose of the combination. Secondary endpoints investigate exploratory biological markers and clinical response rates. Results: All 5 cohorts have been enrolled to date, n=15. Average age is 66 yrs, 3 female and 12 male pts, and smoking history is 27 pack yrs. 13 subjects have stage IV disease and 2 have stage IIIB. The combination has been generally well tolerated without unanticipated toxicities. Of 12 evaluable subjects to date, we have seen 4 partial responses and three patients with stable disease in pts both with and without EGFR activating mutations. The duration of partial response has been 16+-48+ wks. TTP is 62+ weeks in one patient with stable disease. A significant decline in urinary PGE-M was demonstrated after 8 wks of treatment with C at 400mg BID compared with doses of 200mg and 300mg BID. Conclusions: This study defines the optimal biologic dose of celecoxib when combined with an EGFR TKI and may enhance efficacy with an acceptable toxicity profile. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Memorial Award. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech