Eicosanoid modulation in advanced non-small cell lung cancer (NSCLC): CALGB 30203

Abstract

7025 Background: Increased expression of eicosanoids have been associated with adverse prognosis. Specific inhibitors of key enzymes of two eicosanoid pathways, COX-2 (celecoxib) and 5-LOX (zileuton) have been developed. In vitro, the addition of these inhibitors have demonstrated enhancement of cytotoxic chemotherapy. We hypothesized that the addition of eicosanoid inhibitors to standard chemotherapy of carboplatin (C) and gemcitabine (G) could improve outcome in advanced NSCLC. Methods: Patients (pts) with stage IIIb (pleural effusion)/stage IV NSCLC, PS 0–2, no prior therapy were eligible. All pts received up to six cycles of C AUC 5.5 d1 + G (1000 mg/m2) d1,8. Pts were randomized to three arms: A: Celecoxib (CEL) 400 mg po bid. B: Zileuton (Z) 600 mg qid po, C: CEL and Z at the same doses. CEL and Z were begun on the first day of therapy and continued until progression. In this randomized phase II trial, the objective was to demonstrate a 50% failure free survival (FFS) at 9 months. Serum and tissue samples were required. Results: Between 12/05/03 and 9/30/04, 140 pts were entered and 136 were eligible and treated (A: 44, B: 47, C: 45). M: 86, F: 50; PS 0,1,2 = 38,85,13. Toxicity was primarily hematologic with approximately 70% grade 3/4 toxicity on each arm. Response and survival with 95% CI (see table ). Arm C has superior FFS when compared to combined Arms A+B (p =.054, unstratified log rank test), however, this benefit decreases when adjusted for baseline PS (0 vs, 1,2) and stage (IIIB vs. IV) in a Cox model, p=.15, 2-sided Wald test. There was no difference in terms of OS (p=.96). Serum and tissue were submitted for >90%. Analysis of COX-2 and 5-LOX expression are pending. Conclusions: 1. The combination of C/G + eicosanoid modulators was well tolerated. 2. The trend towards improved FFS in Arm C is intriguing, however, did not achieve the primary endpoint. 3. Correlative studies which may be able to identify pts likely to benefit from this approach are in progress. [Table: see text] [Table: see text]