3096 Background: Pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC with malignant pleural effusion (MPE) are unknown. We conducted an exploratory phase II study of gefitinib in patients (pts) with MPE from non-small cell lung cancer (NSCLC), with pharmacokinetic and pharmacodynamic assessments. Methods: Single agent gefitinib 250 mg was given PO daily with concurrent tube drainage and sampling of MPE from NSCLC. Pleural effusion and blood samples were collected at 0, 3, 8, 24, and 72 hrs on gefitinib therapy. Tumor cell-enriched cell blocks were prepared from serial MPE samples and analyzed for EGFR signaling pathway. MPE and serum samples were measured for gefitinib concentration, transforming growth factor-alpha (TGFα), and amphiregulin (AR). Tumor response was assessed by RECIST. Results: From Sep 2006 to Aug 2008, twenty pts were enrolled onto the study. All pts were evaluable for efficacy, toxicity, and biologic outcomes. Patient characteristics include: female, 60%; adenocarcinoma, 100%; and EGFR mutation positive, 65%. Median survival and median progression-free survival were 10.0 months and 5.0 months, respectively. One, nine, and two pts achieved CR, PR, and SD. With single gefitinib dosing, geometric mean Cmax in MPE was 60.3 ng/ml reached at 18.9 ± 13.8 h (mean ± S.D.) following Cmax in plasma of 237.4 ng/ml reached at 6.0 ± 4.8 h. Geometric mean gefitinib concentration in MPE increased from 55.7 ng/ml 24 h after initial dosing to 133.0 ng/ml 24 h after 3-day dosing, suggesting accumulation of gefitinib in MPE. While levels of TGFα in MPE were comparable to those in serum, AR levels in MPE were × 5 higher than in serum and they decreased at 72 h on therapy. In several responders, apoptosis of tumor cells in MPE became detectable as early as 3 h on therapy. Further intensive pharmacodynamics is to be presented. Conclusions: Gefitinib showed clinical efficacy and acceptable toxicity in pts with MPE from NSCLC. MPE seems to be a suitable condition for intensive pharmacokinetic and pharmacodynamic assessments of molecular targeting agents which have less hematologic toxicities. No significant financial relationships to disclose.