7511 Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD2171, a potent tyrosine kinase inhibitor (TKI) of VEGFR1/2 in MPM. Methods: MPM patients (pts) after platinum-based chemotherapy, with PS 0–2, measurable disease and adequate organ function were treated with oral daily dosing of AZD2171 45 mg. Study endpoints were response rate, progression free survival (PFS), overall survival (OS), frequency/severity of toxicities, and correlation of clinical outcomes with tumor and serum biomarkers. Results: 54 pts were registered between November 2005 and April 2008; 45 pts are eligible for response and 46 for toxicity analysis. Median age was 66.8 yrs; M/F: 37/9. Tumor response by RECIST was seen in 4/45 (9%) of pts; of these responders, 2 pts with bulky disease had 56% and 91% tumor shrinkage, respectively. 15/45 (33%) had SD; 21/45 (47%) had PD; 1/45 (2%) had early death. Thirty-five pts have died. For 46 pts, median PFS is estimated at 3 months; median OS is estimated at 10 months. For 46 pts, frequent grade 1–3 toxicities included anorexia (30%), diarrhea (63%), fatigue (60%), hypertension (67%), and proteinuria (28%). There were 8 grade 4 events: Cognitive disturbance, colitis, confusion, ileal perforation, hypertension, hyponatremia, hypotension, and renal failure. Conclusions: AZD2171 has antitumor activity in MPM, with a DCR (CR/PR/SD) of 42% by RECIST, which has limitations in measuring response in pleural tumors. Notably, 2 pt tumors were exquisitely sensitive to this drug. Toxicities were consistent with those of the anti-angiogenic TKI class of drugs. Studies correlating outcome measures with tumor hypoxia- and angiogenesis-related gene expression and circulating endothelial cells are underway. Based on these data, we are proceeding in SWOG with a study of pemetrexed/cisplatin ± AZD2171 (S0905). This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA46441, CA105409, CA13612, CA45808, CA20319, CA86780, CA35090, CA67663, CA46282, CA42777, CA76448, CA04919, CA35176, CA63848, CA27057, CA16385. [Table: see text]