18112 Background: XL999 is a potent spectrum-selective inhibitor of receptor tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, & SRC. A Ph 1 clinical study in pts w/advanced malignancies evaluating weight-based (0.2 - 6.4 mg/kg) & fixed dose (200 mg & 160 mg) XL999 administered by 4hr IV infusion on a wkly or every other wk schedule has shown preliminary evidence of anti- tumor activity (3 PRs & 10 pts w/SD lasting 3–26+ months). The safety profile was characterized by hypertension & cardiovascular changes including EKG, LVEF decrease &/or cardiac enzyme elevation following 1st dose administration. DLTs were cardiac failure & transaminase elevation. A dose of 2.4 mg/kg/wk was selected for phase II evaluation. Methods: The 1 objectives of this phase II study are to determine the RR & to further evaluate the safety & tolerability of XL999. Adult pts w/NSCLC (stage IIIB with malignant effusion, stage IV, or recurrent) & previously treated with no more than 2 prior systemic cytotoxic chemotherapy regimens, including a platinum-or taxane-containing regimen, & no more than one prior target agent targeting VEGF or EGFR, are eligible. Additional inclusion criteria include ECOG PS 0–1 & absence of known brain metastases. Pts with LVEF<50% or below lower limits of normal or with significant cardiovascular abnormalities are excluded. Tumor response is assessed every 8 wks by RECIST criteria. XL999 is administered wkly at 2.4 mg/kg as a 4hr IV infusion. Results: Nine pts received XL999. Three pts remain on study drug. One pt has a confirmed PR with complete resolution of a 2cm lung nodule. Another has a total reduction of 23% in multiple hepatic lesions (by RECIST). A third pt continues with SD for 3.5 months. Six pts with PD are discontinued. AEs reported in at least 2 pts were grade 1 diarrhea, fatigue, anorexia, & dizziness. Grade 3 AEs included 1 report each of N/V. No Grade 4 or 5 AEs or serious cardiac AEs have been reported. Conclusions: Wkly IV dose at 2.4 mg/kg appears generally well-tolerated & shows preliminary evidence of anti-tumor activity in advanced NSCLC pts refractory to multiple prior anti-cancer therapies. No significant financial relationships to disclose.