Background: Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in pts with adv NS-NSCLC. The incorporation into MC regimens of antiangiogenic agents has been shown to further enhance efficacy in preclinical models. The goal of this pilot study was to achieve a 30% improvement in the 6.4 months (M) progression-free survival (PFS) observed in ECOG 4599. Methods: Untreated pts with stage 4 NS-NSCLC, PS 0-1 and measurable disease were treated with a 4-week (W) cycle of paclitaxel (80mg/m² D1, 8, 15), gemcitabine (G) (200-300mg/m² D1, 8, 15) and B (10mg/m² D1, 15) for 6 cycles. Pts without progressive disease or significant toxicity (Tx) received maintenance B every 2 w. Primary endpoint:PFS. Secondary endpoints: ORR, OS, Tx and biomarker (BM) correlation. Blood samples for angiogenic (VEGF, sVEGFR2, BFGF, PLGF, PDGFα, Ang-2, IL-8, E-Selectin, ICAM-1, TGFβ-1, SDF-1α, endocan) and antiangiogenic (Thrombospondin-1, Ang-1) bm were collected at different intervals in 21 pts. Response assessment (RECIST) was performed every 8 w. Results: 33 evaluable pts were enrolled. Pt characteristics: median age 59 yrs (37-76), 60% female, 70% > 5% weight loss, 24% never/light smokers, 48% genetic testing (mut EGFR-4; ALK(+)-1), and 9% brain mets. Efficacy parameters are shown in the table. 24 pts had an OR (CR-1, PR-23) and 6 pts had stable disease. No significant differences were observed in the efficacy parameters between former smokers vs. never/light smokers. Worst hematologic and non-hematologic Tx: gr 3 neutropenia (N=1); gr 3/4 nausea/vomiting (N=1); gr 3/4 fatigue (N=2); ischemic colitis (N=1); cerebral ischemia (N=1); gr 3/4 pneumonitis [related to G] (N=2); gr 3/4 proteinuria (N=3), and no gr 3/4 hypertension. Conclusions: While conclusions are limited by the size of the trial, the results are consistent with the hypothesis that the addition of B to MC may result in enhanced anti-angiogenic effect and clinical benefits in adv NS-NSCLC. Analysis of prognostic or predictive bm of angiogenesis will be presented. Clinical trial information: NCT00655850.