OBJECTIVES: Platinum-based chemotherapy with bevacizumab is a standard therapy for patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with non-squamous (NS) histology. Mechanisms of resistance to bevacizumab include increased VEGF signaling or activation of VEGF receptors. Pazopanib is a multi-targeted VEGF receptor tyrosine kinase with single agent activity in NSCLC. MATERIALS AND METHODS: Stage IIIB/IV patients with adequate organ function, who progressed on a bevacizumab containing therapy were eligible if it had been ≤8 weeks since the last bevacizumab treatment. The primary end-point was disease control rate (DCR), defined as partial or complete response, or stable disease for ≥12 weeks. Patients were assessed radiographically every 2 cycles (6 weeks). A Simon 2-stage design was used, and if in the first stage ≤4 of 17 patients experienced disease control the trial was to have been stopped for futility. An unplanned analysis was performed after 15 patients were evaluable secondary to slow accrual. RESULTS: Between December 2010 and November 2013, 15 patients were treated on trial. The median age was 61 years (range 39-74), and all patients had stage IV disease. Of the 15 patients, 4 discontinued therapy prior to cycle 2 evaluation due to adverse events (n=3) and medical illness (n=1), 5 patients had progressive disease, 4 patients had stable disease for <12 weeks, and 2 patients had stable disease for ≥12 weeks. No responses were observed. The DCR observed was 13% (2/15), and the trial did not meet the criteria to proceed to the second stage. Episodes of grade 3 treatment related toxicities observed included: increased ALT (n=2), increased AST (n=1), anorexia (n=3), fatigue (n=3), hypertension (n=1), infection (n=1), mucositis (n=2), nausea (n=3), pericardial effusion (n=1), and vomiting (n=1). CONCLUSION: Pazopanib has limited activity in NSCLC-NS in patients who have experienced disease progression on bevacizumab.