4523 Background: Outcomes of second-line targeted therapy (TT) after failure of initial anti-VEGF therapy have not been well characterized. Outcome data as well as existing prognostic criteria in this population were evaluated. Methods: Between 2005- 2009, data from patients (pts) treated with initial VEGF TT were collected from 12 cancer centers. The subset of pts who failed their first anti-VEGF therapy and then were subsequently treated with another targeted agent was analyzed for outcomes and prognostic factors. Results: From the initial cohort of 1,084 pts, 321 pts met inclusion criteria and were included in this analysis. The second-line TT was sunitinib (32%), sorafenib (45%), axitinib (3%), bevacizumab (3%), temsirolimus (11%) or everolimus (6%). From the start of the second-line targeted therapy, the median follow-up was 20.6 months (mos), the median progression-free survival was 3.7 mos, and the median overall survival (mOS) was 12.3 mos (95%CI 10-13.3 mos). Using known poor prognostic factors from the first-line setting and applying them to the second-line setting (Heng et al. JCO 2009: anemia, hypercalcemia, thrombocytosis, neutrophilia, Karnofsky performance status<80, diagnosis to treatment<1yr), pts with 0, 1-2, or 3+ risk factors were in the favorable (n=32), intermediate (n=179) and poor (n=74) prognostic groups, respectively and achieved a mOS of not reached, 13, and 5.5 mos after initiation of second-line TT (p<0.0001). The median time on first TT was 8 mos and those who were on the first-line therapy for >8 mos vs. <8 mos had a mOS of 14.3 versus 9.9 mos, respectively (p=0.006). On multivariable analysis, the duration of first-line TT continued to predict OS from initiation of second-line TT with a hazard ratio of 1.53 (95%CI 1.09-2.13). Conclusions: In pts treated with second-line TT after failure of initial anti-VEGF agents, an established prognostic model can discriminate 3 distinct risk groups. Additionally, longer time on first TT was independently associated with OS on second-line agents. No significant financial relationships to disclose.