Background: In mRCC pts who fail first-line VEGF-targeted therapy, there are no available randomized data comparing active drugs. Currently, many clinicians choose a second-line VEGF-targeted therapy based on the type of response to first-line VEGF therapy, although no data exists to support this practice. Methods: Pts treated with targeted therapy in the International mRCC Database Consortium were examined to identify pts who received a second-line VEGF-targeted therapy after failure of a different first-line VEGF-targeted therapy. Response rates and progression-free survival (PFS) were compared in the first- and second-line settings. Results: Of 1,602 total database pts, 464 pts received second-line VEGF-targeted therapy (sunitinib 37%, sorafenib 51%, axitinib 2%, bevacizumab 7%, pazopanib 3%) after failure of first-line VEGF-targeted therapy (sunitinib 54%, sorafenib 33%, bevacizumab 13%). The median overall survival from initiation of first-line therapy for pts who received second-line therapy was 26.5 months. The median first-line and second-line PFS were 7.5 months and 3.9 months (95% CI 3.6-4.5), respectively. There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p=0.59). RECIST-defined objective response rate (ORR) was available for both first- and second-line therapy in 323 pts. The ORR in first- and second-line therapy was 22% and 11%, respectively. There was no significant association between first-line objective response and second-line objective response (chi squared trend test p=0.17; Table). Conclusions: There is no association between first-line and second-line objective response or PFS to VEGF-targeted therapy in mRCC.