Abstract Previous studies using a mouse model of PNET (RIP-Tag2) demonstrated that anti-angiogenic therapy using an antibody that specifically targets murine VEGFR-2, DC101, led to a transitory period of stable disease followed by VEGF-independent revascularization and relapse leading to tumor progression (Casanovas, et al. Cancer Cell. 2005; 8: 299–309). Profiling analysis indicated that FGF was strongly upregulated upon failure of anti- VEGF therapy. Addition of a recombinant adenovirus expressing an FGF-Trap near the end of the response phase impaired revascularization and slowed tumor growth, implicating the FGF family of ligands in evasion of VEGF-targeted anti-angiogenic therapy in this model of PNET. Brivanib, a selective small molecule inhibitor of VEGFR-2,3 and FGFR-1,2,3 (Cai, et al. J Med Chem. 2008; 51:1976–80), is currently being evaluated in clinical trials in CRC and HCC. Brivanib's activity against FGFR signaling prompted investigation of its effects on evasive/adaptive resistance to selective VEGF inhibition. In the work to be presented, the efficacy of brivanib has been characterized as a first line inhibitor versus two different VEGF inhibitors, DC101 and sorafenib, and as a second line inhibitor following the failure of the aforementioned compounds. DC101 is a pure VEGF inhibitor, while sorafenib is a multikinase RTK inhibitor of VEGFR-2, PBGFR , and RAF/MEK/ERK currently approved in renal and liver cancer, and in Phase 3 trials for multiple other indications. Brivanib was comparable to FGF-trap as a second line inhibitor following DC101 failure, reducing tumor size and vascularity compared to continued DC101 monotherapy. Brivanib also showed reasonable efficacy in second line following sorafenib in short term trials. Notably, however, it could not reverse revascularization and tumor growth when sorafenib was allowed to fail in longer term trials. In contrast, first line brivanib therapy over comparable time courses that produced failure of both VEGF inhibitors resulted in tumor stasis and, in some cases, regression. Additionally, first-line brivanib therapy produced sustained blockade of angiogenesis, exhibited a trend for reduced invasiveness and metastasis in comparison to anti-VEGFR2 therapy alone, and significantly extended the lifespan of treated animals. Thus, while brivanib has clear benefits in second line therapy following failure of VEGF inhibitors, it may in some indications, as illustrated by this PNET model, be even more efficacious when used in a first line setting. The results from this mouse model of cancer may inform and facilitate design of future clinical trials of brivanib and other inhibitors of FGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B16.