Translational proof of mechanism (PoM) for sorafenib with bevacizumab: Endpoint analysis and clinical activity

3574 Background: We hypothesized that molecular targeting of tumor and its microenvironment with rational combination therapy would yield improved outcome. Bevacizumab (B) is a monocolonal antibody to vascular endothelial growth factor (VEGFF) and sorafenib (S) is a small molecule inhibitor of the VEGF receptor-2 and RAF-kinase.We have previously reported that S 200mg bid with B 5mg/kg q2wk resulted in partial responses and prolonged disease stabilization (ovarian cancers, renal cell cancer, leiomyosarcoma). Serial tumor biopsies were obtained for translational proof of mechanism analysis. Methods: Percutaneous core biopsies of metastatic sites were obtained at baseline, after 2wk of S (group A) or B (group B), and at 6wks (2 wk into S+B combination therapy). Tissue was used for: lysate array (TLA) proteomic analysis of signaling proteins, IHC for CD31, VEGF, and Ki67, Raf/Ras mutation, and SNP analysis. Results: 18 sets of 3 biopsies were obtained, assessed for morphologic response (MR; decrease to <60% ...