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

Abstract

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% viable tumor seen), and processed for TLA and IHC. 11 pts had morphologic response including all 4 PR and 6/12 SD pts. Greater reduction in change in phospho(p)-ERK was seen at 2wk in group A pts (starting with sorafenib only) (p = 0.003). 9/11 MR pts had inhibition of ERK or AKT activation (p < 0.03). OvCa pts were more likely to have reduction in bRaf (p = 0.02). Pts in group B (starting with bevacizumab only) had lower microvessel density as measured by CD31 IHC (p = 0.05) at 2 wks; there was also a trend to lower VEGF expression by IHC in that group.These effects were muted at time 3, after combination treatment. No relationships to clinical outcomes were found, every pt had at least 1SNP in >1 tested gene; there were no Ras mutations and 1 V600KRaf mutation . Conclusions: These exploratory results demonstrate proof of mechanism in the tumor and its microenvironment for the combination of S and B. Randomization of initial exposure for the first 4 wks allowed interrogation of the role of the independent agents; the Raf/ERK axis was inhibited by S treatment first and there was reduction in tissue angiogenesis markers with B first. The molecularly targeted combination of sorafenib and bevacizumab is biologically active and on target. Phase II studies in multiple tumor types are ongoing. No significant financial relationships to disclose.