However, the clinical benefits were modest with less than 2 months improvement in OS (15,16). Last, regorafenib, a small molecule tyrosine kinase inhibitor targeting VEGF receptors and Tie-2 amongst other tyrosine kinases, in patients who failed all standard agents (including bevacizumab

and anti-EGFR agents in KRAS wild type) has been recently approved based on a statistically significant Inhibitors,research,lifescience,medical improvement in OS of 6 weeks when compared to placebo (17). The clinical benefits associated with bevacizumab, ziv-aflibercept, and regorafenib in metastatic colorectal cancer in terms of OS have been modest and are associated with significant cost to society and patients. These agents should only be used within their label indications and based on current supporting

Inhibitors,research,lifescience,medical evidence, as reviewed by Smaglo and Hwang (1). Moving forward, we can only foresee a substantial clinical benefit from these agents as we better understand their true mechanisms of activity and associated mechanisms of resistance. The mechanisms of resistance Inhibitors,research,lifescience,medical to VEGF targeting can be complex. Clarke and Hurwitz provide a comprehensive review of VEGF axis related resistance, the role non-VEGF modulators of angiogenesis in resistance, and the significance of the stroma in the response to angiogenesis targeting (3). The Clark and Hurwitz article gives further insight as to the potential role of biomarkers in identifying patients least likely to benefit from angiogenesis targeting (3). Unfortunately, none of the current putative biomarkers is supported by ample clinical evidence and significant Inhibitors,research,lifescience,medical progress is still needed in this area. Anti-EGFR therapy: work in progress on the appropriate patient selection Since the approval of cetuximab and panitumumab in the Inhibitors,research,lifescience,medical metastatic colorectal cancer in 2004 and 2006 respectively, significant progress has been made in defining mechanisms of resistance to anti-EGFR therapy and in improving patient selection. In this issue, Harlaldsdottir and Bekaii-Saab provide a comprehensive review on the role of anti-EGFR therapies in colorectal cancer (2). Both

monoclonal antibodies, when administered as monotherapy, have been associated with favorable whatever outcomes in patients with chemotherapy-refractory KRAS wild type colorectal cancer (18,19). Indeed, the OS of patients with chemoresistant disease and KRAS wild type disease is doubled when compared to best supportive care in patients treated with cetuximab monotherapy. Similar advantages in OS are expected from the integration of panitumumab CYC202 price monotherapy (10). Panitumumab monotherapy has been noted to be equivalent to cetuximab monotherapy in a recent phase III clinical trial (ASPECCT) in patients with KRAS wild-type patients (http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1816635). The estimated hazard ratio on the ASPECCT trial was 0.966 (95% CI: 0.839-1.113) favoring the panitumumab arm.