Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials

Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre-treated population that improve efficacy while minimizing cost and toxicity.