Prolonged bevacizumab exposure accompanied by EGFR activation in colorectal cancer (CRC) models to provide a rational for combinations of bevacizumab and erlotinib in the GERCOR DREAM phase III trial.

Abstract

449 Background: Combinations of EGFR and VEGF(R)-targeted agents have consistently shown at least additive activity in preclinical CRC models when the targeted agents were administered alone (Larsen et al., Pharmacol Therap. 131:80, 2011; Poindessous et al., Clin Cancer Res. 17:6522, 2011) paving the way for the GERCOR DREAM-OPTIMOX3 phase III trial in metastatic CRC. Although use of EGFR-directed mAbs are counter-indicated in CRC patients with mutant KRAS, the situation is less clear for EGFR-targeted TKIs like erlotinib. Methods: Three human CRC xenograft models expressing wt KRAS/BRAF, mutant KRAS or mutant BRAF were established in nude mice. Animals were treated with bevacizumab and erlotinib, alone or in combination, and the influence on tumor growth, viability and the presence of phosphorylated ErbB/HER family members was determined. Treatment-related toxicity was estimated by weight loss. Results: Combinations of bevacizumab and erlotinib were significantly more active than either agent alone for all three xenograft models although the advantage of combining the two agents was particularly striking for the KRAS/BRAF wt xenograft model. Unexpectedly, erlotinib alone showed strong antitumor activity in the BRAF mutant HT-29 xenograft model. The bevacizumab plus erlotinib combination was less toxic, as determined by weight loss, compared to erlotinib alone. Interestingly, IHC analysis showed that bevacizumab activates EGFR in all three xenograft models. Conclusions: We here report that bevacizumab and erlotinib combinations are significantly more active than either agent alone in CRC models with different KRAS and BRAF status. We further demonstrate that bevacizumab activates EGFR signaling similar to what has been described for irinotecan and ionizing radiation. Taken together, our findings suggest that mutant KRAS and BRAF have lesser influence on the sensitivity to EGFR-targeted TKIs than is the case for the EGFR directed mAbs and provide a mechanistic basis for the increased activity of the bevacizumab and erlotinib combination.