Cetuximab reduces the accumulation of radiolabeled bevacizumab in cancer xenografts without altering VEGF expression

S. Heskamp, O. Boerman, J. Molkenboer-Kuenen, F. Sweep, A. Geurts-Moespot, M. Engelhardt, W. van der Graaf, W. Oyen and H. van Laarhoven




Introduction: Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Material and methods: Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab or the combination. Before start of cetuximab treatment, and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Results: Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab or the combination, while growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, while tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Conclusion: Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could at least partly explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.