Bevacizumab–erlotinib combined efficacy may depend on VEGF level

By Laura Cowen, medwireNews Reporter

Bevacizumab may enhance the antitumour activity of erlotinib by increasing the intratumoural concentration of erlotinib in some non-small-cell lung cancers (NSCLCs) expressing high levels of vascular endothelial growth factor (VEGF), Japanese researchers report.

Early clinical trials indicated that addition of the anti-VEGF agent bevacizumab to the epithelial growth factor receptor tyrosine kinase inhibitor (EGFR–TKI) erlotinib improved overall survival in patients with advanced NSCLC, but these findings were not replicated in phase III trials.

Koichi Takayama and colleagues from Kyushu University therefore conducted a series of in vitro and in vivo experiments to investigate whether there were specific conditions under which bevacizumab increases the antitumour activity of erlotinib.

They found that bevacizumab alone did not inhibit NSCLC cell growth in vitro, and when used in combination with erlotinib, growth inhibition was similar to that with erlotinib alone.

Of the six cell lines tested, three (H157, H460 and A549) did not carry an EGFR mutation and were therefore resistant to erlotinib. VEGF protein expression varied among these cells; it was high in H157, moderate in H460 and low in A549 cells.

The researchers created mouse xenograft models with each of these cell lines and showed that bevacizumab alone had significant antitumour activity in the H157 and H460 models, but not in the A549 model, with respective growth inhibitions of 80.8%, 65.6% and 57.1%.

By contrast, tumour growth inhibition was below 40% for both the H157 and H460 models when treated with erlotinib alone, while moderate inhibition (approximately 52%) was observed in the A549 model.

Combining the two drugs increased growth inhibition to more than 85% in the high VEGF-expressing H157 model, but had no additional effect when tested in the H460 or A549 models.

“These results suggest that the effect of dual inhibition of EGFR and VEGF is dependent on VEGF expression in EGFR TKI-resistant xenografts”, Takayama et al remark.

In line with this, the team also identified a trend towards increasing tumour tissue concentrations of erlotinib during combination treatment compared with erlotinib alone that appeared to be influenced by the levels of VEGF protein.

The researchers speculate that “partial normalization of tumor vessels by bevacizumab could cause proliferation of the tumor cells, which could make them more sensitive to EGFR TKI.”

They conclude in Cancer Chemotherapy and Pharmacology that “further understanding of mechanisms and modes in dual inhibition of EGFR and VEGF is a priority.”

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