David O. Bates, PhD
Researchers have identified a potential predictive marker for survival in cases of metastatic colorectal cancer (mCRC) treated with bevacizumab (Avastin), suggesting that patients who have the appropriate biomarker could experience a greater benefit when given the drug, whereas others who do not express the biomarker could be spared from receiving unnecessary therapy.
Bevacizumab is approved by the FDA to treat mCRC when given in combination with a standard chemotherapy regimen of ironotecan, 5-fluorouracil, and leucovorin as a first- or second-line therapy. Although clinical trials in patients with mCRC have shown an improvement in survival, no proven predictive markers have yet been identified to determine which patients may experience a greater survival benefit when given the therapy.
The drug works by targeting and blocking VEGF-A, a protein associated with angiogenesis. Since VEGF-A is the product of one gene encoding multiple isoforms, researchers decided to focus on one splice variant of VEGF-A called VEGF165b that was shown to have antiangiogenesis properties. The hypothesis for the study was that patients with relatively low levels of VEGF165b would respond better—measured by progression- free survival (PFS)—when treated with bevacizumab. Researchers posited that in patients with lower levels of VEGF165b, more of the drug might be able to block the angiogenesis-promoting form of protein VEGF165.
Researchers at the University of Bristol used 97 blinded tumor samples from a phase III trial in which patients with mCRC received the FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) chemotherapy regimen with or without bevacizumab. Those tissue samples were assessed for VEGF165b and total VEGF by immunohistochemistry, and the ratio of the two levels was scored relative to normal tissue samples.
An unadjusted analysis of PFS showed that patients with lower VEGF165b:total VEGF ratios treated with the FOLFOX4 and bevacizumab regimen (n = 24) had a longer median PFS than those who received FOLFOX4 alone (n = 26; median, 8.0 months vs 5.2 months; P <.02). However, no beneficial effect on PFS was observed in patients with higher VEGF165b:total VEGF ratios when the combination regimen (n = 20) was compared with FOLFOX4 alone (n = 27; median, 5.9 months vs 6.3 months).
Although patients with a lower VEGF165b ratio achieved a higher median overall survival (OS) when given FOLFOX4 and bevacizumab (median, 13.6 months) compared with patients who received FOLFOX4 alone (median, 10.6 months), the results did not reach statistical significance. No difference in OS was observed in the higher VEGF165b ratio group when comparing the FOLFOX4 and bevacizumab regimen (median, 10.8 months) with FOLFOX4 alone (11.3 months).
“Avastin has shown great potential for a minority of people with bowel cancer, but it’s been impossible to predict who will benefit from the drug,” said David O. Bates, PhD, lead researcher from the University of Bristol School of Physiology and Pharmacology and lead author of the study. “We now need to look at cancer samples from a larger group of patients about to start taking Avastin and determine if the amount of VEGF165b can accurately identify those patients that will benefit and so potentially open a new treatment option for some people with advanced bowel cancer.”
Bates DO, Catalano PJ, Symonds KE, et al. Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab [published online ahead of print October 25, 2012]. Clin Cancer Res