Strong Biomarker Candidates for Predicting Clinical Response to Bevacizumab

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Plasma vascular endothelial growth factor A (VEGF-A) and tumor neuropilin-1 “are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer” after treatment with bevacizumab (Avastin). This was the conclusion of a mandatory biomarker program following up on AVAGAST study findings that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response, but not overall survival. The results of the AVAGAST trial were reported in the Journal of Clinical Oncology in 2011 and the biomarker evaluation was published by JCO online in May 2012.1

Using plasma samples available from 712 patients (92%) and tumor samples available from 727 patients (94%), researchers identified baseline plasma VEGF-A levels and tumor neuropilin-1 expression as potential predictors of bevacizumab efficacy. “Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival” compared to patients with low VEGF-A levels, the authors reported.

“Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival” compared to patients with high neuropilin-1 expression. “For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions,” the researchers noted.

Earlier Studies

“Pretreatment levels of circulating VEGF-A have been previously studied as a biomarker for VEGF-targeted therapies, but have been shown to be primarily prognostic rather than predictive,” the authors wrote. “In AVAGAST, we demonstrate that high plasma VEGF-A levels are associated with worse prognosis in metastatic gastric cancer. In addition, we demonstrate that high plasma levels of VEGF-A at baseline are associated with a trend toward a larger bevacizumab effect in terms of overall survival, progression-free survival, and overall response rate. These benefits were not evident in patients with low baseline VEGF-A levels. The potential predictive role of plasma VEGF-A identified in AVAGAST is supported by two other recent independent biomarker analyses performed in patients with metastatic breast cancer (AVADO study) and pancreatic cancer (AViTA study).”

In the AVAGAST study, “patients with low levels of neuropilin-1 expression appeared to derive more benefit from bevacizumab therapy than patients with higher levels of expression in terms of overall survival, progression-free survival, and overall response rate,” the researchers reported. “These observations are consistent with two recent retrospective, exploratory biomarker analyses in colorectal cancer (NO16966 study) and breast cancer (AVF2119g study), although different antibodies and methodologies were used in all studies.”

AVAGAST, a global, randomized, double-blind, phase III study, randomly assigned patients with previously untreated, locally advanced or metastatic gastric cancer to bevacizumab or placebo (387 in each group) in combination with cisplatin plus capecitabine (Xeloda), or fluorouracil in patients unable to take oral medications.

“Although bevacizumab was associated with a significantly longer progression-free survival vs placebo (median, 6.7 vs 5.3 months; HR = 0.80; P = .0037) and higher overall response rate (46.0% vs 37.4%; P = .0315), the difference in overall survival, the primary study endpoint, did not reach statistical significance (12.1 vs 10.1 months; HR, 0.87; P = .1002),” the researchers reported. ■


1. Van Cutsem E, de Haas S, Kang YK, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial J Clin Oncol. May 7, 2012 (early release online).