Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Biomarker Evaluation From the AVAGAST Randomized Phase III Trial

• Published in: Journal of clinical oncology Vol. 30; no. 17; pp. 2119 - 2127
• Main Authors: VAN CUTSEM, Eric, DE HAAS, S. Anne, SHAH, Manish A, KANG, Yoon-Koo, OHTSU, Atsushi, TEBBUTT, Niall C, JIAN MING XU, WEI PENG YONG, LANGER, Bernd, DELMAR, Paul, SCHERER, Stefan J
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 10-06-2012
• Subjects: Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Biomarkers, Tumor - metabolism; Disease-Free Survival; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Medical sciences; Neoplasm Metastasis; Neuropilin-1 - biosynthesis; Placebos; Proportional Hazards Models; Prospective Studies; Stomach Neoplasms - drug therapy; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Treatment Outcome; Tumors; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor Receptor-1 - biosynthesis; Vascular Endothelial Growth Factor Receptor-2 - biosynthesis; Antineoplastic agent; Phase III trial; Drug combination; Biological marker; Monoclonal antibody; Malignant tumor; Stomach cancer; Bevacizumab; First line treatment; Chemotherapy; Randomization; Treatment; Cancerology; Vascular endothelium growth factor; Digestive diseases; Clinical trial; Advanced stage; Combined treatment; Antiangiogenic agent; Cancer; Gastric disease
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2011.39.9824

The AVAGAST study showed that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response rate but not overall survival. To examine the hypothesis that angiogenic markers may have predictive value for bevacizumab efficacy in gastric cancer, AVAGAST included a prospective, mandatory biomarker program.
Patients with previously untreated, locally advanced or metastatic gastric cancer were randomly assigned to bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Blood and tumor tissue samples were collected at baseline. Prespecified biomarkers included plasma vascular endothelial growth factor-A (VEGF-A), protein expression of neuropilin-1, and VEGF receptors-1 and -2 (VEGFR-1 and VEGFR-2). Correlations between biomarkers and clinical outcomes were assessed by using a Cox proportional hazards model.
Plasma was available from 712 patients (92%), and tumor samples were available from 727 patients (94%). Baseline plasma VEGF-A levels and tumor neuropilin-1 expression were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival (hazard ratio [HR], 0.72; 95% CI, 0.57 to 0.93) versus patients with low VEGF-A levels (HR, 1.01; 95% CI, 0.77 to 1.31; interaction P = .07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75; 95% CI, 0.59 to 0.97) versus patients with high neuropilin-1 expression (HR, 1.07; 95% CI, 0.81 to 1.40; interaction P = .06). For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions.
Plasma VEGF-A and tumor neuropilin-1 are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer treated with bevacizumab.