Bevacizumab in Gastric Cancer: Results From AVAGAST

Bevacizumab in Combination With Chemotherapy as First-line Therapy in Advanced Gastric Cancer: A Randomized, Double-blind, Placebo-controlled Phase III Study

Ohtsu A, Shah MA, Van Cutsem E, et al
J Clin Oncol. 2011;29:3968-3976

Study Summary

This large, multinational study evaluated the efficacy of the anti-vascular endothelial growth factor antibody, bevacizumab, when added to capecitabine and cisplatin as first-line treatment of advanced gastric cancer. In total, 774 patients were randomly assigned to either bevacizumab 7.5 mg/kg or placebo, followed by cisplatin 80 mg/m² on day 1 plus capecitabine 1000 mg/m² twice daily for 14 days every 3 weeks. (In patients unable to take oral medications, 5-fluorouracil was substituted.) The study fell short in achieving its primary endpoint of improving median survival, although a trend in favor of adding bevacizumab (12.1 months vs 10.1 months, hazard ratio [HR] 0.87, P = 0.1) was evident. However, other endpoints were met and again favored bevacizumab over placebo, including median progression-free survival (6.7 vs 5.3 months for placebo-chemotherapy; HR, 0.80; P = .0037) and overall response rate (46.0% vs 37.4%; P = .0315). Known adverse effects of bevacizumab, including hypertension and gastrointestinal perforation (2.3%), occurred at expected frequencies, based on results of previous bevacizumab studies. Preplanned subgroup analyses suggested regional differences in efficacy. Patients from North and South America appeared to have a survival benefit with the addition of bevacizumab (median, 11.5 vs 6.8 months for placebo-chemotherapy; HR, 0.63; 95% confidence interval [CI], 0.43-0.94), whereas patients enrolled in Asia (90% from Japan and Korea) appeared to have no benefit (HR, 0.97; 95% CI, 0.75-1.25), and European patients had intermediate results (HR, 0.85; 95% CI, 0.63-1.14).

Viewpoint

Findings from this large, randomized study suggest clinical activity of bevacizumab in advanced gastric cancer without significant worsening of toxicity (although, as always with bevacizumab, rare toxicities such as perforation can have significant consequences for individual patients). Because the trial did not meet its primary endpoint, widespread use of bevacizumab is precluded in this population. Identifying subgroups of patients who clearly benefit from treatment would allow for better selection and individualization of therapy. Unfortunately, unlike epidermal growth factor receptor inhibitors, bevacizumab is not associated with any recognized biomarkers predictive of response to the drug. Correlative biomarker analyses from patients enrolled in this study are ongoing and may provide additional information in the future.

Another important lesson learned from this study is the importance of regional disparities in outcomes. Gastric cancer in Asian populations is epidemiologically quite distinct from North American gastric cancer and it is possible that different targeted therapeutic agents may have different outcomes, as suggested by subgroup analysis of this study. In this era of globalization of trials, it is important to keep in mind that these differences may have meaningful impact on study outcomes. For now, bevacizumab cannot be recommended as standard first-line therapy for advanced gastric cancer.

Abstract