SAN FRANCISCO – The benefit of bevacizumab in some patients with advanced gastric cancer appears to vary by disease subtype, based on an exploratory analysis of data from the phase III AVAGAST trial.
The global trial randomized 774 patients to chemotherapy plus placebo or bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF). Results for the entire trial population, which were reported previously (J. Clin. Oncol. 2011;29:3968-76), showed no significant gain in overall survival from the addition of bevacizumab.
In the new analysis, presented at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology, investigators divided the patients according to three types of disease with distinct histology and clinical and environmental risk factors. About 10% of all patients had proximal (also known as type 1) disease, 50% had diffuse (type 2) disease, and 40% had distal (type 3) disease.
The main results showed that the addition of bevacizumab to chemotherapy was associated with a significant, one-third reduction in the risk of death for patients from Europe and the Americas who had diffuse or distal disease. Patients with proximal disease, and patients from the Asia-Pacific region with any disease type, did not show significant benefit.
Dr. Manish A. Shah
Additionally, in the trial’s control arm, overall survival in patients from Europe and the Americas differed across the three types, with the diffuse type carrying the poorest prognosis. And levels of two biomarkers showing marginal correlation with bevacizumab efficacy – tumor neuropilin-1 (NRP-1) and plasma VEGF-A – varied across the types in ways that were consistent with the observed drug benefit.
"Gastric cancers really are more than one disease. The subtypes have different prognoses; they have different [bevacizumab] efficacy," said first author Dr. Manish A. Shah, a gastrointestinal oncologist with the Memorial Sloan-Kettering Cancer Center in New York. These subtypes "may form the basis of a new classification schema for gastric cancer."
In addition, the candidate biomarkers tumor NRP-1 and plasma VEGF-A may actually provide a rationale for gastric cancer and/or subtype-specific outcomes with bevacizumab, he said.
Discussant Dr. David H. Ilson agreed that etiologic and molecular data show that "these are likely biologically different diseases. The caveat from Dr. Shah’s analysis, however, is that this is a small, unplanned subset analysis and is at best hypothesis generating."
Numerous Asian trials of chemotherapy in gastric cancer have not found diffuse histology to be either prognostic or predictive, and Western trials have often not considered disease type, Dr. Ilson noted. Thus, "the potential prognostic and predictive impact of diffuse histology needs to be validated in other cohorts. And the potential bevacizumab biomarkers also require validation."