Gastric Cancer Subtype May Affect Bevacizumab Benefit

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.

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."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.

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.

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."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.

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.

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."

The need for further study of bevacizumab in gastric cancer in the West is debatable, according to Dr. Ilson, also of the Memorial Sloan-Kettering Cancer Center. "And I think an even bigger and overarching question is, Are agents targeting only one pathway really worth investigating? Should we be looking at multitargeted agents," or combining agents?

"The holy grail here, which never gets enough mention, is that we need to identify and validate biomarkers to direct therapy to the appropriate patient," he said.

In the unplanned, exploratory analysis, Dr. Shah and his team found that among patients from Europe and the Americas, the addition of bevacizumab improved overall survival significantly for those having diffuse disease (hazard ratio, 0.68) and marginally for those having distal disease (0.72). When these two groups were combined, the risk of death was reduced by one-third (0.67).

In an analysis of potential biomarkers of bevacizumab efficacy, survival benefit differed by tumor NRP-1 level (P = .06) – with only patients having below-median levels deriving benefit – and by plasma VEGF-A level (P = .07) – with only patients having above-median values deriving benefit.

Proximal tumors generally had higher tumor NRP-1 levels and lower plasma VEGF-A levels. By comparison, diffuse tumors had relatively low NRP-1 levels, and distal tumors had relatively high plasma VEGF-A levels.

"There is heterogeneity with these biomarkers across the different subtypes, and this is in support of the concept that subtypes are clinically meaningful," Dr. Shah commented. "Proximal tumors tend to have the worst profile, if you will, for bevacizumab."

Dr. Shah reported that he is a consultant to Genentech. Dr. Ilson reported that he receives research funding from Bayer, BMS-Imclone, Roche-Genentech, and Sanofi-Aventis.