Can a Biomarker Revive Everolimus for Advanced Gastric Cancer?

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.

SAN FRANCISCO – Despite disappointing results in an international randomized phase III trial, investigators are hoping a biomarker will help them to find a role for everolimus in advanced gastric cancer.

The oral mammalian target of rapamycin (mTOR) inhibitor appeared to have limited efficacy as second- or third-line therapy in the GRANITE-1 study of more than 650 patients.

Overall survival was statistically indistinguishable between patients given everolimus (Afinitor) and those given a placebo, each added to best supportive care. Statistically, progression-free survival was significantly better with everolimus, but the absolute benefit was small, just 0.3 months.

"This trial was negative," Dr. Eric Van Cutsem told attendees when he reported the results at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. But the story did not end there.

"What is going to be crucial – and we hope to present at future meetings – is the biomarker analysis to show which are the patients who had the minor responses and had some activity," he added, with initial focus on biomarkers in the PI3 kinase/Akt/mTOR pathway.

The findings came on the heels of a phase II trial that suggested everolimus had promising efficacy in this hard-to-treat cancer (J. Clin. Oncol. 2010;28:1904-10). The PI3 kinase/Akt/mTOR pathway is a logical target in this disease, as it is dysregulated in 50%-60% of cases, according to Dr. Van Cutsem, an oncologist at University Hospital Gasthuisberg in Leuven, Belgium.

"The progression-free survival curve is somewhat provocative," said discussant Dr. David H. Ilson of the Memorial Sloan-Kettering Cancer Center in New York.

"We clearly need the study of biomarkers to identify the likely small subset of patients who may benefit from treatment with this agent," he said. "However, I would give a caveat here: This does not mean that we should mandate a biomarker up front in all of our new studies because we may miss detection of activity in all patients by mandating biomarkers up front."

Dr. Ilson noted that the magnitude of benefit may be important to taking everolimus forward in gastric cancer. "How high should the bar be set to consider developing new agents? Is a 1- to 2-month improvement in progression-free survival or overall survival enough of an adequate benchmark?" he questioned.

Patients were eligible for GRANITE-1 if they had advanced gastric cancer (or gastroesophageal junction cancer, provided the majority of the tumor was in the stomach) and had experienced progression after one or two lines of systemic chemotherapy.

In all, 656 patients were randomized 2:1 to everolimus 10 mg daily or placebo, each along with best supportive care. They had a median age of 62 years, and about 55% were from Asia. They were almost evenly split as far as having received one or two prior lines of chemotherapy.

The median duration of treatment was 7.1 weeks with everolimus and 6.4 weeks with placebo, Dr. Van Cutsem reported.

"The safety profile of everolimus was similar to that observed with everolimus in other cancers, with no new safety signals identified," he said. The rate of any grade 3 or 4 adverse event was 71% with everolimus and 54% with placebo, with the largest differences seen for certain gastrointestinal and hematologic adverse events.

Median overall survival, the trial’s primary end point, was 5.4 months with everolimus and 4.3 months with placebo, a nonsignificant difference. Subgroup analyses failed to identify any specific subgroup that had significant benefit.

Median progression-free survival was 1.7 months with everolimus and 1.4 months with placebo (hazard ratio, 0.66; P less than .0001). The overall response rate was 4.5% and 2.1%, respectively.

Dr. Van Cutsem disclosed that he receives research funding from Novartis. Dr. Ilson disclosed that he receives research funding from Bayer, BMS-ImClone, Roche-Genentech, and Sanofi-Aventis.