Panel Backs Everolimus for Pancreatic Neuroendocrine Tumors

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 10-0 that everolimus had a favorable risk-benefit profile when used to treat people with advanced pancreatic neuroendocrine tumors, but cautioned that it should not be used in all patients with this diagnosis.

At their April 12 meeting, members of the FDA’s Oncologic Drugs Advisory Committee cited the unmet need for treatments for this rare disease and evidence that everolimus (Afinitor) is effective in some patients with more aggressive disease.

They cautioned, however, that it should not be used in every patient with advanced pancreatic neuroendocrine tumors (PNET). The disease can be indolent, they noted, and there was evidence that everolimus has a more favorable risk-benefit profile in patients with progressive disease.

The panel members recommended that more work be done to identify the subset of patients with the disease who can benefit most from treatment with everolimus. They also recommended that it not be used to treat patients with carcinoid tumors because it has not been shown to be effective and may be harmful in this population.

Novartis Pharmaceuticals Corp., which markets Afinitor, has proposed that it be approved for the treatment of patients with advanced PNET. Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a key protein kinase that regulates cell growth, proliferation, and survival. It was approved in the United States in 2009 for treating advanced renal cell carcinoma and in 2010 for subependymal giant cell astrocytoma.

In the pivotal, double-blind, placebo-controlled phase III study, in patients with unresectable or metastatic biopsy-proven PNET, 207 patients treated with 10 mg of everolimus daily plus best supportive care were compared with 203 patients on placebo and best supportive care. Almost all patients enrolled had metastatic disease.

The primary end point, median progression-free survival as determined by the investigators, was 11 months in the everolimus arm, compared with 4.6 months in the placebo arm, a reduced risk of 65% that was statistically significant. There was no difference in overall survival between the two groups.

There were 12 deaths in the treatment group: 5 due to disease progression and 7 due to an adverse event related to treatment. In the placebo group, there were 4 deaths, 3 due to disease progression. Sixty-two percent of those on everolimus had a grade 3/4 adverse event, compared with 40% of those on placebo. Pneumonitis, opportunistic infections, and renal failure were among the significant adverse events associated with everolimus therapy.

The incidence of pancreatic neuroendocrine tumors is about 3 per million people a year, according to Novartis. A decision on approval is expected in the second quarter of this year, according to a Novartis spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict, but that did not occur at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 10-0 that everolimus had a favorable risk-benefit profile when used to treat people with advanced pancreatic neuroendocrine tumors, but cautioned that it should not be used in all patients with this diagnosis.

At their April 12 meeting, members of the FDA’s Oncologic Drugs Advisory Committee cited the unmet need for treatments for this rare disease and evidence that everolimus (Afinitor) is effective in some patients with more aggressive disease.

They cautioned, however, that it should not be used in every patient with advanced pancreatic neuroendocrine tumors (PNET). The disease can be indolent, they noted, and there was evidence that everolimus has a more favorable risk-benefit profile in patients with progressive disease.

The panel members recommended that more work be done to identify the subset of patients with the disease who can benefit most from treatment with everolimus. They also recommended that it not be used to treat patients with carcinoid tumors because it has not been shown to be effective and may be harmful in this population.

Novartis Pharmaceuticals Corp., which markets Afinitor, has proposed that it be approved for the treatment of patients with advanced PNET. Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a key protein kinase that regulates cell growth, proliferation, and survival. It was approved in the United States in 2009 for treating advanced renal cell carcinoma and in 2010 for subependymal giant cell astrocytoma.

In the pivotal, double-blind, placebo-controlled phase III study, in patients with unresectable or metastatic biopsy-proven PNET, 207 patients treated with 10 mg of everolimus daily plus best supportive care were compared with 203 patients on placebo and best supportive care. Almost all patients enrolled had metastatic disease.

The primary end point, median progression-free survival as determined by the investigators, was 11 months in the everolimus arm, compared with 4.6 months in the placebo arm, a reduced risk of 65% that was statistically significant. There was no difference in overall survival between the two groups.

There were 12 deaths in the treatment group: 5 due to disease progression and 7 due to an adverse event related to treatment. In the placebo group, there were 4 deaths, 3 due to disease progression. Sixty-two percent of those on everolimus had a grade 3/4 adverse event, compared with 40% of those on placebo. Pneumonitis, opportunistic infections, and renal failure were among the significant adverse events associated with everolimus therapy.

The incidence of pancreatic neuroendocrine tumors is about 3 per million people a year, according to Novartis. A decision on approval is expected in the second quarter of this year, according to a Novartis spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict, but that did not occur at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 10-0 that everolimus had a favorable risk-benefit profile when used to treat people with advanced pancreatic neuroendocrine tumors, but cautioned that it should not be used in all patients with this diagnosis.

At their April 12 meeting, members of the FDA’s Oncologic Drugs Advisory Committee cited the unmet need for treatments for this rare disease and evidence that everolimus (Afinitor) is effective in some patients with more aggressive disease.

They cautioned, however, that it should not be used in every patient with advanced pancreatic neuroendocrine tumors (PNET). The disease can be indolent, they noted, and there was evidence that everolimus has a more favorable risk-benefit profile in patients with progressive disease.

The panel members recommended that more work be done to identify the subset of patients with the disease who can benefit most from treatment with everolimus. They also recommended that it not be used to treat patients with carcinoid tumors because it has not been shown to be effective and may be harmful in this population.

Novartis Pharmaceuticals Corp., which markets Afinitor, has proposed that it be approved for the treatment of patients with advanced PNET. Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a key protein kinase that regulates cell growth, proliferation, and survival. It was approved in the United States in 2009 for treating advanced renal cell carcinoma and in 2010 for subependymal giant cell astrocytoma.

In the pivotal, double-blind, placebo-controlled phase III study, in patients with unresectable or metastatic biopsy-proven PNET, 207 patients treated with 10 mg of everolimus daily plus best supportive care were compared with 203 patients on placebo and best supportive care. Almost all patients enrolled had metastatic disease.

The primary end point, median progression-free survival as determined by the investigators, was 11 months in the everolimus arm, compared with 4.6 months in the placebo arm, a reduced risk of 65% that was statistically significant. There was no difference in overall survival between the two groups.

There were 12 deaths in the treatment group: 5 due to disease progression and 7 due to an adverse event related to treatment. In the placebo group, there were 4 deaths, 3 due to disease progression. Sixty-two percent of those on everolimus had a grade 3/4 adverse event, compared with 40% of those on placebo. Pneumonitis, opportunistic infections, and renal failure were among the significant adverse events associated with everolimus therapy.

The incidence of pancreatic neuroendocrine tumors is about 3 per million people a year, according to Novartis. A decision on approval is expected in the second quarter of this year, according to a Novartis spokesperson.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA prior to meetings; occasionally, the FDA grants a waiver to a panelist with a conflict, but that did not occur at this meeting.