Everolimus Gets Nod for Pancreatic Neuroendocrine Tumors

The U.S. Food and Drug Administration has approved everolimus as the first new drug in roughly 30 years for the treatment of advanced pancreatic neuroendocrine tumors.

The move was widely anticipated following the unanimous vote last month by the FDA’s Oncologic Drugs Advisory Committee (ODAC) that the drug’s benefit outweighs its risks for this disease. Everolimus is marketed as Afinitor by Novartis, and fills a therapeutic void for this rare, slow-growing cancer.

"Patients with this cancer have few effective treatment options," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Afinitor has demonstrated the ability to slow the growth and spread of neuroendocrine tumors of the pancreas."

Dr. Johanna Bendell, director of GI oncology research at the Sarah Cannon Research Institute in Nashville, said in an interview that for patients with advanced disease, the only approved therapies had been cytotoxic regimens that carry the potential for significant side effects with questionable benefit.

"This approval is an important step forward in the treatment of patients with PNET [pancreatic neuroendocrine tumors] who formerly had limited treatment options," she said. "We hope to see a second agent approved for these patients in the near future."

Indeed, it’s possible that patients with PNET may have an additional option in the coming months. At the same April 12 advisory meeting in which everolimus received unanimous support, ODAC voted 8-2 in favor of Pfizer’s sunitinib malate (Sutent) for treating patients with unresectable PNET. Some reservations were expressed over the magnitude of the drug’s effect on progression-free survival in a key trial that was terminated early because of significant benefits in the sunitinib arm compared with a placebo.

Pfizer continues to work closely with the FDA to finalize its review of Sutent’s supplemental new drug application for PNET in an effort to continue to advance treatment for this disease.

"What we can say at this time is that a decision from the FDA is expected by mid-year," Christopher Loder, Pfizer head of U.S. media relations, said in an interview.

Fewer than 1,000 new cases of PNET are estimated to occur in the United States each year. The FDA announcement specifies that everolimus is indicated for patients with progressive tumors "that cannot be removed by surgery or that have spread to other parts of the body (metastatic)."

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was approved on the strength of the phase III RADIANT-3 trial in 410 patients with advanced low- or intermediate grade PNET. Everolimus 10 mg per day plus best supportive care provided a median gain of 6.4 months of progression-free survival when compared with best supportive care alone (11 months vs. 4.6 months). This translated into a significant 65% reduction in the risk of progression compared with placebo.

"Everolimus should be considered the standard of care for patients with [advanced pancreatic] neuroendocrine tumors," Dr. James C. Yao, with the University of Texas M.D. Anderson Cancer Center in Houston, said when presenting the RADIANT-3 findings at last year’s European Society for Medical Oncology meeting in Milan.

In the RADIANT-3 trial, 62% of patient 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 most commonly reported side effects included inflammation of the mouth, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever and headache.

Importantly, ODAC members cautioned that everolimus and sunitinib shouldn’t automatically be given to all patients with PNET, noting the often indolent nature of the cancer and that the treatments appear to have a more favorable risk-benefit profile in patients with aggressive disease.

Panelists 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.

Several ODAC panelists also pointed out that sunitinib’s labeling should indicate that most patients in the phase III pivotal trial had metastatic disease and that sunitinib should not be used to treat patients with indolent forms of the disease.

Dr. Bendell pointed out that that benefits from everolimus and sunitinib were comparable. When the data were unblinded from the phase III sunitinib trial, the significant improvement in progression-free survival for patients had a hazard ratio of 0.418. The phase III everolimus vs. placebo study also showed a significant improvement in progression-free survival, (HR, 0.34).

"There is really no known specific benefit over sunitinib or vice versa, as noted in the PFS data," she said. "The hazard ratios were the same."

Other currently available treatment options for patients with PNET include interferon, somatostatin analogs, metabolic radiotherapy, and chemotherapy.

Everolimus was approved in the United States in 2009 for treating advanced renal cell carcinoma, and in 2010 for subependymal giant cell astrocytoma. It is also known by the trade name Zortress and is used in some adults to prevent organ rejection after kidney transplantation.

* This article was updated with additional information on 5/7/2011.

The U.S. Food and Drug Administration has approved everolimus as the first new drug in roughly 30 years for the treatment of advanced pancreatic neuroendocrine tumors.

The move was widely anticipated following the unanimous vote last month by the FDA’s Oncologic Drugs Advisory Committee (ODAC) that the drug’s benefit outweighs its risks for this disease. Everolimus is marketed as Afinitor by Novartis, and fills a therapeutic void for this rare, slow-growing cancer.

"Patients with this cancer have few effective treatment options," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Afinitor has demonstrated the ability to slow the growth and spread of neuroendocrine tumors of the pancreas."

Dr. Johanna Bendell, director of GI oncology research at the Sarah Cannon Research Institute in Nashville, said in an interview that for patients with advanced disease, the only approved therapies had been cytotoxic regimens that carry the potential for significant side effects with questionable benefit.

"This approval is an important step forward in the treatment of patients with PNET [pancreatic neuroendocrine tumors] who formerly had limited treatment options," she said. "We hope to see a second agent approved for these patients in the near future."

Indeed, it’s possible that patients with PNET may have an additional option in the coming months. At the same April 12 advisory meeting in which everolimus received unanimous support, ODAC voted 8-2 in favor of Pfizer’s sunitinib malate (Sutent) for treating patients with unresectable PNET. Some reservations were expressed over the magnitude of the drug’s effect on progression-free survival in a key trial that was terminated early because of significant benefits in the sunitinib arm compared with a placebo.

Pfizer continues to work closely with the FDA to finalize its review of Sutent’s supplemental new drug application for PNET in an effort to continue to advance treatment for this disease.

"What we can say at this time is that a decision from the FDA is expected by mid-year," Christopher Loder, Pfizer head of U.S. media relations, said in an interview.

Fewer than 1,000 new cases of PNET are estimated to occur in the United States each year. The FDA announcement specifies that everolimus is indicated for patients with progressive tumors "that cannot be removed by surgery or that have spread to other parts of the body (metastatic)."

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was approved on the strength of the phase III RADIANT-3 trial in 410 patients with advanced low- or intermediate grade PNET. Everolimus 10 mg per day plus best supportive care provided a median gain of 6.4 months of progression-free survival when compared with best supportive care alone (11 months vs. 4.6 months). This translated into a significant 65% reduction in the risk of progression compared with placebo.

"Everolimus should be considered the standard of care for patients with [advanced pancreatic] neuroendocrine tumors," Dr. James C. Yao, with the University of Texas M.D. Anderson Cancer Center in Houston, said when presenting the RADIANT-3 findings at last year’s European Society for Medical Oncology meeting in Milan.

In the RADIANT-3 trial, 62% of patient 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 most commonly reported side effects included inflammation of the mouth, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever and headache.

Importantly, ODAC members cautioned that everolimus and sunitinib shouldn’t automatically be given to all patients with PNET, noting the often indolent nature of the cancer and that the treatments appear to have a more favorable risk-benefit profile in patients with aggressive disease.

Panelists 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.

Several ODAC panelists also pointed out that sunitinib’s labeling should indicate that most patients in the phase III pivotal trial had metastatic disease and that sunitinib should not be used to treat patients with indolent forms of the disease.

Dr. Bendell pointed out that that benefits from everolimus and sunitinib were comparable. When the data were unblinded from the phase III sunitinib trial, the significant improvement in progression-free survival for patients had a hazard ratio of 0.418. The phase III everolimus vs. placebo study also showed a significant improvement in progression-free survival, (HR, 0.34).

"There is really no known specific benefit over sunitinib or vice versa, as noted in the PFS data," she said. "The hazard ratios were the same."

Other currently available treatment options for patients with PNET include interferon, somatostatin analogs, metabolic radiotherapy, and chemotherapy.

Everolimus was approved in the United States in 2009 for treating advanced renal cell carcinoma, and in 2010 for subependymal giant cell astrocytoma. It is also known by the trade name Zortress and is used in some adults to prevent organ rejection after kidney transplantation.

* This article was updated with additional information on 5/7/2011.

The U.S. Food and Drug Administration has approved everolimus as the first new drug in roughly 30 years for the treatment of advanced pancreatic neuroendocrine tumors.

The move was widely anticipated following the unanimous vote last month by the FDA’s Oncologic Drugs Advisory Committee (ODAC) that the drug’s benefit outweighs its risks for this disease. Everolimus is marketed as Afinitor by Novartis, and fills a therapeutic void for this rare, slow-growing cancer.

"Patients with this cancer have few effective treatment options," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Afinitor has demonstrated the ability to slow the growth and spread of neuroendocrine tumors of the pancreas."

Dr. Johanna Bendell, director of GI oncology research at the Sarah Cannon Research Institute in Nashville, said in an interview that for patients with advanced disease, the only approved therapies had been cytotoxic regimens that carry the potential for significant side effects with questionable benefit.

"This approval is an important step forward in the treatment of patients with PNET [pancreatic neuroendocrine tumors] who formerly had limited treatment options," she said. "We hope to see a second agent approved for these patients in the near future."

Indeed, it’s possible that patients with PNET may have an additional option in the coming months. At the same April 12 advisory meeting in which everolimus received unanimous support, ODAC voted 8-2 in favor of Pfizer’s sunitinib malate (Sutent) for treating patients with unresectable PNET. Some reservations were expressed over the magnitude of the drug’s effect on progression-free survival in a key trial that was terminated early because of significant benefits in the sunitinib arm compared with a placebo.

Pfizer continues to work closely with the FDA to finalize its review of Sutent’s supplemental new drug application for PNET in an effort to continue to advance treatment for this disease.

"What we can say at this time is that a decision from the FDA is expected by mid-year," Christopher Loder, Pfizer head of U.S. media relations, said in an interview.

Fewer than 1,000 new cases of PNET are estimated to occur in the United States each year. The FDA announcement specifies that everolimus is indicated for patients with progressive tumors "that cannot be removed by surgery or that have spread to other parts of the body (metastatic)."

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was approved on the strength of the phase III RADIANT-3 trial in 410 patients with advanced low- or intermediate grade PNET. Everolimus 10 mg per day plus best supportive care provided a median gain of 6.4 months of progression-free survival when compared with best supportive care alone (11 months vs. 4.6 months). This translated into a significant 65% reduction in the risk of progression compared with placebo.

"Everolimus should be considered the standard of care for patients with [advanced pancreatic] neuroendocrine tumors," Dr. James C. Yao, with the University of Texas M.D. Anderson Cancer Center in Houston, said when presenting the RADIANT-3 findings at last year’s European Society for Medical Oncology meeting in Milan.

In the RADIANT-3 trial, 62% of patient 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 most commonly reported side effects included inflammation of the mouth, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever and headache.

Importantly, ODAC members cautioned that everolimus and sunitinib shouldn’t automatically be given to all patients with PNET, noting the often indolent nature of the cancer and that the treatments appear to have a more favorable risk-benefit profile in patients with aggressive disease.

Panelists 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.

Several ODAC panelists also pointed out that sunitinib’s labeling should indicate that most patients in the phase III pivotal trial had metastatic disease and that sunitinib should not be used to treat patients with indolent forms of the disease.

Dr. Bendell pointed out that that benefits from everolimus and sunitinib were comparable. When the data were unblinded from the phase III sunitinib trial, the significant improvement in progression-free survival for patients had a hazard ratio of 0.418. The phase III everolimus vs. placebo study also showed a significant improvement in progression-free survival, (HR, 0.34).

"There is really no known specific benefit over sunitinib or vice versa, as noted in the PFS data," she said. "The hazard ratios were the same."

Other currently available treatment options for patients with PNET include interferon, somatostatin analogs, metabolic radiotherapy, and chemotherapy.

Everolimus was approved in the United States in 2009 for treating advanced renal cell carcinoma, and in 2010 for subependymal giant cell astrocytoma. It is also known by the trade name Zortress and is used in some adults to prevent organ rejection after kidney transplantation.

* This article was updated with additional information on 5/7/2011.