RADIANT Trials: Everolimus Outshines Placebo in Neuroendocrine Tumors

MILAN – Everolimus gave a 5.1-month gain in median progression-free survival when it was added to the standard therapy of octreotide LAR in the treatment of patients with advanced nonpancreatic neuroendocrine tumors in the phase III RADIANT-2 trial.

In the treatment of advanced pancreatic neuroendocrine tumors, everolimus (Afinitor) was also associated with a significant 6.4-month increase in median progression-free survival vs. placebo when it was added to the best supportive care in the RADIANT-3 trial (P less than .0001).

Based on these results reported at the annual meeting of the European Society for Medical Oncology, Novartis has announced that it will seek regulatory approvals worldwide for everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Everolimus is approved in advanced renal cell cancer that has not improved after treatment with sunitinib (Sutent) or sorafenib (Nexavar).

RADIANT-2: Nonpancreatic NET

Neuroendocrine tumors (NETs) are a rare form of cancer arising from hormone-producing cells. Although the result of the RADIANT-2 trial “just missed statistical significance” (P = .026) at the predetermined level set by the study’s design (P = .0246), the findings are important, as they expand treatment options for patients with this difficult-to-treat tumor type said Dr. Marianne Pavel, who reported results of the Novartis-sponsored trial.

“We really have an unmet medical need ... and for the first time we have a drug that may work in this type of neuroendocrine tumor,” Dr. Pavel, professor of neuroendocrine disease at the Charité Medical University Berlin, said in an interview. She noted that advanced NET could be fatal within 5 years of diagnosis in about two-thirds of patients.

The 429 patients who were randomized into the trial between January 2007 and March 2008 all had advanced NET with a history of carcinoid symptoms. Of these, 216 patients were assigned to everolimus 10 mg/day and octreotide LAR (Sandostatin LAR Depot) 30 mg every 28 days, and 213 received the somatostatin analog plus placebo.

Median progression-free survival reached 16.4 months with everolimus vs. 11.3 months in the control arm (hazard ratio, 0.77), with benefits seen in all subgroups.

Interim analysis demonstrated no overall gain in overall survival (HR, 1.22; P = .908), with 2-year overall survival rates of 57.1% in the everolimus–octreotide LAR arm vs. 63.3% in the placebo–octreotide LAR arm. Another 67 events are needed before the final overall survival analysis can be performed, however.

The tolerability of the combination was acceptable, Dr. Pavel noted, with all-grade stomatitis (62% vs. 14%), infections (20% vs. 6%), and pulmonary events (12% vs. 0%) more common in the experimental arm than in the control arm.

“The everolimus and octreotide LAR combination demonstrates a clinically meaningful prolongation” of median progression-free survival, Dr. Pavel said. “Together with the data from the RADIANT-3 trial, these results support the efficacy in advanced NET. We now need to establish the subpopulations that might benefit from this combination, and from the early use of this combination.”

RADIANT-3: Pancreatic NET

“Everolimus should be considered a standard of care for patients with [advanced pancreatic] neuroendocrine tumors,” said Dr. James C. Yao, who presented the RADIANT-3 findings.

The trial randomized 410 patients with advanced low- or intermediate-grade NET to 10 mg/day of everolimus plus best supportive care or to best supportive care plus placebo until progression.

Dr. Yao of the University of Texas M.D. Anderson Cancer Center in Houston reported that everolimus produced a statistically significant 65% reduction in the risk for progression, compared with placebo (P less than .0001). Median progression-free survival was 11 months with everolimus plus best supportive care, compared with 4.6 months for placebo plus best supportive care. All subgroups benefited from everolimus.

Overall survival was not different, but 148 control arm patients received everolimus after their disease progressed.

“The 18-months’ progression-free survival rate of 34% vs. 9% for placebo demonstrates that the benefit provided by everolimus is durable,” Dr. Yao said.

Commenting on the two RADIANT trials, Dr. Michel Ducreux of the Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the treatment of well-differentiated NET has changed. Clearly the RADIANT-3 results show that everolimus is now an option alongside others such as interferon, somatostatin analogs, metabolic radiotherapy, sunitinib, and chemotherapy.

For nonpancreatic NET, however, the situation is less clear. “We have less weapons to fight the disease,” Dr. Ducreux said, noting that it does not respond well to chemotherapy.

“A lot of treatments are more active in pancreatic NET than in nonpancreatic NET,” he added with the observation that pancreatic NET is more aggressive, but easier to treat.

In a press statement, Dr. Roberto Labianca from the Ospedali Riuniti di Bergamo (Italy) said of the RADIANT-2 results, “This trial should be considered a practice-changing achievement, but it is essential that selection criteria are refined in order to identify the population more likely to respond to this approach.”

Novartis sponsored both studies. Dr. Pavel and Dr. Yao and several coauthors have received honoraria, consultancy fees, and research support from Novartis, or were employees or stockholders in the company. Dr. Yao has also received research support from Genentech Inc. and acted as an advisor to the Ipsen Group, Pfizer Inc., and Endo Pharmaceuticals. Dr. Ducreux had no personal disclosures other than noting some of his patients had been treated in RADIANT-2 and -3.

MILAN – Everolimus gave a 5.1-month gain in median progression-free survival when it was added to the standard therapy of octreotide LAR in the treatment of patients with advanced nonpancreatic neuroendocrine tumors in the phase III RADIANT-2 trial.

In the treatment of advanced pancreatic neuroendocrine tumors, everolimus (Afinitor) was also associated with a significant 6.4-month increase in median progression-free survival vs. placebo when it was added to the best supportive care in the RADIANT-3 trial (P less than .0001).

Based on these results reported at the annual meeting of the European Society for Medical Oncology, Novartis has announced that it will seek regulatory approvals worldwide for everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Everolimus is approved in advanced renal cell cancer that has not improved after treatment with sunitinib (Sutent) or sorafenib (Nexavar).

RADIANT-2: Nonpancreatic NET

Neuroendocrine tumors (NETs) are a rare form of cancer arising from hormone-producing cells. Although the result of the RADIANT-2 trial “just missed statistical significance” (P = .026) at the predetermined level set by the study’s design (P = .0246), the findings are important, as they expand treatment options for patients with this difficult-to-treat tumor type said Dr. Marianne Pavel, who reported results of the Novartis-sponsored trial.

“We really have an unmet medical need ... and for the first time we have a drug that may work in this type of neuroendocrine tumor,” Dr. Pavel, professor of neuroendocrine disease at the Charité Medical University Berlin, said in an interview. She noted that advanced NET could be fatal within 5 years of diagnosis in about two-thirds of patients.

The 429 patients who were randomized into the trial between January 2007 and March 2008 all had advanced NET with a history of carcinoid symptoms. Of these, 216 patients were assigned to everolimus 10 mg/day and octreotide LAR (Sandostatin LAR Depot) 30 mg every 28 days, and 213 received the somatostatin analog plus placebo.

Median progression-free survival reached 16.4 months with everolimus vs. 11.3 months in the control arm (hazard ratio, 0.77), with benefits seen in all subgroups.

Interim analysis demonstrated no overall gain in overall survival (HR, 1.22; P = .908), with 2-year overall survival rates of 57.1% in the everolimus–octreotide LAR arm vs. 63.3% in the placebo–octreotide LAR arm. Another 67 events are needed before the final overall survival analysis can be performed, however.

The tolerability of the combination was acceptable, Dr. Pavel noted, with all-grade stomatitis (62% vs. 14%), infections (20% vs. 6%), and pulmonary events (12% vs. 0%) more common in the experimental arm than in the control arm.

“The everolimus and octreotide LAR combination demonstrates a clinically meaningful prolongation” of median progression-free survival, Dr. Pavel said. “Together with the data from the RADIANT-3 trial, these results support the efficacy in advanced NET. We now need to establish the subpopulations that might benefit from this combination, and from the early use of this combination.”

RADIANT-3: Pancreatic NET

“Everolimus should be considered a standard of care for patients with [advanced pancreatic] neuroendocrine tumors,” said Dr. James C. Yao, who presented the RADIANT-3 findings.

The trial randomized 410 patients with advanced low- or intermediate-grade NET to 10 mg/day of everolimus plus best supportive care or to best supportive care plus placebo until progression.

Dr. Yao of the University of Texas M.D. Anderson Cancer Center in Houston reported that everolimus produced a statistically significant 65% reduction in the risk for progression, compared with placebo (P less than .0001). Median progression-free survival was 11 months with everolimus plus best supportive care, compared with 4.6 months for placebo plus best supportive care. All subgroups benefited from everolimus.

Overall survival was not different, but 148 control arm patients received everolimus after their disease progressed.

“The 18-months’ progression-free survival rate of 34% vs. 9% for placebo demonstrates that the benefit provided by everolimus is durable,” Dr. Yao said.

Commenting on the two RADIANT trials, Dr. Michel Ducreux of the Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the treatment of well-differentiated NET has changed. Clearly the RADIANT-3 results show that everolimus is now an option alongside others such as interferon, somatostatin analogs, metabolic radiotherapy, sunitinib, and chemotherapy.

For nonpancreatic NET, however, the situation is less clear. “We have less weapons to fight the disease,” Dr. Ducreux said, noting that it does not respond well to chemotherapy.

“A lot of treatments are more active in pancreatic NET than in nonpancreatic NET,” he added with the observation that pancreatic NET is more aggressive, but easier to treat.

In a press statement, Dr. Roberto Labianca from the Ospedali Riuniti di Bergamo (Italy) said of the RADIANT-2 results, “This trial should be considered a practice-changing achievement, but it is essential that selection criteria are refined in order to identify the population more likely to respond to this approach.”

Novartis sponsored both studies. Dr. Pavel and Dr. Yao and several coauthors have received honoraria, consultancy fees, and research support from Novartis, or were employees or stockholders in the company. Dr. Yao has also received research support from Genentech Inc. and acted as an advisor to the Ipsen Group, Pfizer Inc., and Endo Pharmaceuticals. Dr. Ducreux had no personal disclosures other than noting some of his patients had been treated in RADIANT-2 and -3.

MILAN – Everolimus gave a 5.1-month gain in median progression-free survival when it was added to the standard therapy of octreotide LAR in the treatment of patients with advanced nonpancreatic neuroendocrine tumors in the phase III RADIANT-2 trial.

In the treatment of advanced pancreatic neuroendocrine tumors, everolimus (Afinitor) was also associated with a significant 6.4-month increase in median progression-free survival vs. placebo when it was added to the best supportive care in the RADIANT-3 trial (P less than .0001).

Based on these results reported at the annual meeting of the European Society for Medical Oncology, Novartis has announced that it will seek regulatory approvals worldwide for everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Everolimus is approved in advanced renal cell cancer that has not improved after treatment with sunitinib (Sutent) or sorafenib (Nexavar).

RADIANT-2: Nonpancreatic NET

Neuroendocrine tumors (NETs) are a rare form of cancer arising from hormone-producing cells. Although the result of the RADIANT-2 trial “just missed statistical significance” (P = .026) at the predetermined level set by the study’s design (P = .0246), the findings are important, as they expand treatment options for patients with this difficult-to-treat tumor type said Dr. Marianne Pavel, who reported results of the Novartis-sponsored trial.

“We really have an unmet medical need ... and for the first time we have a drug that may work in this type of neuroendocrine tumor,” Dr. Pavel, professor of neuroendocrine disease at the Charité Medical University Berlin, said in an interview. She noted that advanced NET could be fatal within 5 years of diagnosis in about two-thirds of patients.

The 429 patients who were randomized into the trial between January 2007 and March 2008 all had advanced NET with a history of carcinoid symptoms. Of these, 216 patients were assigned to everolimus 10 mg/day and octreotide LAR (Sandostatin LAR Depot) 30 mg every 28 days, and 213 received the somatostatin analog plus placebo.

Median progression-free survival reached 16.4 months with everolimus vs. 11.3 months in the control arm (hazard ratio, 0.77), with benefits seen in all subgroups.

Interim analysis demonstrated no overall gain in overall survival (HR, 1.22; P = .908), with 2-year overall survival rates of 57.1% in the everolimus–octreotide LAR arm vs. 63.3% in the placebo–octreotide LAR arm. Another 67 events are needed before the final overall survival analysis can be performed, however.

The tolerability of the combination was acceptable, Dr. Pavel noted, with all-grade stomatitis (62% vs. 14%), infections (20% vs. 6%), and pulmonary events (12% vs. 0%) more common in the experimental arm than in the control arm.

“The everolimus and octreotide LAR combination demonstrates a clinically meaningful prolongation” of median progression-free survival, Dr. Pavel said. “Together with the data from the RADIANT-3 trial, these results support the efficacy in advanced NET. We now need to establish the subpopulations that might benefit from this combination, and from the early use of this combination.”

RADIANT-3: Pancreatic NET

“Everolimus should be considered a standard of care for patients with [advanced pancreatic] neuroendocrine tumors,” said Dr. James C. Yao, who presented the RADIANT-3 findings.

The trial randomized 410 patients with advanced low- or intermediate-grade NET to 10 mg/day of everolimus plus best supportive care or to best supportive care plus placebo until progression.

Dr. Yao of the University of Texas M.D. Anderson Cancer Center in Houston reported that everolimus produced a statistically significant 65% reduction in the risk for progression, compared with placebo (P less than .0001). Median progression-free survival was 11 months with everolimus plus best supportive care, compared with 4.6 months for placebo plus best supportive care. All subgroups benefited from everolimus.

Overall survival was not different, but 148 control arm patients received everolimus after their disease progressed.

“The 18-months’ progression-free survival rate of 34% vs. 9% for placebo demonstrates that the benefit provided by everolimus is durable,” Dr. Yao said.

Commenting on the two RADIANT trials, Dr. Michel Ducreux of the Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the treatment of well-differentiated NET has changed. Clearly the RADIANT-3 results show that everolimus is now an option alongside others such as interferon, somatostatin analogs, metabolic radiotherapy, sunitinib, and chemotherapy.

For nonpancreatic NET, however, the situation is less clear. “We have less weapons to fight the disease,” Dr. Ducreux said, noting that it does not respond well to chemotherapy.

“A lot of treatments are more active in pancreatic NET than in nonpancreatic NET,” he added with the observation that pancreatic NET is more aggressive, but easier to treat.

In a press statement, Dr. Roberto Labianca from the Ospedali Riuniti di Bergamo (Italy) said of the RADIANT-2 results, “This trial should be considered a practice-changing achievement, but it is essential that selection criteria are refined in order to identify the population more likely to respond to this approach.”

Novartis sponsored both studies. Dr. Pavel and Dr. Yao and several coauthors have received honoraria, consultancy fees, and research support from Novartis, or were employees or stockholders in the company. Dr. Yao has also received research support from Genentech Inc. and acted as an advisor to the Ipsen Group, Pfizer Inc., and Endo Pharmaceuticals. Dr. Ducreux had no personal disclosures other than noting some of his patients had been treated in RADIANT-2 and -3.