Sunitinib Improves Survival in Advanced Pancreatic Neuroendocrine Tumors

The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.

The oral tyrosine kinase inhibitor sunitinib doubled median progression-free survival for patients with advanced pancreatic neuroendocrine tumors from 5.5 months to 11.4 months in a randomized, placebo-controlled, phase III trial reported Feb. 9 in the New England Journal of Medicine.

The hazard ratio for disease progression with sunitinib (Sutent) was 0.42 (P less than .001). The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group, according to the published results (N. Engl. J. Med. 2011;364:501-13).

"An exploratory analysis to determine the potential influence of patient and tumor characteristics on treatment effect showed that in all subgroups analyzed, the hazard ratio for progression or death favored sunitinib," wrote Dr. Eric Raymond of the Hôpital Beaujon in Clichy, France, and his coinvestigators.

A separate trial (the RADIANT-3 study) reported in the same issue also produced significant improvements in progression-free survival for patients with advanced pancreatic neuroendocrine tumors (PNETs). In that 410-patient study, everolimus (Afinitor) at a dose of 10 mg/day caused a 65% reduction in the estimated risk of progression or death. Progression-free survival reached 11.0 months with everolimus vs. 4.6 months with placebo (P less than .001). At 18 months, the progression-free survival rate reached 34% with everolimus vs. 9% with placebo (N. Engl. J. Med. 2011;364:514-23).

[RADIANT Trials Show Benefit of Everolimus in Neuroendocrine Tumors]

The sunitinib trial randomized 171 patients to either 37.5 mg/day of oral sunitinib or matching placebo at 42 centers in 11 countries. It was halted after a data and safety monitoring committee recommended discontinuation in February 2009 because of the greater number of deaths and serious adverse events in the placebo group, based on 154 patients who had been randomized at that point.

The last patient received a study drug in April 2009, and patients were offered open-label sunitinib treatment in a separate trial. A total of 44 patients in the sunitinib group and 59 patients in the placebo group entered these studies.

Patients received sunitinib for a median of 4.6 months and placebo for a median of 3.7 months. In all, 19 patients (22%) who were randomly assigned to sunitinib remained on the study for more than 1 year, as did 4 patients randomly assigned to placebo (5%).

"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," wrote the investigators.

They reported there were 9 deaths in the sunitinib group (10%) vs. 21 deaths in the placebo group (25%). The hazard ratio for death was 0.41 (P = .02) in favor of sunitinib.

Eight patients on sunitinib had confirmed tumor responses (two complete responses and six partial responses) for an objective response rate of 9.3%. No objective responses were observed with placebo.

"Improvement in progression-free survival among patients who received sunitinib, as compared with those who received placebo, was achieved without adversely affecting the quality of life and, per a recently reported post hoc analysis, was associated with a delay in the time to deterioration in the quality of life and emotional and physical functioning," the investigators noted.

Sunitinib is active against vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). The trial results support "previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of VEGFRs and PDGFR," the investigators said.

Patients were eligible for the trial if they had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both. They could not be candidates for surgery. In addition, they had to have documented disease progression within the last 12 months based on RECIST (Response Evaluation Criteria in Solid Tumors), at least one measurable target lesion, and an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients could receive somatostatin analogues at the investigator’s discretion before and/or during the trial.

Most adverse events were grade 1 or 2 in severity. Among those who received sunitinib, each of the most common adverse events (diarrhea, nausea, asthenia, vomiting, and fatigue) occurred in more than 30% of patients. Palmar-plantar erythrodysesthesia and hypertension also were reported in 23% and 26% of patients, respectively. Neutropenia (12%) and hypertension (10%) were the most common grade 3 or 4 adverse events in patients who received sunitinib. The most common adverse events leading to discontinuation of sunitinib were fatigue (4%), diarrhea (2%), and cardiac failure (2%).

At least one dose interruption was reported in 30% and 12% of patients in the sunitinib and placebo groups, respectively. Adverse events were the primary reason for interruption.

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at improving disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," wrote Dr. Robert T. Jensen, a researcher at the Digestive Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, and Dr. Gianfranco Delle Fave, professor of gastroenterology at Sapienza University of Rome, in an accompanying editorial (N. Engl. J. Med. 2011;364:564-5).

However, a number of unanswered questions make that optimism guarded, according to the editorial. Will the improvement in disease-free survival seen with everolimus translate to improved overall survival? Will patients in this population need to continue taking these drugs for years, given that both seem primarily to stabilize disease, rather than cure it? If patients stop responding to one drug, can they be treated with the other or a combination of both? Can these drugs be used in the neoadjuvant or adjuvant setting, or in combination with other treatments?

Perhaps most importantly, it’s unclear how the side effect profiles will affect long-term adherence to treatment, particularly given that many patients have excellent quality of life with no treatment until late in the disease course.

The study was sponsored and designed by Pfizer, which makes Sutent. Data collection and statistical analyses were also performed by the company. In addition, the first draft of the article was prepared by Dr. Raymond with help from Pfizer and medical writers paid by the company. All of the study authors reported relevant financial relationships with Pfizer. Several coauthors are employed by Pfizer. Dr. Jensen and Dr. Delle Fave reported having no relevant financial relationships.