Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

Eric Raymond, Laetitia Dahan, Jean Luc Raoul, Yung Jue Bang, Ivan Borbath, Catherine Lombard-Bohas, Juan Valle, Peter Metrakos, Denis Smith, Aaron Vinik, Jen Shi Chen, Dieter Hörsch, Pascal Hammel, Bertram Wiedenmann, Eric Van Cutsem, Shem Patyna, Dongrui Ray Lu, Carolyn Blanckmeister, Richard Chao, Philippe Ruszniewski

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Abstract

BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)

Original languageEnglish
Pages (from-to)501-513
Number of pages13
JournalNew England Journal of Medicine
Volume364
Issue number6
DOIs
StatePublished - 10 Feb 2011

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Neuroendocrine Tumors
Placebos
Disease-Free Survival
Therapeutics
Clinical Trials Data Monitoring Committees
sunitinib
Confidence Intervals
Safety
Asthenia
Protein-Tyrosine Kinases
Nausea
Vomiting
Fatigue
Disease Progression
Diarrhea
Survival Rate
Survival

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Raymond, E., Dahan, L., Raoul, J. L., Bang, Y. J., Borbath, I., Lombard-Bohas, C., ... Ruszniewski, P. (2011). Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine, 364(6), 501-513. https://doi.org/10.1056/NEJMoa1003825
Raymond, Eric ; Dahan, Laetitia ; Raoul, Jean Luc ; Bang, Yung Jue ; Borbath, Ivan ; Lombard-Bohas, Catherine ; Valle, Juan ; Metrakos, Peter ; Smith, Denis ; Vinik, Aaron ; Chen, Jen Shi ; Hörsch, Dieter ; Hammel, Pascal ; Wiedenmann, Bertram ; Van Cutsem, Eric ; Patyna, Shem ; Lu, Dongrui Ray ; Blanckmeister, Carolyn ; Chao, Richard ; Ruszniewski, Philippe. / Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. In: New England Journal of Medicine. 2011 ; Vol. 364, No. 6. pp. 501-513.
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abstract = "BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95{\%} confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3{\%} in the sunitinib group versus 0{\%} in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10{\%}) versus 21 deaths in the placebo group (25{\%}) (hazard ratio for death, 0.41; 95{\%} CI, 0.19 to 0.89; P = 0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)",
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Raymond, E, Dahan, L, Raoul, JL, Bang, YJ, Borbath, I, Lombard-Bohas, C, Valle, J, Metrakos, P, Smith, D, Vinik, A, Chen, JS, Hörsch, D, Hammel, P, Wiedenmann, B, Van Cutsem, E, Patyna, S, Lu, DR, Blanckmeister, C, Chao, R & Ruszniewski, P 2011, 'Sunitinib malate for the treatment of pancreatic neuroendocrine tumors', New England Journal of Medicine, vol. 364, no. 6, pp. 501-513. https://doi.org/10.1056/NEJMoa1003825

Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. / Raymond, Eric; Dahan, Laetitia; Raoul, Jean Luc; Bang, Yung Jue; Borbath, Ivan; Lombard-Bohas, Catherine; Valle, Juan; Metrakos, Peter; Smith, Denis; Vinik, Aaron; Chen, Jen Shi; Hörsch, Dieter; Hammel, Pascal; Wiedenmann, Bertram; Van Cutsem, Eric; Patyna, Shem; Lu, Dongrui Ray; Blanckmeister, Carolyn; Chao, Richard; Ruszniewski, Philippe.

In: New England Journal of Medicine, Vol. 364, No. 6, 10.02.2011, p. 501-513.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

AU - Raymond, Eric

AU - Dahan, Laetitia

AU - Raoul, Jean Luc

AU - Bang, Yung Jue

AU - Borbath, Ivan

AU - Lombard-Bohas, Catherine

AU - Valle, Juan

AU - Metrakos, Peter

AU - Smith, Denis

AU - Vinik, Aaron

AU - Chen, Jen Shi

AU - Hörsch, Dieter

AU - Hammel, Pascal

AU - Wiedenmann, Bertram

AU - Van Cutsem, Eric

AU - Patyna, Shem

AU - Lu, Dongrui Ray

AU - Blanckmeister, Carolyn

AU - Chao, Richard

AU - Ruszniewski, Philippe

PY - 2011/2/10

Y1 - 2011/2/10

N2 - BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)

AB - BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)

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DO - 10.1056/NEJMoa1003825

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