Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.

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.).

• Authors: 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
• Journal: The New England journal of medicine (N Engl J Med) Vol. 364 Issue 6 Pg. 501-13 (Feb 10 2011) ISSN: 1533-4406 [Electronic] United States
• PMID: 21306237 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• Pyrroles
• Receptors, Vascular Endothelial Growth Factor
• Sunitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Disease Progression
• Double-Blind Method
• Female
• Humans
• Indoles (adverse effects, therapeutic use)
• Intention to Treat Analysis
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neuroendocrine Tumors (drug therapy, mortality)
• Pancreatic Neoplasms (drug therapy, mortality)
• Proportional Hazards Models
• Protein Kinase Inhibitors (therapeutic use)
• Pyrroles (adverse effects, therapeutic use)
• Quality of Life
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Sunitinib