Everolimus for advanced pancreatic neuroendocrine tumors
- PMID: 21306238
- PMCID: PMC4208619
- DOI: 10.1056/NEJMoa1009290
Everolimus for advanced pancreatic neuroendocrine tumors
Abstract
Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.
Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.
Results: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).
Conclusions: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
Figures
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Comment in
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Promising advances in the treatment of malignant pancreatic endocrine tumors.N Engl J Med. 2011 Feb 10;364(6):564-5. doi: 10.1056/NEJMe1013903. N Engl J Med. 2011. PMID: 21306243 No abstract available.
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Targeted therapies: hope for pancreatic neuroendocrine tumors.Nat Rev Clin Oncol. 2011 Mar 15;8(4):191. doi: 10.1038/nrclinonc.2011.33. Nat Rev Clin Oncol. 2011. PMID: 21451489 No abstract available.
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Advances in pancreatic neuroendocrine tumor treatment.N Engl J Med. 2011 May 12;364(19):1873; author reply 1873-5. doi: 10.1056/NEJMc1102746. N Engl J Med. 2011. PMID: 21561355 No abstract available.
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[Improved survival in patients with NET of the pancreas with molecular therapies].Z Gastroenterol. 2011 Nov;49(11):1489-90. doi: 10.1055/s-0031-1281595. Epub 2011 Nov 8. Z Gastroenterol. 2011. PMID: 22069050 German. No abstract available.
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