PMID- 21306238 OWN - NLM STAT- MEDLINE DCOM- 20110217 LR - 20220419 IS - 1533-4406 (Electronic) IS - 0028-4793 (Print) IS - 0028-4793 (Linking) VI - 364 IP - 6 DP - 2011 Feb 10 TI - Everolimus for advanced pancreatic neuroendocrine tumors. PG - 514-23 LID - 10.1056/NEJMoa1009290 [doi] AB - 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.). FAU - Yao, James C AU - Yao JC AD - University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jyao@mdanderson.org FAU - Shah, Manisha H AU - Shah MH FAU - Ito, Tetsuhide AU - Ito T FAU - Bohas, Catherine Lombard AU - Bohas CL FAU - Wolin, Edward M AU - Wolin EM FAU - Van Cutsem, Eric AU - Van Cutsem E FAU - Hobday, Timothy J AU - Hobday TJ FAU - Okusaka, Takuji AU - Okusaka T FAU - Capdevila, Jaume AU - Capdevila J FAU - de Vries, Elisabeth G E AU - de Vries EG FAU - Tomassetti, Paola AU - Tomassetti P FAU - Pavel, Marianne E AU - Pavel ME FAU - Hoosen, Sakina AU - Hoosen S FAU - Haas, Tomas AU - Haas T FAU - Lincy, Jeremie AU - Lincy J FAU - Lebwohl, David AU - Lebwohl D FAU - Oberg, Kjell AU - Oberg K CN - RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group LA - eng SI - ClinicalTrials.gov/NCT00510068 GR - P30 CA016058/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - N Engl J Med. 2011 Feb 10;364(6):564-5. PMID: 21306243 CIN - Nat Rev Clin Oncol. 2011 Apr;8(4):191. PMID: 21451489 CIN - N Engl J Med. 2011 May 12;364(19):1873; author reply 1873-5. PMID: 21561355 CIN - Z Gastroenterol. 2011 Nov;49(11):1489-90. PMID: 22069050 MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/adverse effects/*therapeutic use MH - Disease Progression MH - Double-Blind Method MH - Everolimus MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Neuroendocrine Tumors/*drug therapy/mortality MH - Pancreatic Neoplasms/*drug therapy/mortality MH - Proportional Hazards Models MH - Protein Kinase Inhibitors/*therapeutic use MH - Sirolimus/adverse effects/*analogs & derivatives/therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Young Adult PMC - PMC4208619 MID - NIHMS633685 EDAT- 2011/02/11 06:00 MHDA- 2011/02/18 06:00 PMCR- 2014/10/24 CRDT- 2011/02/11 06:00 PHST- 2011/02/11 06:00 [entrez] PHST- 2011/02/11 06:00 [pubmed] PHST- 2011/02/18 06:00 [medline] PHST- 2014/10/24 00:00 [pmc-release] AID - 10.1056/NEJMoa1009290 [doi] PST - ppublish SO - N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.