title: Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer.
abstract: OBJECTIVE
  The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.
  
  
  METHODS
  Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival.
  
  
  RESULTS
  Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as > or = 50% reduction in serum CA19-9.
  
  
  CONCLUSIONS
  Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA. bwolpin@partners.org
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Thomas
authors.initials: T
authors.lastname: Abrams
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Brittany
authors.initials: B
authors.lastname: Allen
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000068338:Everolimus; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine; C546842:MTOR protein, human