title: Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer.
abstract: BACKGROUND
  Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC).
  
  
  METHODS
  Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily.
  
  
  RESULTS
  Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients.
  
  
  CONCLUSIONS
  For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Milton
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Gomez
authors.forename: Robert T
authors.initials: RT
authors.lastname: Heelan
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Barbara
authors.initials: B
authors.lastname: Pizzo
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
chemical_list: D011799:Quinazolines; D000068338:Everolimus; D000077156:Gefitinib; D020123:Sirolimus