title: A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens.
abstract: BACKGROUND
  AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count.
  
  
  RESULTS
  Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed.
  
  
  CONCLUSIONS
  Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN 37203, USA. jhainsworth@tnonc.com
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Cebotaru
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kanarev
authors.forename: Tudor E
authors.initials: TE
authors.lastname: Ciuleanu
authors.forename: Danail
authors.initials: D
authors.lastname: Damyanov
authors.forename: Phillip
authors.initials: P
authors.lastname: Stella
authors.forename: Hristo
authors.initials: H
authors.lastname: Ganchev
authors.forename: Gillian
authors.initials: G
authors.lastname: Pover
authors.forename: Clive
authors.initials: C
authors.lastname: Morris
authors.forename: Valentina
authors.initials: V
authors.lastname: Tzekova
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D012449:Safety; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C517975:AZD 6244; D000964:Antimetabolites, Antineoplastic; D001562:Benzimidazoles; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine