title: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
abstract: BACKGROUND
  In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown.
  
  
  METHODS
  We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival.
  
  
  RESULTS
  The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.
  
  
  CONCLUSIONS
  Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114, USA. ashaw1@partners.org
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinó
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Pas
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Shrividya
authors.initials: S
authors.lastname: Iyer
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tassell
authors.forename: Anna
authors.initials: A
authors.lastname: Polli
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D000077547:Crizotinib; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005971:Glutamates / Q000009:adverse effects / Q000627:therapeutic use; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D000077547:Crizotinib; D006147:Guanine