title: First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
abstract: BACKGROUND
  The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown.
  
  
  METHODS
  We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review.
  
  
  RESULTS
  Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life.
  
  
  CONCLUSIONS
  Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).
authors.affiliation: From Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.); State Key Laboratory of South China, Hong Kong Cancer Institute, Department of Clinical Oncology, Chinese University of Hong Kong, Shatin (T. Mok), and Guangdong Lung Cancer Institute, Guangzhou (Y.-L.W.) - both in China; Seoul National University Hospital, Seoul, South Korea (D.-W.K.); Kinki University, Osaka, Japan (K.N.); Florida Hospital Cancer Institute, Orlando (T. Mekhail); Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona (E.F.); Istituto Toscano Tumori, Livorno (F.C.), and Pfizer Oncology, Milan (J.P., T.U., J.T.) - both in Italy; Pfizer Oncology (S.I.) and Pfizer Global Innovative Pharma Business (A.R.) - both in New York; Pfizer Oncology, La Jolla, CA (K.D.W.); and the Christie Hospital and Institute of Cancer Sciences, Manchester University, Manchester, United Kingdom (F.B.).
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Tarek
authors.initials: T
authors.lastname: Mekhail
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: Jolanda
authors.initials: J
authors.lastname: Paolini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Usari
authors.forename: Shrividya
authors.initials: S
authors.lastname: Iyer
authors.forename: Arlene
authors.initials: A
authors.lastname: Reisman
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tursi
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; 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*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000068437:Pemetrexed; D000077547:Crizotinib; D006147:Guanine; D016190:Carboplatin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D002945:Cisplatin