title: Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer.
abstract: OBJECTIVE
  This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m(2) per day on days 1 and 8) and cisplatin (75 mg/m(2) on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP).
  
  
  RESULTS
  The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed.
  
  
  CONCLUSIONS
  This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.
authors.affiliation: Medical Oncology Department, Hospital Universitario Virgen del Rocío, Instituto de Investigaciones Biomédicas de Sevilla, Avenida Manuel Siurot s/n, Seville, Spain 41013. lpazares@hotmail.com
authors.forename: Luis G
authors.initials: LG
authors.lastname: Paz-Ares
authors.forename: Bonne
authors.initials: B
authors.lastname: Biesma
authors.forename: David
authors.initials: D
authors.lastname: Heigener
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Timothy
authors.initials: T
authors.lastname: Eisen
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Meilin
authors.initials: M
authors.lastname: Liao
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Steven
authors.initials: S
authors.lastname: Gans
authors.forename: Kostas
authors.initials: K
authors.lastname: Syrigos
authors.forename: Etienne
authors.initials: E
authors.lastname: Le Marie
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
authors.forename: Johan
authors.initials: J
authors.lastname: Vansteenkiste
authors.forename: Vincente
authors.initials: V
authors.lastname: Alberola
authors.forename: Uwe Phillip
authors.initials: UP
authors.lastname: Strauss
authors.forename: Elaine
authors.initials: E
authors.lastname: Montegriffo
authors.forename: Teng Jin
authors.initials: TJ
authors.lastname: Ong
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D002945:Cisplatin; D000093542:Gemcitabine