title: Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in this multicenter phase II trial.
  
  
  METHODS
  Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib.
  
  
  RESULTS
  One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib.
  
  
  CONCLUSIONS
  Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.
authors.affiliation: Sarah Cannon Research Institute, 250 25th Ave North, Ste 110, Nashville, TN 37203, USA. dspigel@tnonc.com
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
authors.forename: Dianna L
authors.initials: DL
authors.lastname: Shipley
authors.forename: Elke K
authors.initials: EK
authors.lastname: Friedman
authors.forename: David M
authors.initials: DM
authors.lastname: Waterhouse
authors.forename: Robert C
authors.initials: RC
authors.lastname: Whorf
authors.forename: R Brian
authors.initials: RB
authors.lastname: Mitchell
authors.forename: Davey B
authors.initials: DB
authors.lastname: Daniel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Zangmeister
authors.forename: J David
authors.initials: JD
authors.lastname: Bass
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D018773:Genes, erbB-1; D011905:Genes, ras; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016879:Salvage Therapy; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride