title: Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.
abstract: OBJECTIVE
  To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.
  
  
  METHODS
  Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).
  
  
  RESULTS
  A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance.
  
  
  CONCLUSIONS
  Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.
authors.affiliation: Authors' Affiliations: Departments of Thoracic/Head and Neck Medical Oncology, Biostatistics and Applied Mathematics, Translational Molecular Pathology, Diagnostic Imaging, Diagnostic Radiology, and Bioinformatics and Computational Biology; Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston; The Hamon Center for Therapeutic Oncology Research and Departments of Internal Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas; Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Charlotte, North Carolina; Medical Oncology, Yale Cancer Center, New Haven, Connecticut; Division of Medical Oncology, University of Ottawa, Ottawa, Ontario; Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland; UC San Diego Moores Cancer Center, La Jolla, California; and Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: Pierre
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authors.lastname: Saintigny
authors.forename: Suyu
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authors.lastname: Liu
authors.forename: Edward S
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authors.lastname: Kim
authors.forename: Anne S
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authors.lastname: Tsao
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Christine
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authors.lastname: Alden
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Merrill S
authors.initials: MS
authors.lastname: Kies
authors.forename: Frank V
authors.initials: FV
authors.lastname: Fossella
authors.forename: Hai T
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authors.lastname: Tran
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authors.lastname: Mao
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Hicks
authors.forename: Jeremy
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authors.lastname: Erasmus
authors.forename: Sanjay
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authors.lastname: Gupta
authors.forename: Luc
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authors.lastname: Girard
authors.forename: Michael
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authors.lastname: Peyton
authors.forename: Lixia
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authors.lastname: Diao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Davis
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib
chemical_list: D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors