title: Biomarker analyses from a randomized, placebo-controlled, phase IIIb trial comparing bevacizumab with or without erlotinib as maintenance therapy for the treatment of advanced non-small-cell lung cancer (ATLAS).
abstract: BACKGROUND
  ATLAS compared bevacizumab plus erlotinib (B+E) with bevacizumab plus placebo (B+P) as maintenance therapy after first-line bevacizumab plus chemotherapy (B+C) for advanced non-small-cell lung cancer (NSCLC). Prespecified biomarkers were prospectively evaluated.
  
  
  METHODS
  Tumor samples were analyzed for: epidermal growth factor receptor (EGFR) expression (immunohistochemistry [IHC]); EGFR gene copy number (fluorescence in-situ hybridization [FISH]); EGFR mutations (exon 19 deletions/L858R mutations); and KRAS mutations (exons 2/3). Progression-free survival (PFS) and overall survival (OS) were estimated.
  
  
  RESULTS
  Of 743 patients randomized to receive maintenance treatment (after four cycles of B+C without progression), 190 (B+E) and 177 (B+P) were evaluable for biomarker status. Median PFS (from randomization) was 4.4 months (B+E) versus 3.7 months (B+P; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.99), which was numerically similar to the intent-to-treat PFS. PFS benefit of B+E was observed across most biomarker subgroups. EGFR IHC, EGFR FISH, and EGFR/KRAS mutation status were not predictive of outcome. B+E-treated patients with EGFR mutation-positive NSCLC had longer PFS compared with B+P-treated patients (HR, 0.44; 95% CI, 0.22-0.86; p = 0.0139). Patients with KRAS wild-type disease had significant PFS improvements with B+E, compared with B+P (HR, 0.66; 95% CI, 0.485-0.914; p = 0.0105). No OS benefit of B+E was observed.
  
  
  CONCLUSIONS
  Patients with KRAS wild-type or EGFR mutation-positive NSCLC derived PFS benefits from B+E. However, EGFR IHC, EGFR FISH, and EGFR or KRAS mutation status were not strongly predictive of survival. A larger sample size would be needed to confirm the initial trends observed in this study.
authors.affiliation: *University of California Los Angeles, Los Angeles, CA; †Kaiser Permanente Northern CA, Antioch, CA; ‡Sarah Cannon Research Institute, Nashville, TN; §Northwest Medical Specialties, Tacoma, WA; ‖Sibley Memorial Hospital, Washington, DC; ¶Integrated Community Oncology Network, Jacksonville, FL; #The Mark H. Zangmeister Center, Columbus, OH; **Florida Cancer Specialists, Bonita Springs, FL; ††Arch Medical Services Inc., The Center for Cancer Care and Research, Saint Louis, MO; ‡‡National Taiwan University, Taipei, Taiwan; §§F. Hoffmann-La Roche Ltd., Basel, Switzerland; ‖‖Genentech Inc., South San Francisco, CA; ¶¶Weill Cornell Medical College and Thoracic Oncology Service, New York, NY; and ##Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Fairooz
authors.initials: F
authors.lastname: Kabbinavar
authors.forename: Louis
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
authors.forename: Saifuddin
authors.initials: S
authors.lastname: Kasubhai
authors.forename: Bruce
authors.initials: B
authors.lastname: Kressel
authors.forename: Thomas
authors.initials: T
authors.lastname: Marsland
authors.forename: Taral
authors.initials: T
authors.lastname: Patel
authors.forename: Mark
authors.initials: M
authors.lastname: Rubin
authors.forename: Leonard
authors.initials: L
authors.lastname: White
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Barbara
authors.initials: B
authors.lastname: Klughammer
authors.forename: Dawn
authors.initials: D
authors.lastname: Colburn
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology; D042461:Vascular Endothelial Growth Factor A; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors