title: Plasma biomarker signature associated with improved survival in advanced non-small cell lung cancer patients on linifanib.
abstract: OBJECTIVE
  Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent.
  
  
  METHODS
  Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival.
  
  
  RESULTS
  A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5 mg, linifanib 12.5 mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5 mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5 mg (HR=0.54, p=0.137).
  
  
  CONCLUSIONS
  This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit.
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA. Electronic address: evelyn.mckeegan@abbvie.com.
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ansell
authors.affiliation: Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Davis
authors.affiliation: Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chan
authors.affiliation: Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Chandran
authors.affiliation: Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Gawel
authors.affiliation: Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Barry L
authors.initials: BL
authors.lastname: Dowell
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Anahita
authors.initials: A
authors.lastname: Bhathena
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Arunava
authors.initials: A
authors.lastname: Chakravartty
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKee
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Ricker
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Carlson
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Viswanath
authors.initials: V
authors.lastname: Devanarayan
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D016190:Carboplatin / Q000008:administration & dosage; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D053539:Keratin-19 / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D007191:Indazoles; D053539:Keratin-19; D010671:Phenylurea Compounds; C102012:antigen CYFRA21.1; D016190:Carboplatin; C513486:linifanib; D017239:Paclitaxel
keywords: Biomarker; Carcinoembryonic antigen (CEA); Cytokeratin 19 fragments CYFRA 21-1; Linifanib; Predictive value; non-small cell lung cancer (NSCLC)