title: Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial.
abstract: OBJECTIVE
  Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.
  
  
  METHODS
  A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.
  
  
  RESULTS
  Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm-independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.
  
  
  CONCLUSIONS
  Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 22(19); 4870-9. ©2016 AACR.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@mgh.harvard.edu.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Hepatology, Hôpital de la Pitié-Salpétrière, Sorbonne Universités, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rosmorduc
authors.affiliation: Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.affiliation: Humanitas Cancer Center, Rozzano-Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: King's College Hospital, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Ross
authors.affiliation: New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand.
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Jeffers
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Carol E A
authors.initials: CE
authors.lastname: Peña
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D000077157:Sorafenib
chemical_list: D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride