title: Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials.
abstract: BACKGROUND
  Several targeted drugs are approved for treatment of patients with metastatic renal-cell cancer, but no validated biomarkers are available for prediction of clinical outcome. We aimed to assess the prognostic and predictive associations of pretreatment plasma concentrations of cytokine and angiogenic factors (CAFs) with data from a phase 2 and a phase 3 trial of pazopanib treatment.
  
  
  METHODS
  We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers. We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib. We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform. We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib.
  
  
  RESULTS
  Five candidate markers emerged from initial screening-interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib. In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations. In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (p(interaction)=0·009); standard clinical classifications were not predictive of PFS benefit.
  
  
  CONCLUSIONS
  CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Hai T
authors: HT
authors: Tran
authors: Yuan
authors: Y
authors: Liu
authors: Amado J
authors: AJ
authors: Zurita
authors: Ying
authors: Y
authors: Lin
authors: Katherine L
authors: KL
authors: Baker-Neblett
authors: Anne-Marie
authors: AM
authors: Martin
authors: Robert A
authors: RA
authors: Figlin
authors: Thomas E
authors: TE
authors: Hutson
authors: Cora N
authors: CN
authors: Sternberg
authors: Rafael G
authors: RG
authors: Amado
authors: Lini N
authors: LN
authors: Pandite
authors: John V
authors: JV
authors: Heymach
mesh_terms: D042501:Angiogenic Proteins / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood*; D018572:Disease-Free Survival; D006801:Humans; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016014:Linear Models; D016015:Logistic Models; D015337:Multicenter Studies as Topic; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016207:Cytokines; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib