title: Challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience.
abstract: OBJECTIVE
  We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer.
  
  
  METHODS
  Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models.
  
  
  RESULTS
  In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12-0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79-1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67-1.15, P = 0.340).
  
  
  CONCLUSIONS
  Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00460317, NCT00369070.
authors.affiliation: Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.affiliation: Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.affiliation: Oncology Development, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Hei
authors.affiliation: Global Biostatistical Science, Amgen Inc. South San Francisco, San Francisco, CA, United States of America.
authors.forename: Yining
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Diagnostics Division Research and Development, Abbott Laboratories, Abbott Park, IL, United States of America.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Davis
authors.affiliation: Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Davis
authors.affiliation: Diagnostics Division Research and Development, Abbott Laboratories, Abbott Park, IL, United States of America.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Kaesdorf
authors.affiliation: Diagnostics Division Research and Development, Abbott Laboratories, Abbott Park, IL, United States of America.
authors.forename: Sabrina S
authors.initials: SS
authors.lastname: Chan
authors.affiliation: Medical Sciences, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Patterson
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009841:Oligonucleotides; D017239:Paclitaxel / Q000008:administration & dosage; D015990:Placebo Effect; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood*; D016016:Proportional Hazards Models; D012372:ROC Curve; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D009841:Oligonucleotides; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D009536:Niacinamide; D016190:Carboplatin; C519562:imetelstat; D017239:Paclitaxel