title: Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure.
abstract: OBJECTIVE
  To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study.
  
  
  METHODS
  Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis.
  
  
  RESULTS
  From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40).
  
  
  CONCLUSIONS
  The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings.
authors.affiliation: Pfizer Oncology, San Diego, California, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Deprimo
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Martin E
authors.initials: ME
authors.lastname: Blackstein
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Garrett
authors.forename: Charles S
authors.initials: CS
authors.lastname: Harmon
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Charles M
authors.initials: CM
authors.lastname: Baum
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood*; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D019009:Proto-Oncogene Proteins c-kit / Q000097:blood* / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D012995:Solubility; D000077210:Sunitinib; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib