title: Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials.
abstract: Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with (18)F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients.
  
  
  METHODS
  (18)F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mm-diameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellular-signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds.
  
  
  RESULTS
  Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. (18)F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in (18)F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P = 0.052). Furthermore, a more pronounced relationship was seen between the change in (18)F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. (18)F-FDG was able to identify early nonresponding patients with a 97% negative predictive value.
  
  
  CONCLUSIONS
  These data exemplify the role of (18)F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment.
authors.affiliation: Nuclear Medicine Department, University Hospital-ICO-INSERM UMR 892, Nantes, France. francoise.bodere@chu-nantes.fr
authors.forename: Françoise
authors.initials: F
authors.lastname: Kraeber-Bodéré
authors.forename: Thomas
authors.initials: T
authors.lastname: Carlier
authors.forename: Valérie Meresse
authors.initials: VM
authors.lastname: Naegelen
authors.forename: Eliezer
authors.initials: E
authors.lastname: Shochat
authors.forename: Jean
authors.initials: J
authors.lastname: Lumbroso
authors.forename: Carlos
authors.initials: C
authors.lastname: Trampal
authors.forename: James
authors.initials: J
authors.lastname: Nagarajah
authors.forename: Sue
authors.initials: S
authors.lastname: Chua
authors.forename: Florent
authors.initials: F
authors.lastname: Hugonnet
authors.forename: Marcel
authors.initials: M
authors.lastname: Stokkel
authors.forename: Fergus
authors.initials: F
authors.lastname: Gleeson
authors.forename: Jean
authors.initials: J
authors.lastname: Tessier
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D003374:Coumarins / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D001549:Benzamides; C559138:CH 4987655; D003374:Coumarins; D010078:Oxazines; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C577924:RO5126766; D019788:Fluorodeoxyglucose F18; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases