title: Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations.
abstract: OBJECTIVE
  This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.
  
  
  METHODS
  We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.
  
  
  RESULTS
  Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.
  
  
  CONCLUSIONS
  Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR.
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Phase I unit, CIC- CPCET, Marseille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Department of Medical Oncology, Hospital del Mar and Cancer Research Program, IMIM, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Garcia
authors.affiliation: Institute Curie, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dieras
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Hôpital La Pitié-Salpêtrière, IUC/UPMC, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Spano
authors.affiliation: Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: START Madrid, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Hospital Virgen del Rocio, Seville, Spain.
authors.forename: Luiz
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: University of Cambridge, Department of Oncology, Cambridge, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Pacey
authors.affiliation: Pharma Research and Early Development, Oncology, Roche Penzberg, Germany.
authors.forename: Miro
authors.initials: M
authors.lastname: Venturi
authors.affiliation: Nuclear Medicine Department, Hôtel-Dieu University Hospital, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Kraeber-Bodéré
authors.affiliation: Pharma Research and Early Development, Oncology, Roche, Switzerland.
authors.forename: Jean J L
authors.initials: JJ
authors.lastname: Tessier
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany. wilfried.eberhardt@uni-duisburg-essen.de.
authors.forename: Wilfried Ernst Erich
authors.initials: WE
authors.lastname: Eberhardt
authors.affiliation: Clinical Investigation Center 1423, Quinze-Vingts Hospital, Paris 6 University, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.affiliation: Pharma Research and Early Development, Oncology, Roche, Switzerland.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guarin
authors.affiliation: Pharma Research and Early Development, Oncology, Roche, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Meresse
authors.affiliation: SITEP, Gustave Roussy Cancer Center, University Paris-Sud, Villejuif, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010078:Oxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018579:Patient Selection; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014018:Tissue Distribution; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D001549:Benzamides; C559138:CH 4987655; C117307:KRAS protein, human; D010078:Oxazines; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins