title: Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer.
abstract: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.
  
  
  
  Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.
  
  
  
  Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).
  
  
  
  Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.
authors.affiliation: Department of Gastroenterology, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070, Brussels, Belgium. JL.VanLaethem@erasme.ulb.ac.be.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charity Hospital, Virchow-Klinikum Campus, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Riess
authors.affiliation: Department of Oncology and Radiotherapy, Medical University of Gdansk, M. Skłodowskiej-Curie 3a Street, Gdansk, 80-210, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Department of Hematology and Oncology, University of Munich Medical Center, Marchioninistraße 15, 81366, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haas
authors.affiliation: Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, Am Gesundbrunnen 20-26, 74078, Heilbronn, Germany.
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Martens
authors.affiliation: Division of Medical Oncology, University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO, 80045, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Weekes
authors.affiliation: Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Department of Medical Oncology, Guy's & St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Ross
authors.affiliation: Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Department of Oncology, Palacky University Medical School and University Hospital Olomouc, Křížkovského 8, 771 47, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Department of Medical Oncology, A.O.U. United Hospitals, Polytechnic University of Marche, Piazza Roma, 22, Ancona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial Cancer Center, ul. W.K. Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Saramak
authors.affiliation: Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital of Giessen and Marburg, Baldingerstraße, 35043, Marburg, Germany.|Universitätsklinikum Halle - University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Michl
authors.affiliation: Department of Radiotherapy, UZ Brussels, Avenue du Laerbeek 101, 1090, Brussels, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Van Brummelen
authors.affiliation: Department of Medical Oncology, Poliambulanza Foundation Hospital Institute, Via Bissolati, 57, Brescia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zaniboni
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University Hospital Bochum, Alexandrinenstraße 1, Bochum, 44791, Germany.
authors.forename: Wollf
authors.initials: W
authors.lastname: Schmiegel
authors.affiliation: Department of Oncology, Oslo University Radium Hospital, Trondheimsveien 235, Bjerke, 0514, Oslo, Norway.
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Giurescu
authors.affiliation: Bayer S.p.A., Viale Certosa 126-130, 20156, Milan, Italy.
authors.forename: Vittorio L
authors.initials: VL
authors.lastname: Garosi
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Roth
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Seidel
authors.affiliation: Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Rajagopalan
authors.affiliation: Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Teufel
authors.affiliation: Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA.
authors.forename: Barrett H
authors.initials: BH
authors.lastname: Childs
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D013449:Sulfonamides; D003841:Deoxycytidine; D004159:Diphenylamine; D000093542:Gemcitabine