title: A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.
abstract: BACKGROUND
  Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.
  
  
  METHODS
  Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.
  
  
  RESULTS
  Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.
  
  
  CONCLUSIONS
  The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, United States. Electronic address: jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: The West Clinic, Memphis, TN, United States.
authors.forename: Bradley G
authors.initials: BG
authors.lastname: Somer
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.affiliation: Northwest Medical Specialties, PLLC, Tacoma, WA, United States.
authors.forename: Saifuddin M
authors.initials: SM
authors.lastname: Kasubhai
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: GlaxoSmithKline, Collegeville, PA, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: GlaxoSmithKline, Collegeville, PA, United States.
authors.forename: Suman
authors.initials: S
authors.lastname: Redhu
authors.affiliation: GlaxoSmithKline, Collegeville, PA, United States.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Steplewski
authors.affiliation: Novartis, East Hanover, NJ, United States.
authors.forename: Ngocdiep
authors.initials: N
authors.lastname: Le
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000556:secondary; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D003841:Deoxycytidine; C560077:trametinib; D000093542:Gemcitabine
keywords: Gemcitabine; MEK inhibitor; Pancreas; Randomised; Trametinib