title: Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.
abstract: RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.
  
  
  
  This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).
  
  
  
  The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.
  
  
  
  The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871-9. © 2016 American Cancer Society.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: City of Hope Medical Center, Duarte, California.
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyiadzis
authors.affiliation: University of Alabama Hospital, Birmingham, Alabama.
authors.forename: James
authors.initials: J
authors.lastname: Foran
authors.affiliation: Carl Gustav Carus University Hospital, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Paoli-Calmettes Institute, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.affiliation: University of California San Francisco, San Francisco, California.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Olin
authors.affiliation: Columbia University Medical Center, New York, New York.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: Marien Hospital, Dusseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: Mayo Clinic, Rochester, New York.
authors.forename: Aref
authors.initials: A
authors.lastname: Al-Kali
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Quintiles, Durham, North Carolina.
authors.forename: John W
authors.initials: JW
authors.lastname: Bauman
authors.affiliation: Merck & Company, Incorporated, North Wales, Pennsylvania.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Pfizer Oncology, La Jolla, California.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Dan
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Teva Pharmaceuticals, Frazier, Pennsylvania.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: Pfizer, Incorporated, Collegeville, Pennsylvania.
authors.forename: Paul
authors.initials: P
authors.lastname: Wissel
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D012008:Recurrence; D055815:Young Adult
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; NRAS; acute myeloid leukemia; chronic myelomonocytic leukemia; myelodysplastic syndromes; trametinib