title: Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial.
abstract: OBJECTIVE
  Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation.
  
  
  OBJECTIVE
  To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma.
  
  
  METHODS
  Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada.
  
  
  METHODS
  One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression.
  
  
  METHODS
  Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013.
  
  
  RESULTS
  Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction.
  
  
  CONCLUSIONS
  In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01143402.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Jorge Fernando
authors.initials: JF
authors.lastname: Quevedo
authors.affiliation: University of Iowa Hospital and Clinics, Iowa City.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Milhem
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Ragini R
authors.initials: RR
authors.lastname: Kudchadkar
authors.affiliation: Washington University, St Louis, Missouri.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Linette
authors.affiliation: University of Chicago, Chicago, Illinois.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida.
authors.forename: Jose
authors.initials: J
authors.lastname: Lutzky
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: David H
authors.initials: DH
authors.lastname: Lawson
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lao
authors.affiliation: Metro Minnesota Community Clinical Oncology Program, St Louis Park.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Flynn
authors.affiliation: University of Wisconsin, Madison.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Albertini
authors.affiliation: Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Takami
authors.initials: T
authors.lastname: Sato
authors.affiliation: University of Colorado, Aurora.
authors.forename: Karl
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Investigational Drug Branch, National Cancer Institute, Rockville, Maryland.
authors.forename: Austin
authors.initials: A
authors.lastname: Doyle
authors.affiliation: Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ancell
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: Bluth
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hedvat
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Erinjeri
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Grazia
authors.initials: G
authors.lastname: Ambrosini
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Brian
authors.initials: B
authors.lastname: Marr
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: Mark Andrew
authors.initials: MA
authors.lastname: Dickson
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome; D014604:Uveal Neoplasms / Q000188:drug therapy*; D000098943:Uveal Melanoma
chemical_list: C517975:AZD 6244; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D003606:Dacarbazine; D000077204:Temozolomide