title: Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
abstract: There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma.
  
  
  
  NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51.
  
  
  
  Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group.
  
  
  
  Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy.
  
  
  
  Array BioPharma and Novartis Pharmaceuticals Corporation.
authors.affiliation: Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: reinhard.dummer@usz.ch.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Via Mariano Semmola, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.affiliation: Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dutriaux
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Viale Bracci, Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Del Vecchio
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandala
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon Sud, Lyons Cancer Research Center, Lyon 1 University, Pierre Bénite, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.affiliation: N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russian Federation.
authors.forename: Lev
authors.initials: L
authors.lastname: Demidov
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Medicine, University Health Network/Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.affiliation: Department of Dermatology, National Institute of Oncology, Budapest, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Liszkay
authors.affiliation: Department of Medical Oncology, Institute for Cancer Research, IRCCS San Martino, Largo Rosanna Benzi, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Wasserman
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: James
authors.initials: J
authors.lastname: Ford
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Marine
authors.initials: M
authors.lastname: Weill
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
authors.forename: L Andres
authors.initials: LA
authors.lastname: Sirulnik
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Valentine
authors.initials: V
authors.lastname: Jehl
authors.affiliation: Array BioPharma, Boulder, CO, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Bozón
authors.affiliation: Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
chemical_list: D001562:Benzimidazoles; D008565:Membrane Proteins; C581313:binimetinib; D003606:Dacarbazine; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human