2. Academic Validation
  3. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

  • Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8.
Reinhard Dummer 1,  Dirk Schadendorf 2,  Paolo A Ascierto 3,  Ana Arance 4,  Caroline Dutriaux 5,  Anna Maria Di Giacomo 6,  Piotr Rutkowski 7,  Michele Del Vecchio 8,  Ralf Gutzmer 9,  Mario Mandala 10,  Luc Thomas 11,  Lev Demidov 12,  Claus Garbe 13,  David Hogg 14,  Gabriella Liszkay 15,  Paola Queirolo 16,  Ernesto Wasserman 17,  James Ford 17,  Marine Weill 18,  L Andres Sirulnik 17,  Valentine Jehl 18,  Viviana Bozón 19,  Georgina V Long 20,  Keith Flaherty 21
Affiliations

Affiliations

  • 1 Department of Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland. Electronic address: [email protected].
  • 2 Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany.
  • 3 Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Via Mariano Semmola, Naples, Italy.
  • 4 Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
  • 5 Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France.
  • 6 Medical Oncology and Immunotherapy, University Hospital of Siena, Viale Bracci, Siena, Italy.
  • 7 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
  • 8 Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, Milan, Italy.
  • 9 Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
  • 10 Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
  • 11 Department of Dermatology, Centre Hospitalier Lyon Sud, Lyons Cancer Research Center, Lyon 1 University, Pierre Bénite, France.
  • 12 N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russian Federation.
  • 13 Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
  • 14 Department of Medicine, University Health Network/Princess Margaret Hospital, Toronto, ON, Canada.
  • 15 Department of Dermatology, National Institute of Oncology, Budapest, Hungary.
  • 16 Department of Medical Oncology, Institute for Cancer Research, IRCCS San Martino, Largo Rosanna Benzi, Genova, Italy.
  • 17 Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, USA.
  • 18 Novartis Pharma AG, Basel, Switzerland.
  • 19 Array BioPharma, Boulder, CO, USA.
  • 20 Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
  • 21 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
PMID: 28284557 DOI: 10.1016/S1470-2045(17)30180-8
Abstract

Background: 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.

Methods: 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/m2 intravenously 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.

Findings: 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.

Interpretation: 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.

Funding: Array BioPharma and Novartis Pharmaceuticals Corporation.

Figures