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
  • 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.