Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

Caroline Robert, Jean J Grob, Daniil Stroyakovskiy, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion Sileni, Jacob Schachter, Claus Garbe, Igor Bondarenko, Helen Gogas, Mario Mandalá, John B A G Haanen, Celeste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Paul D Nathan, Antoni Ribas, Michael A Davies, Keith T FlahertyPaul Burgess, Monique Tan, Eduard Gasal, Maurizio Voi, Dirk Schadendorf, Georgina V Long

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.

RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.

CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d number, NCT01584648; COMBI-v number, NCT01597908.).

Original languageEnglish
Pages (from-to)626-636
Number of pages11
JournalThe New England journal of medicine
Issue number7
Publication statusPublished - Aug 15 2019


  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Imidazoles/administration & dosage
  • MAP Kinase Kinase Kinases/antagonists & inhibitors
  • Male
  • Melanoma/drug therapy
  • Middle Aged
  • Mutation
  • Oximes/administration & dosage
  • Progression-Free Survival
  • Protein Kinase Inhibitors/administration & dosage
  • Proto-Oncogene Proteins B-raf/antagonists & inhibitors
  • Pyridones/administration & dosage
  • Pyrimidinones/administration & dosage
  • Skin Neoplasms/drug therapy
  • Survival Rate
  • Young Adult

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