Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma

C. Robert*, J. J. Grob, D. Stroyakovskiy, B. Karaszewska, A. Hauschild, E. Levchenko, V. Chiarion Sileni, J. Schachter, C. Garbe, I. Bondarenko, H. Gogas, M. Mandalá, J. B.A.G. Haanen, C. Lebbé, A. MacKiewicz, P. Rutkowski, P. D. Nathan, A. Ribas, M. A. Davies, K. T. FlahertyP. Burgess, M. Tan, E. Gasal, M. Voi, D. Schadendorf, G. V. Long

*Corresponding author for this work

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 progressionfree 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.

Original languageEnglish
Pages (from-to)626-636
Number of pages11
JournalNew England Journal of Medicine
Issue number7
StatePublished - 15 Aug 2019
Externally publishedYes


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