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Cited by 1,389Melanoma and MAPK PathwaysCutaneous Melanoma Detection and ManagementColorectal Cancer Treatments and Studies

Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma

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Robert, Caroline, Grob, Jean J., Stroyakovskiy, Daniil, Karaszewska, Boguslawa, Hauschild, Axel, Levchenko, Evgeny, Chiarion Sileni, Vanna, Schachter, Jacob +18 more·2019·New England Journal of Medicine
DOI 10.1056/nejmoa1904059
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Abstract

BACKGROUND: 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: V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).

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Crossref · 10.1056/nejmoa1904059

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  • Regimens that combine different anticancer drugs target pro-growth or pro-survival signaling pathways in either a synergistic or additive manner, which reduces drug resistance.

    “Mechanistically, regimens that combine different anticancer drugs target pro-growth or pro-survival signaling pathways in either a synergistic or an additive manner, which reduces drug resistance.77,78”

    From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [77]

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Authors
Robert, C., Grob, J. J., Stroyakovskiy, D., Karaszewska, B., Hauschild, A., Levchenko, E., Chiarion Sileni, V., Schachter, J., Garbe, C., Bondarenko, I., Gogas, H., Mandalá, M., Haanen, J. B. A. G., Lebbé, C., Mackiewicz, A., Rutkowski, P., Nathan, P. D., Ribas, A., Davies, M. A., Flaherty, K. T., Burgess, P., Tan, M., Gasal, E., Voi, M., Schadendorf, D., & Long, G. V.
Affiliations
  • Université Paris Cité (FR)
  • From Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Aix-Marseille University, Marseille (J.J.G.), and Assistance Publique–Hôpitaux de Paris Dermatology and Clinical Investigation Center, Unité 976, Université de Paris, Hôpital Saint-Louis, Paris (C.L.) — all in France; Moscow City Oncology Hospital, Moscow (D. Stroyakovskiy), and the Petrov Research Institute of Oncology, St. Petersburg (E.L.) — both in Russia; Przychodnia Lekarska Komed, Konin (B.K.), the...
  • Tel Aviv University (IL)
  • National and Kapodistrian University of Athens (GR)
  • Poznan University of Medical Sciences (PL)
  • University of California, Los Angeles (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Harvard University (US)
  • Novartis (Switzerland) (CH)
  • The University of Sydney (AU)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2019-08-15
Volume
381
Issue
7
Pages
626-636
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1904059
OpenAlex
W2948155539
Cited by
1,389
References
21
Citations by year
2026: 101 · 2025: 178 · 2024: 182 · 2023: 217 · 2022: 227 · 2021: 249 · 2020: 186 · 2019: 43
FWCI
58.52
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
Funders
  • GlaxoSmithKline
  • Novartis Pharmaceuticals Corporation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
metastatic melanoma, dabrafenib, trametinib, BRAF V600E/K mutation, long-term survival, progression-free survival, overall survival, prognostic factors, complete response
MeSH terms
Progression-Free Survival, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Female, Follow-Up Studies, Humans, Imidazoles, Male, Melanoma, Middle Aged, Mutation, Oximes, Pyridones, Pyrimidinones, Skin Neoplasms, Survival Rate, MAP Kinase Kinase Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Young Adult

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