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Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
Journal article

Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.

  • Goldinger SM Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland. Electronic address: simone.goldinger@usz.ch.
  • Zimmer L Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
  • Schulz C Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
  • Ugurel S Department of Dermatology, University Hospital Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
  • Hoeller C Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
  • Kaehler KC Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
  • Schadendorf D Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
  • Hassel JC Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
  • Becker J Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
  • Hauschild A Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
  • Dummer R Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.
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  • 2013-11-05
Published in:
  • European journal of cancer (Oxford, England : 1990). - 2014
BRAF inhibitor
Downstream inhibition
MAPK pathway
MEK inhibitor
Melanoma
Sequenced administration
Upstream inhibition
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Benzimidazoles
Disease Progression
Disease-Free Survival
Feasibility Studies
Female
Humans
Imidazoles
Indoles
MAP Kinase Signaling System
Male
Melanoma
Middle Aged
Mitogen-Activated Protein Kinases
Mutation
Outcome Assessment, Health Care
Oximes
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Pyridones
Pyrimidinones
Retrospective Studies
Sulfonamides
Time Factors
Vemurafenib
English BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/255188
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