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European journal of cancer (Oxford, England : 1990). 2013 Oct 29. pii: S0959-8049(13)00876-9. doi: 10.1016/j.ejca.2013.09.014

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

Goldinger SM¹, Zimmer L², Schulz C³, Ugurel S⁴, Hoeller C⁵, Kaehler KC⁶, Schadendorf D⁷, Hassel JC⁸, Becker J⁹, Hauschild A¹⁰, Dummer R¹¹

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¹Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland. Electronic address: simone.goldinger@usz.ch.
²Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
³Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
⁴Department of Dermatology, University Hospital Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
⁵Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
⁶Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
⁷Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
⁸Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
⁹Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
¹⁰Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
¹¹Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.

Abstract

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.

KEYWORDS: BRAF inhibitor, Downstream inhibition, MAPK pathway, MEK inhibitor, Melanoma, Sequenced administration, Upstream inhibition

Publikations ID: 24183461
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