title: Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
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.
authors.affiliation: Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland. Electronic address: simone.goldinger@usz.ch.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schulz
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
authors.forename: Selma
authors.initials: S
authors.lastname: Ugurel
authors.affiliation: Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoeller
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
authors.forename: Katharina C
authors.initials: KC
authors.lastname: Kaehler
authors.affiliation: Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hassel
authors.affiliation: Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
authors.forename: Juergen
authors.initials: J
authors.lastname: Becker
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D017063:Outcome Assessment, Health Care / Q000379:methods; D010091:Oximes / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012189:Retrospective Studies; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D000077484:Vemurafenib
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; C561627:dabrafenib
keywords: BRAF inhibitor; Downstream inhibition; MAPK pathway; MEK inhibitor; Melanoma; Sequenced administration; Upstream inhibition