title: A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.
abstract: BACKGROUND
  Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib.
  
  
  METHODS
  This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib.
  
  
  RESULTS
  A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors.
  
  
  CONCLUSIONS
  Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.
authors.affiliation: Department of Dermatology, University of Essen, Essen Department of Dermatology, University of Würzburg, Würzburg selma.ugurel@uk-essen.de.
authors.forename: S
authors.initials: S
authors.lastname: Ugurel
authors.affiliation: Department of Dermatology, University of Mainz, Mainz.
authors.forename: C
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Department of Dermatology, University of Kiel, Kiel.
authors.forename: K
authors.initials: K
authors.lastname: Kähler
authors.affiliation: Department of Dermatology, University of Heidelberg, Heidelberg.
authors.forename: J
authors.initials: J
authors.lastname: Hassel
authors.affiliation: Department of Dermatology, Ludwig-Maximilians-University of München, München.
authors.forename: C
authors.initials: C
authors.lastname: Berking
authors.affiliation: Department of Dermatology, University of Essen, Essen.
authors.forename: L
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Institute of Biometry and Statistics, University of Würzburg, Würzburg.
authors.forename: I
authors.initials: I
authors.lastname: Haubitz
authors.affiliation: Department of Dermatology, Hannover Medical School, Hannover, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Satzger
authors.affiliation: Department of Dermatology, University of Mainz, Mainz.
authors.forename: T
authors.initials: T
authors.lastname: Müller-Brenne
authors.affiliation: Department of Dermatology, University of Kiel, Kiel.
authors.forename: N C
authors.initials: NC
authors.lastname: Mikhaimer
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: J C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Dermatology, Ludwig-Maximilians-University of München, München.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kilian
authors.affiliation: Department of Dermatology, University of Essen, Essen.
authors.forename: D
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Dermatology, University of Erlangen, Erlangen.
authors.forename: L
authors.initials: L
authors.lastname: Heinzerling
authors.affiliation: Department of Dermatology, SRH Waldklinikum Gera, Gera Department of Dermatology, University of Jena, Jena.
authors.forename: M
authors.initials: M
authors.lastname: Kaatz
authors.affiliation: Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Heidelberg.
authors.forename: J
authors.initials: J
authors.lastname: Utikal
authors.affiliation: Department of Dermatology, University of Magdeburg, Magdeburg.
authors.forename: D
authors.initials: D
authors.lastname: Göppner
authors.affiliation: Department of Dermatology, Saarland University Hospital, Saarland.
authors.forename: C
authors.initials: C
authors.lastname: Pföhler
authors.affiliation: Department of Dermatology, University of Tübingen, Tübingen.
authors.forename: A
authors.initials: A
authors.lastname: Pflugfelder
authors.affiliation: Department of Dermatology, University of Göttingen, Göttingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mössner
authors.affiliation: Department of Dermatology, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gutzmer
mesh_terms: D000328:Adult; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000188:drug therapy*; D008875:Middle Aged; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: BRAF inhibition; melanoma; predictive factors; therapy outcome; vemurafenib