title: Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury.
abstract: BACKGROUND
  A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF.
  
  
  METHODS
  To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-), and further subdivided into three groups according to AKI severity (stage 1-5).
  
  
  RESULTS
  Of 38 patients, 29 (76%) were AKI-, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI-, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF-CB vs. VMF monotherapy was reduced by 60%.
  
  
  CONCLUSIONS
  We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.
authors.affiliation: Department of Nephrology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Université de Lyon, UCBL, INSERM, 165, Chemin du Grand Revoyet, 69495, Pierre Bénite, France. cecile.teuma@hotmail.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Teuma
authors.affiliation: Department of Nephrology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Université de Lyon, UCBL, INSERM, 165, Chemin du Grand Revoyet, 69495, Pierre Bénite, France.
authors.forename: Solenne
authors.initials: S
authors.lastname: Pelletier
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, 69495, Pierre Bénite, France.
authors.forename: Mona
authors.initials: M
authors.lastname: Amini-Adl
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, 69495, Pierre Bénite, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Perier-Muzet
authors.affiliation: Service de Bio statistique, Hospices Civils de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|Université Lyon 1, Villeurbanne, France.|CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Bio Statistique-Santé, Villeurbanne, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Maucort-Boulch
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, 69495, Pierre Bénite, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Department of Nephrology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Université de Lyon, UCBL, INSERM, 165, Chemin du Grand Revoyet, 69495, Pierre Bénite, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Laville
authors.affiliation: Department of Nephrology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Université de Lyon, UCBL, INSERM, 165, Chemin du Grand Revoyet, 69495, Pierre Bénite, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Fouque
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, 69495, Pierre Bénite, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dalle
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000453:epidemiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage; D003404:Creatinine / Q000097:blood; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D015994:Incidence; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D004791:Enzyme Inhibitors; D007211:Indoles; D010880:Piperidines; D013449:Sulfonamides; D000077484:Vemurafenib; D003404:Creatinine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C574276:cobimetinib
keywords: BRAF inhibitor; Combined modality therapies; MEK inhibitor; Melanoma; Nephrotoxicity