title: Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.
abstract: BACKGROUND
  Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance.
  
  
  METHODS
  Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression.
  
  
  RESULTS
  We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects.
  
  
  CONCLUSIONS
  PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.
authors.affiliation: Department of Dermatology, AP-HP, Ambroise Paré Hospital, Boulogne-Billancourt University of Versailles-Saint-Quentin-en-Yvelines, Research Unit EA 4340 'Biomarkers in Cancerology and in Hemato-oncology', Boulogne-Billancourt.
authors.forename: E
authors.initials: E
authors.lastname: Funck-Brentano
authors.affiliation: Department of Toxicology, AP-HP, Raymond Poincaré Hospital, Boulogne-Billancourt University of Versailles-Saint-Quentin-en-Yvelines, Boulogne-Billancourt.
authors.forename: J C
authors.initials: JC
authors.lastname: Alvarez
authors.affiliation: Department of Dermatology, AP-HP, Ambroise Paré Hospital, Boulogne-Billancourt University of Versailles-Saint-Quentin-en-Yvelines, Research Unit EA 4340 'Biomarkers in Cancerology and in Hemato-oncology', Boulogne-Billancourt.
authors.forename: C
authors.initials: C
authors.lastname: Longvert
authors.affiliation: Department of Toxicology, AP-HP, Raymond Poincaré Hospital, Boulogne-Billancourt University of Versailles-Saint-Quentin-en-Yvelines, Boulogne-Billancourt.
authors.forename: E
authors.initials: E
authors.lastname: Abe
authors.affiliation: University of Versailles-Saint-Quentin-en-Yvelines, Boulogne-Billancourt Department of Public Health, AP-HP, Ambroise Paré Hospital, Boulogne-Billancourt.
authors.forename: A
authors.initials: A
authors.lastname: Beauchet
authors.affiliation: INSERM, CIC-1421 and UMR ICAN 1166, Paris Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris Department of Pharmacology and UMR ICAN 1166, Faculty of Medicine, Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Funck-Brentano
authors.affiliation: Department of Dermatology, AP-HP, Ambroise Paré Hospital, Boulogne-Billancourt University of Versailles-Saint-Quentin-en-Yvelines, Research Unit EA 4340 'Biomarkers in Cancerology and in Hemato-oncology', Boulogne-Billancourt philippe.saiag@uvsq.fr.
authors.forename: P
authors.initials: P
authors.lastname: Saiag
mesh_terms: D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood*; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: melanoma progression; metastatic melanoma; pharmacokinetics; tolerance; tumour response; vemurafenib