title: Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma.
abstract: Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG  ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Kramkimel
authors.affiliation: Centre d'étude et de recours sur les inhibiteurs de l'angiogénèse (CERIA), Paris, France.|Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.|UMR8638 CNRS, UFR de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Thomas-Schoemann
authors.affiliation: CHRU de Lille, Service de Dermatologie, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Sakji
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Biostatistiques, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Jl
authors.initials: J
authors.lastname: Golmard
authors.affiliation: Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Noe
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Regnier-Rosencher
authors.affiliation: Assistance Publique Hôpitaux de Paris, Service d'Hématologie biologique, Hôpital Cochin, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Bichat, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Maubec
authors.affiliation: Centre d'étude et de recours sur les inhibiteurs de l'angiogénèse (CERIA), Paris, France.|Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.|UMR8638 CNRS, UFR de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France.|Institut Cochin, Institut National de la Sante et de la Recherche Médicale (INSERM) U1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Faculté de médecine, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: Mf
authors.initials: M
authors.lastname: Avril
authors.affiliation: Centre d'étude et de recours sur les inhibiteurs de l'angiogénèse (CERIA), Paris, France.|Institut Cochin, Institut National de la Sante et de la Recherche Médicale (INSERM) U1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Faculté de médecine, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.|Assistance Publique Hôpitaux de Paris, Service de Cancérologie médicale, Hôpital Cochin, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Goldwasser
authors.affiliation: CHRU de Lille, Service de Dermatologie, Paris, France.|INSERM U 837, Faculté de Médecine, Université de Lille II, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Mortier
authors.affiliation: Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France.|Institut Cochin, Institut National de la Sante et de la Recherche Médicale (INSERM) U1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Faculté de médecine, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Dupin
authors.affiliation: Centre d'étude et de recours sur les inhibiteurs de l'angiogénèse (CERIA), Paris, France. benoit.blanchet@cch.aphp.fr.|Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. benoit.blanchet@cch.aphp.fr.
authors.forename: B
authors.initials: B
authors.lastname: Blanchet
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf