title: Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients.
abstract: The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAFV600mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS.
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: Alicja
authors.initials: A
authors.lastname: Puszkiel
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM, Université de Toulouse, 1 avenue Irène Juliot-Curie, 31059 Toulouse, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: White-Koning
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Département de Dermatologie, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; Institut Cochin, Inserm U1016, Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Mechain, 75014 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupin
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Département de Dermatologie, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
authors.forename: Nora
authors.initials: N
authors.lastname: Kramkimel
authors.affiliation: Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Thomas-Schoemann
authors.affiliation: Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Noé
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Laboratoire d'Hématologie biologique, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Institut Cochin, Inserm U1016, Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Mechain, 75014 Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie médicale, 123 Boulevard Port Royal, 75014 Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM, Université de Toulouse, 1 avenue Irène Juliot-Curie, 31059 Toulouse, France; Institut Claudius Regaud, IUCT - Oncopole, 2 avenue Hubert Curien, 31037 Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.affiliation: Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. Electronic address: benoit.blanchet@aphp.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Blanchet
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D007211:Indoles / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D017228:Hepatocyte Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Hepatocyte growth factor; Melanoma; PK/PD; Population pharmacokinetics; Total lymphocytes count; Vemurafenib