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Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

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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.

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Acknowledgments

We are grateful to J. Lecas (Centre de Langues de la Maison des Langues, Université Paris Descartes) in proofreading the manuscript and to Ms. Scheer-Senyarich for her technical assistance.

Funding sources

None.

Conflict of Interest

N. Kramkimel, A. Thomas-Schoemann, L. Sakji, JL. Golmard, G. Noe, E. Regnier-Rosencher, N. Chapuis, M. Vidal, F. Goldwasser, N. Dupin and B. Blanchet have no conflicts of interest to declare. E. Maubec is involved in an advisory Board for Roche. L. Mortier is involved with advisory boards for Roche, Bristol-Myers Squibb, GlaxoSmithKline and MSD. MF. Avril is involved in a steering committee for Roche.

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    Authors and Affiliations

    1. Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France

      N. Kramkimel, E. Regnier-Rosencher, MF. Avril & N. Dupin

    2. Centre d’étude et de recours sur les inhibiteurs de l’angiogénèse (CERIA), Paris, France

      A. Thomas-Schoemann, M. Vidal, F. Goldwasser & B. Blanchet

    3. Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France

      A. Thomas-Schoemann, G. Noe, M. Vidal & B. Blanchet

    4. UMR8638 CNRS, UFR de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France

      A. Thomas-Schoemann & M. Vidal

    5. CHRU de Lille, Service de Dermatologie, Paris, France

      L. Sakji & L. Mortier

    6. Assistance Publique Hôpitaux de Paris, Département de Biostatistiques, Hôpital Pitié-Salpêtrière, Paris, France

      JL. Golmard

    7. Assistance Publique Hôpitaux de Paris, Service d’Hématologie biologique, Hôpital Cochin, Paris, France

      N. Chapuis

    8. Assistance Publique Hôpitaux de Paris, Département de Dermatologie, Hôpital Bichat, Paris, France

      E. Maubec

    9. 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

      MF. Avril, F. Goldwasser & N. Dupin

    10. Assistance Publique Hôpitaux de Paris, Service de Cancérologie médicale, Hôpital Cochin, Paris, France

      F. Goldwasser

    11. INSERM U 837, Faculté de Médecine, Université de Lille II, Lille, France

      L. Mortier

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    1. N. Kramkimel
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    Correspondence to B. Blanchet.

    Additional information

    N. Kramkimel, A. Thomas-Schoemann, N. Dupin, and B. Blanchet contributed equally to this work.

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    Kramkimel, N., Thomas-Schoemann, A., Sakji, L. et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Targ Oncol 11, 59–69 (2016). https://doi.org/10.1007/s11523-015-0375-8

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    • DOI: https://doi.org/10.1007/s11523-015-0375-8

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