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Erschienen in: Targeted Oncology 1/2016

01.02.2016 | Original Research

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

verfasst von: N. Kramkimel, A. Thomas-Schoemann, L. Sakji, JL. Golmard, G. Noe, E. Regnier-Rosencher, N. Chapuis, E. Maubec, M. Vidal, MF. Avril, F. Goldwasser, L. Mortier, N. Dupin, B. Blanchet

Erschienen in: Targeted Oncology | Ausgabe 1/2016

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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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Metadaten
Titel
Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma
verfasst von
N. Kramkimel
A. Thomas-Schoemann
L. Sakji
JL. Golmard
G. Noe
E. Regnier-Rosencher
N. Chapuis
E. Maubec
M. Vidal
MF. Avril
F. Goldwasser
L. Mortier
N. Dupin
B. Blanchet
Publikationsdatum
01.02.2016
Verlag
Springer International Publishing
Erschienen in
Targeted Oncology / Ausgabe 1/2016
Print ISSN: 1776-2596
Elektronische ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-015-0375-8

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