Purpose
Dabrafenib plus trametinib combination has greatly improved survival in
BRAF
V600
mut
metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in ...real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients.
Methods
BRAF
V600
mut
metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC
0–
τ
and
C
trough
) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed.
Results
Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3
n
= 10, G4
n
= 0). In univariate analysis, median dabrafenib
C
trough
within intermediate range was associated with a significantly higher PFS (HR 95% CI = 0.41 0.18; 0.91,
p
= 0.029) and DOR (HR 95% CI = 0.39 0.16; 0.94,
p
= 0.024), and association with DOR remained significant in multivariate analysis (HR 95% CI = 0.34 0.12; 0.95,
p
= 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE.
Conclusion
In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in
BRAF
V600
mut
metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.
Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous melanoma cases are due to inherited ...variants or de novo mutations in approximately 20 genes, found using linkage, next-generation sequencing and association studies. Based on these studies, 3 classes of predisposing melanoma genes have been defined based on the frequency of the variants in the general population and lifetime risk of developing a melanoma: (i) ultra-rare variants with a high risk, (ii) rare with a moderate risk, and (iii) frequent variants with a low risk. Most of the proteins encoded by these genes have been shown to be involved in melanoma initiation, including proliferation and senescence bypass. This paper reviews the role(s) of these genes in the transformation of melanocytes into melanoma. It also describes their function in the establishment and renewal of melanocytes and the biology of pigment cells, if known.
PDF
