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

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• 作者：Alicja Puszkiel^a ; Mé ; lanie White-Koning^b ; Nicolas Dupin^c ; ^d ; Nora Kramkimel^c ; Audrey Thomas-Schoemann^a ; ^e ; Gaë ; lle Noé ; ^a ; ^e ; Nicolas Chapuis^f ; Michel Vidal^a ; ^e ; Franç ; ois Goldwasser^d ; ^g ; Etienne Chatelut^b ; ^h ; Benoit Blanchet^a ; ^{benoit.blanchet@aphp.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AAG ; alpha-1 acid glycoprotein ; AJCC ; American Joint Committee on Cancer ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; AUC ; Area Under the Curve ; CI ; Confidence Interval ; CL/F ; Apparent clearance ; CRP ; C Reactive Protein ; EGFR ; Epidermal Growth Factor Receptor ; ECOG ; Eastern Cooperative Oncology Group ; F ; Bioavailability ; FOCE-I ; First-Order Conditional Estimation with Interaction ; HGF ; Hepatocyte Growth Factor ; HPLC ; High Performance Liquid Chromatography ; IOV ; Inter-occasion
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：113
• 期：part_PA
• 页码：709-718
• 全文大小：1133 K

文摘

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 BRAF^V600 mutated 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 15 days (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.