Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma

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Abstract

Abstract: Purpose To validate a plasma vemurafenib steady-state trough concentration (Css,min) threshold that predicts survival outcomes of patients with BrafV600 mutated melanoma.

Methods: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal Css,min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib Css,min and survival was modelled using Cox proportional hazards regression.

Results: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib Css,min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib Css,min, the threshold was still associated with overall survival and not in the monotherapy cohort.

Conclusion: A plasma vemurafenib Css,min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.

Original languageEnglish
Pages (from-to)615-620
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume85
Issue number3
Early online date30 Nov 2019
DOIs
Publication statusE-pub ahead of print - 30 Nov 2019

Keywords

  • Melanoma
  • Survival
  • Threshold concentration
  • Vemurafenib

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