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01-03-2020 | Melanoma | Short Communication

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

Authors: Ganessan Kichenadasse, Jim Henry Hughes, John O. Miners, Arduino A. Mangoni, Andrew Rowland, Ashley M. Hopkins, Michael J. Sorich

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2020

Abstract

Purpose To validate a plasma vemurafenib steady-state trough concentration (C_ss,_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 C_ss,_min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib C_ss,_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 C_ss,_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 C_ss,_min, the threshold was still associated with overall survival and not in the monotherapy cohort.

Conclusion

A plasma vemurafenib C_ss,_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.

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Title: Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma
Authors: Ganessan Kichenadasse
Jim Henry Hughes
John O. Miners
Arduino A. Mangoni
Andrew Rowland
Ashley M. Hopkins
Michael J. Sorich
Publication date: 01-03-2020
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Pharmacokinetics
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-04002-1

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