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

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

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.

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.

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.