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 language | English |
|---|---|
| Pages (from-to) | 615-620 |
| Number of pages | 6 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 85 |
| Issue number | 3 |
| Early online date | 30 Nov 2019 |
| DOIs | |
| Publication status | Published - 1 Mar 2020 |
Keywords
- Melanoma
- Survival
- Threshold concentration
- Vemurafenib