Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma

Abstract

Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4±26.2 and 0.47±0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98±0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response.

Emerging findings into molecular mechanism of brain metastasis

“…However, most of the patients ultimately relapsed because of acquired resistance 102. The mean ratio of CSF/plasma vemurafenib concentration is only 0.98%±0.84%, indicating the poor ability to penetrate BBB 103. Under the circumstances, combined stereotactic radiosurgery (SRS) with BRAF inhibitors therapy were proposed and get increased overall survival of patients indeed 104…”

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy

“…In a small study of 24 patients with unresectable and previously treated brain metastases, a 42% ORR was observed at both intracranial and extracranial sies of disease with vemurafenib treatment [Dummer et al 2014]. Limited data have been reported on low cerebrospinal fluid (CSF) concentrations of vemurafenib in patients, although CSF drug concentration may not necessarily be the optimum surrogate marker for concentration of a drug in brain tumor tissue [Sakji-Dupré et al 2015]; there have also been case reports of melanoma patients with leptomeningeal disease who have had responses to vemurafenib [Schäfer et al 2013;Kim et al 2015]. There is an ongoing phase II study of the dabrafenib and trametinib combination in patients with BRAF mutation-positive melanoma that has metastasized to the brain; cohorts will include patients with symptomatic and asymptomatic brain metastases, and with or without prior therapy to the brain [Davies et al 2014].…”

Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy

“…Interestingly, the brain penetration of dabrafenib in mice was higher than vemurafenib, perhaps making this a better choice for patients with BRAF ‐mutant LMM and MBM . Recent clinical data on vemurafenib levels in the CSF of melanoma patients with MBM confirmed the animal findings and showed CSF levels to be significantly lower (0.47 ± 0.37 mg/ml) than those in plasma (53.4 ± 26.2 mg/ml) . No relationship was noted between the levels of the drug in the CSF and the plasma .…”