Leptomeningeal tumor response to combined MAPK/ERK inhibition in V600E-mutated gliomas despite undetectable CSF drug levels
Authors: A.F. Hottinger, D. Bensaid, R. De Micheli, B. Moura, K. Mokhtari, E. Cardoso, A. Idbaih, R. Stupp
Journal: Annals of Oncology (2018)

BRAF mutations of the hotspot V600E result in constitutive activation with subsequent uncontrolled cell proliferation and have been reported in various cancers including selected primary brain tumors (3%–5% of all gliomas). BRAF mutations and downstream signaling can be successfully targeted with small molecule inhibitors such as dabrafenib or trametinib, which block BRAF-V600E and MEK, respectively. Nevertheless, preclinical studies have suggested that both agents may only insufficiently cross the blood-brain barrier or be rapidly excreted by multi-substrate efflux transporters [1.Mittapalli R.K. Vaidhyanathan S. Dudek A.Z. Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases.J Pharmacol Exp Ther. 2013; 344: 655-664Crossref PubMed Scopus (128) Google Scholar, 2.Vaidhyanathan S. Mittapalli R.K. Sarkaria J.N. Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.Drug Metab Dispos. 2014; 42: 1292-1300Crossref PubMed Scopus (73) Google Scholar]. We here report on the successful treatment of two patients suffering from a BRAF-mutated glioma with leptomeningeal dissemination with combined BRAF/MEK inhibition. Patient 1: a 40-year-old male presented a V600E-BRAF mutated WHO grade I pilocytic astrocytoma of the cerebellar vermis. In October 2017, a rapidly deteriorating cerebellar syndrome was associated with local leptomeningeal dissemination. Combination treatment with dabrafenib (150 mg b.i.d.) and trametinib (2 mg QD) resulted in marked clinical and radiologic improvement within 2 months (Figure 1) that is now ongoing for 9 months, such that he resumed professional mountaineering. Drug plasma concentrations of dabrafenib and trametinib were quantified by liquid chromatography coupled to tandem mass spectrometry [3.Cardoso E. Mercier T. Wagner A.D. et al.Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2018; 1083: 124-136Crossref PubMed Scopus (25) Google Scholar] (lower limits of quantification: dabrafenib: 2.5 ng/ml; trametinib: 1 ng/ml). End-of-dose plasma levels of dabrafenib and trametinib were 16.8 and 10 ng/ml, respectively. Neither compound was detectable in the cerebro-spinal fluid (CSF). Patient 2: a 31-year-old female presented in 2017 with new onset headaches linked to a right posterior lobe anaplastic astrocytoma with V600E-BRAF mutation. Six months after treatment with concomitant chemoradiotherapy with temozolomide, she presented with leptomeningeal dissemination with vertigo and right-sided facial paralysis, confirmed by malignant cells in the CSF and radiologic findings. Treatment with dabrafenib and trametinib led to rapid clinical improvement and clearance of tumor cells documented in the CSF as early as 8 weeks after treatment initiation and lasting for 3.5 months. Our reports demonstrate safety and efficacy of dual BRAF/MEK inhibition in BRAF-mutated glioma. Both our patients who suffered from extensive leptomenigeal disease, a clinical condition that is commonly resistant to therapeutic approaches, responded. In patient 1 we were able to determine both plasma and CSF drug levels. In the CSF drug concentrations were below the detectable analytic threshold. This may be due to strong plasma protein binding. Furthermore, dabrafenib and trametinib are substrates of the efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein [1.Mittapalli R.K. Vaidhyanathan S. Dudek A.Z. Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases.J Pharmacol Exp Ther. 2013; 344: 655-664Crossref PubMed Scopus (128) Google Scholar, 2.Vaidhyanathan S. Mittapalli R.K. Sarkaria J.N. Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.Drug Metab Dispos. 2014; 42: 1292-1300Crossref PubMed Scopus (73) Google Scholar]. This may explain the therapeutic efficacy in the absence of detectable CSF drug levels. Acquired resistance to single agent BRAF inhibitors is a frequent, albeit poorly understood cause of failure. Although long-term responses have been described in patients with BRAF-mutated gliomas treated with single BRAF inhibitors [4.Hyman D.M. Puzanov I. Subbiah V. et al.Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.N Engl J Med. 2015; 373: 726-736Crossref PubMed Scopus (1257) Google Scholar], we postulated that the aggressive nature of the disease in these patients warranted combined dabrafenib and trametinib treatment. In melanoma, an improved outcome of dual BRAF/MEK inhibition as well as reduced incidence of secondary cancers have been shown in randomized trials [5.Long G.V. Stroyakovskiy D. Gogas H. et al.Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.N Engl J Med. 2014; 371: 1877-1888Crossref PubMed Scopus (1275) Google Scholar]. This combination became the standard of care for V600E-BRAF-mutated melanoma. We postulate that combined targeted therapy should also be the first-line therapy option in recurrent or progressive BRAF-mutated glioma. None declared.