Melanoma Brain Metastases and Vemurafenib: Need for Further Investigation

Division of Medical Oncology, Mayo Clinic, Rochester, MN.
Mayo Clinic Proceedings (Impact Factor: 6.26). 10/2012; 87(10):976-81. DOI: 10.1016/j.mayocp.2012.07.006
Source: PubMed


Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. With the development of targeted agents for the treatment of metastatic melanoma, a great deal of interest has focused on whether selective BRAF inhibitors may play a role in the treatment of brain metastases in lieu of or in addition to surgery and/or radiation therapy. However, relatively little is known about the intracranial effectiveness of vemurafenib, the only US Food and Drug Administration-approved selective BRAF V600E inhibitor, because patients with brain metastases have historically been excluded from vemurafenib clinical trials. We describe 3 patients with BRAF V600E mutation metastatic melanoma in whom treatment with vemurafenib resulted in prompt extracranial disease response but progression of metastatic disease in the brain. Further, we discuss possible mechanisms responsible for the suboptimal central nervous system response observed in these patients and alternative therapies for patients with melanoma metastatic to the brain.

Download full-text


Available from: Roxana S Dronca, Sep 03, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E) which is commonly found in metastatic melanoma. Clinical trials with dabrafenib are showing encouraging results, however the CNS distribution of dabrafenib remains unknown. Thus the objective of the current study was to evaluate the brain distribution of dabrafenib in mouse and to see whether active efflux by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) restrict its delivery across blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II (MDCKII) cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in basolateral to apical direction with corrected efflux ratios of greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the Kp (AUCbrain / AUCplasma) of dabrafenib after an iv dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b-/-Bcrp1-/- mice to 0.42. Dabrafenib plasma exposure was ~2-fold greater in Mdr1 a/b-/-Bcrp1-/- mice as compared to wild-type with an oral dose (25 mg/kg), however the brain distribution was increased by ~10-fold with a resulting Kp of 0.25. Further, compared to vemurafenib, dabrafenib has greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.
    Journal of Pharmacology and Experimental Therapeutics 12/2012; 344(3). DOI:10.1124/jpet.112.201475 · 3.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Brain metastases in malignant melanoma carries a poor prognosis with minimal response to any therapy. The purpose of this pilot analysis was to find the effectiveness of vemurafenib, an oral BRAF inhibitor, and radiation therapy in V600 mutated melanoma with brain metastases. BRAF mutation status of the melanoma patients was determined by real-time PCR assay. Retrospective analysis was performed on twelve patients who had the mutation and were treated with either stereotactic radiosurgery or whole brain radiation therapy prior to or along with vemurafenib at a dose of 960 mg orally twice a day. Clinical and radiological responses, development of new brain metastases, overall survival and toxicity were assessed. Improvement in neurological symptoms was seen in 7/11 (64 %) following therapy. Radiographic responses were noted in 36/48 (75 %) of index lesions with 23 (48 %) complete responses and 13 (27 %) partial responses. Six month local control, freedom from new brain metastases and overall survival were 75, 57 and 92 %. Four patients had intra-tumoral bleed prior to therapy and two patients developed steroid dependence. One patient experienced radiation necrosis. This retrospective study suggests that melanoma patients with brain metastases harboring BRAF mutation appear to be a distinct sub-group with a favorable response to vemurafenib and radiation therapy and acceptable morbidity.
    Journal of Neuro-Oncology 04/2013; 113(3). DOI:10.1007/s11060-013-1127-1 · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Aberrant activation of RAF signalling is a frequent finding in human cancers. BRAF is the only RAF family member that is commonly mutated, whilst CRAF and ARAF play important roles in the signal transduction from mutant RAS. BRAF-specific inhibitors have been more effective in the treatment of BRAF-mutant melanoma than BRAF-mutant thyroid and colorectal cancers. Areas covered: The review summarises the experience with RAF kinase inhibitors, including efficacy, modes of acquired resistance, and the mechanism behind the progression of pre-malignant RAS-mutant lesions observed with RAF kinase inhibitors. The authors review all the completed and ongoing Phase I or II clinical trials of RAF kinase inhibitors and discuss in detail the rationale behind the combinatorial approaches. Expert opinion: The success of RAF kinase inhibitors has demonstrated the necessity of genotype-driven treatment selection for cancer patients. The spectrum of responses in different tumour types is explained by feedback events that are determined by cell lineage. Dissection of these events and the mechanisms of acquired resistance will determine the appropriate combination therapies. Ongoing characterisation of RAS-MAPK regulation in malignant cells may aid the development of novel agents that have greater potency for the inhibition of activated RAF kinase, and lesser propensity for promotion of RAS-mutant tumours.
    Expert Opinion on Investigational Drugs 05/2013; 22(6). DOI:10.1517/13543784.2013.797964 · 5.53 Impact Factor
Show more