BRAF-MEK inhibition in melanoma brain metastases: a new hope

Abstract

About 30% of patients with stage IV melanoma manifest clinically apparent melanoma brain metastasis at some point in their disease course. Until about 5 years ago, few patients with melanoma brain metastasis were eligible for clinical trials, and survival rates were dismal. The development of brain metastases is a complex process that involves tumour cells escaping from the primary or other metastatic sites, intravasating into the systemic circulation, and arresting in and extravasating from intracranial capillary beds, ultimately resulting in the establishment of new and progressive tumours. Although the biology of melanoma brain metastasis remains poorly understood, a number of signalling pathways have been implicated. STAT3 signalling is involved in extravasation, angiogenesis, and prevention of anoikis (death due to inadequate attachment to extracellular matrix). Increased PI3K/AKT signalling, often caused by loss of the negative regulator PTEN, has been reported in melanoma brain metastasis compared with matched extracranial lesions. 1 Chen G Chakravarti N Aardalen K et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res. 2014; 20: 5537-5546 Crossref PubMed Scopus (126) Google Scholar Preclinical evidence also shows that the brain microenvironment contributes to melanoma growth and treatment resistance. 2 Niessner H Forschner A Klumpp B et al. Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med. 2013; 2: 76-85 Crossref PubMed Google Scholar Although the blood–brain barrier prevents most drugs from accessing normal brain, it is compromised in brain metastases, so therapeutics with extracranial activity frequently show intracranial activity. BRAF inhibitors have potent activity against extracranial BRAFV600-mutant metastatic melanoma; a trial 3 Long VB Trefzer U Davies MA et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 13: 1087-1095 Summary Full Text Full Text PDF PubMed Scopus (734) Google Scholar of dabrafenib monotherapy showed that 39% of patients with melanoma brain metastases responded, despite little or no penetration through the intact blood–brain barrier. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trialDabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. Full-Text PDF