Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Abstract

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

“…The role of this novel therapy in patients with brain metastases was long unexplored since many studies excluded patients with intracranial metastasis. Finally, studies that included these patients showed an intracranial disease control rate of 60–79% and a median overall survival of 9.5 and 11.2 months, proving that targeted therapy has an effect despite the blood brain barrier [ 65 ]. However, all this data is accurate for BRAFV600E mutated tumors, but not for melanoma with an NRAS mutation.…”

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

“…Recent data indicates that glioma tumors with low TMB are more likely to respond to IT (19). Clinical trials have demonstrated that IT can work for intracranial metastatic disease (20,21). Clinically significant tumor mutations are also annotated within the tumor biobank data repository.…”

CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease

“…Among melanoma patients with CNS metastases, those with LMD have the worst outcomes, with overall survival from diagnosis of typically weeks to a few months (1,2). Patients with parenchymal brain metastases have multiple treatment options including surgery, stereotactic radiosurgery, systemic therapies including the BRAF and MEK inhibitors, monotherapy with the immune checkpoint inhibitors ipilimumab or pembrolizumab, and/or the combination ipilimumab and nivolumab, which have demonstrated efficacy in clinical trials for metastatic melanoma patients with parenchymal brain metastases (3)(4)(5)(6)(7)(8). In contrast, there are very few treatment options for LMD patients (9,10), especially once patients develop LMD while on these agents.…”