Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

Papadatos-Pastos, Dionysis; Januszewski, Adam; Dalgleish, Angus

doi:10.1586/era.13.33

Cited by 7 publications

(5 citation statements)

References 71 publications

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“…In patients with CNS metastases treated with dabrafenib, extra‐ and intracranial PFS was similar and there was little difference seen in efficacy between extra‐ and intracranial sites, but number of patients was limited (n = 23) and the analysis did not discriminate between sites of extracranial metastasis or the possibility that there was a larger initial number of extracranial metastases (Azer et al., ). Case reports have also reported solitary brain progression on vemurafenib with ongoing extracranial response, and different resistance mechanisms in the brain have therefore been suggested (Papadatos‐Pastos et al., ).…”

Section: Introductionmentioning

confidence: 99%

Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Seifert¹,

Hirata

Gore³

et al. 2015

Pigment Cell Melanoma Res

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SummaryHere, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600‐mutant metastatic melanoma for organ‐specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system (CNS) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression.Based on this, we tested in vitro the efficacy of the BRAF inhibitors PLX4720 and dabrafenib in the presence of cerebrospinal fluid (CSF). Exogenous CSF dramatically reduced cell death in response to both BRAF inhibitors. Effective cell killing was restored by co‐administration of a PI‐3 kinase inhibitor.We conclude that the efficacy of vemurafenib is variable in different organs with CNS being particularly prone to resistance. Extrinsic factors, such as ERK‐ and PI3K‐activating factors in CSF, may mediate BRAF inhibitor resistance in the CNS.

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Section: Introductionmentioning

confidence: 99%

Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Seifert¹,

Hirata

Gore³

et al. 2015

Pigment Cell Melanoma Res

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“…However, once LMD develops while on or after prior exposure to targeted therapy, survival remains poor [2]. Numerous studies have investigated the mechanisms of escape from BRAF inhibition [104]. Several lines of evidence suggest that BRAF inhibitors may have limited penetration into the brain and leptomeningeal lesions due to active drug efflux transporters [105].…”

Section: Targeted Therapymentioning

confidence: 99%

Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment

Steininger

Gellrich

Engellandt

et al. 2023

IJMS

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Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10–15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood–brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.

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“…The mechanisms of escape from BRAF inhibition have been intensively studied [ 90 ]. Some evidence describes how BRAF inhibitors could have less access to the brain and leptomeningeal lesions because of active drug efflux transporters [ 91 ].…”

Section: Leptomeningeal Involvementmentioning

confidence: 99%

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

Becco

Gallo²,

Poletto

et al. 2020

Cancers

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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.

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Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

Cited by 7 publications

References 71 publications

Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases

Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment

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

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