Dataset Information

Melanoma brain metastases and vemurafenib: need for further investigation.

ABSTRACT: 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.

SUBMITTER: Rochet NM

PROVIDER: S-EPMC3538399 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Melanoma brain metastases and vemurafenib: need for further investigation.

Rochet Nicole M NM Dronca Roxana S RS Kottschade Lisa A LA Chavan Rahul N RN Gorman Brian B Gilbertson Julie R JR Markovic Svetomir N SN

Mayo Clinic proceedings 20121001 10

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- ...[more]

PMID: 23036672

Similar Datasets

Project description:BackgroundRAF inhibitors are an effective therapy for patients with BRAF-mutant melanoma and brain metastasis. Efficacy data are derived from clinical studies enriched with physiologically fit patients; therefore, it is of interest to assess the real-world experience of vemurafenib in this population. Tumor-specific genetic variants that influence sensitivity to RAF kinase inhibitors also require investigation.MethodsRecords of patients with BRAF-mutant melanoma and brain metastases who were treated with vemurafenib were reviewed. Clinical data were extracted to determine extracranial and intracranial objective response rates, progression-free survival (PFS), overall survival (OS), and safety. A bait-capture, next-generation sequencing assay was used to identify mutations in pretreatment tumors that could explain primary resistance to vemurafenib.ResultsAmong patients with intracranial disease treated with vemurafenib, 27 were included in survival analyses and 22 patients were assessable for response. The extracranial and intracranial objective response rates were 71% and 50%, respectively. Discordant responses were observed between extracranial and intracranial metastatic sites in 4 of 19 evaluable patients. Median PFS was 4.1 months (95% confidence interval [CI]: 2.6-7.9); median intracranial PFS was 4.6 months (95% CI: 2.7-7.9), median OS was 7.5 months (95% CI: 4.3-not reached), with a 30.4% 1-year OS rate. Outcomes were influenced by performance status. Vemurafenib was tolerable, although radiation-induced dermatitis occurred in some patients who received whole-brain radiotherapy. Adequate samples for next-generation sequencing analysis were available for seven patients. Melanomas categorized as "poorly sensitive" (?20% tumor growth, new lesions, or ?50% shrinkage for <4 months) harbored co-occurring mutations in genes predicted to activate the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway.ConclusionVemurafenib is highly active in BRAF-mutant melanoma brain metastases but has limited activity in patients with poor performance status. The safety and efficacy of concurrent radiotherapy and RAF inhibition requires careful clinical evaluation. Combination strategies blocking the MAPK and PI3K-AKT pathway may be warranted in a subset of patients.Implications for practiceVemurafenib is active for BRAF-mutant intracranial melanoma metastases in an unselected patient population typical of routine oncologic practice. Patients with poor performance status appear to have poor outcomes despite vemurafenib therapy. Preliminary data indicate that co-occurring or secondary alterations in the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway are involved in resistance to RAF inhibition, thus providing a rationale for dual MAPK and PI3K-AKT pathway inhibition in this patient population.

Dataset Information

Melanoma brain metastases and vemurafenib: need for further investigation.

Publications

Melanoma brain metastases and vemurafenib: need for further investigation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets