title: A Retrospective Evaluation of Vemurafenib as Treatment for BRAF-Mutant Melanoma Brain Metastases.
abstract: BACKGROUND
  RAF 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.
  
  
  METHODS
  Records 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.
  
  
  RESULTS
  Among 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.
  
  
  CONCLUSIONS
  Vemurafenib 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.
  
  
  CONCLUSIONS
  Vemurafenib 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.
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA HardinJ1@mskcc.org.
authors.forename: James J
authors.initials: JJ
authors.lastname: Harding
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Catalanotti
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Munhoz
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Donavan T
authors.initials: DT
authors.lastname: Cheng
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Yaqubie
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kelly
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: McDermott
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Romona
authors.initials: R
authors.lastname: Kersellius
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Human Oncology and Pathogenesis Program, Memorial Hospital Research Laboratories, New York, New York, USA; Immunology and Molecular and Pharmacology and Chemistry Programs, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Brain metastasis; Melanoma; Vemurafenib