title: Inhibition of mutated, activated BRAF in metastatic melanoma.
abstract: BACKGROUND
  The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.
  
  
  METHODS
  We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.
  
  
  RESULTS
  A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.
  
  
  CONCLUSIONS
  Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA. kflaherty@partners.org
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
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