title: Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma.
abstract: OBJECTIVE
  The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma.
  
  
  METHODS
  In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m(2) intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity.
  
  
  RESULTS
  In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference.
  
  
  CONCLUSIONS
  Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.
authors.affiliation: Massachusetts General Hospital, 55 Fruit St, Yawkey 9E, Boston, MA 02114, USA. kflaherty@partners.org
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhao
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: Lawrence
authors.initials: L
authors.lastname: Flaherty
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Philip
authors.initials: P
authors.lastname: Leming
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; D017239:Paclitaxel