title: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
abstract: BACKGROUND
  Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.
  
  
  METHODS
  We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.
  
  
  RESULTS
  Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.
  
  
  CONCLUSIONS
  Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).
authors.affiliation: Institute Gustave, Roussy, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.forename: Steven
authors.initials: S
authors.lastname: O'Day
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Baurain
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Neville
authors.initials: N
authors.lastname: Davidson
authors.forename: Jon
authors.initials: J
authors.lastname: Richards
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.forename: Pere
authors.initials: P
authors.lastname: Gascon
authors.forename: Michal
authors.initials: M
authors.lastname: Lotem
authors.forename: Kaan
authors.initials: K
authors.lastname: Harmankaya
authors.forename: Ramy
authors.initials: R
authors.lastname: Ibrahim
authors.forename: Stephen
authors.initials: S
authors.lastname: Francis
authors.forename: Tai-Tsang
authors.initials: TT
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Humphrey
authors.forename: Axel
authors.initials: A
authors.lastname: Hoos
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008111:Liver Function Tests; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D016016:Proportional Hazards Models
chemical_list: D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D000074324:Ipilimumab; D003606:Dacarbazine