title: Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
abstract: OBJECTIVE
  In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.
  
  
  METHODS
  Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).
  
  
  RESULTS
  In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.
  
  
  CONCLUSIONS
  This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.
authors.affiliation: Division of Hematology-Oncology, 11-934 Factor Building, UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Marshall
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.forename: Maribel
authors.initials: M
authors.lastname: Marmol
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Gerald
authors.initials: G
authors.lastname: Linette
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Kari L
authors.initials: KL
authors.lastname: Kendra
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.forename: Michael
authors.initials: M
authors.lastname: Smylie
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.forename: Paul D
authors.initials: PD
authors.lastname: Nathan
authors.forename: Jacek
authors.initials: J
authors.lastname: Mackiewicz
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomez-Navarro
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Dmitri
authors.initials: D
authors.lastname: Pavlov
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011537:Pruritus / Q000139:chemically induced; D016879:Salvage Therapy / Q000379:methods; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; C520704:tremelimumab