title: Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.
abstract: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.
  
  
  
  This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.
  
  
  
  Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events.
  
  
  
  In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.
  
  
  
  Bristol-Myers Squibb.
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Medical Oncology, National Cancer Institute, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Del Vecchio
authors.affiliation: Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mackiewicz
authors.affiliation: IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy.
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.affiliation: Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.affiliation: AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France.
authors.forename: Céleste
authors.initials: C
authors.lastname: Lebbé
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Bastholt
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.affiliation: Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McNeil
authors.affiliation: Eberhard Karls University, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: University Medical Center, Mainz, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Hospital de la Timone, Marseille, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: National Institute of Oncology, Budapest, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Liszkay
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: Marta
authors.initials: M
authors.lastname: Nyakas
authors.affiliation: Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Wojewodzkie Centrum Oncologii, Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pikiel
authors.affiliation: Department of Dermatology, Reims University Hospital, Reims, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Grange
authors.affiliation: Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoeller
authors.affiliation: Istituti Fisioterapici Ospitalieri, Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferraresi
authors.affiliation: Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Smylie
authors.affiliation: University Hospital Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Hôspital Claude Huriez, Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.affiliation: Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Hennicken
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Anila
authors.initials: A
authors.lastname: Qureshi
authors.affiliation: University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
mesh_terms: D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003092:Colitis / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000072659:Hypophysitis / Q000139:chemically induced; D057194:Intention to Treat Analysis; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D000410:Alanine Transaminase