title: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
abstract: BACKGROUND
  Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma.
  
  
  METHODS
  We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here.
  
  
  RESULTS
  The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.
  
  
  CONCLUSIONS
  Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
authors.affiliation: From the Department of Medical Oncology, Royal Marsden Hospital, London (J.L.), and South West Wales Cancer Institute, Singleton Hospital, Swansea (J.W.) - both in the United Kingdom; Melanoma Oncology Unit, Veneto Region Oncology Research Institute, Padua (V.C.-S.), Oncology of Melanoma Unit, European Institute of Oncology, Milan (P.F.F.), University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy; Division of Medical Oncology, University of Colorado, Denver, Denver (R.G.); Aix-Marseille University, Hôpital de La Timone, Assitance Publique-Hôpitaux de Marseille, Marseille (J.J.G.), and Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.) - both in France; Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); Departments of Internal Medicine and Dermatology, University of Michigan, Ann Arbor (C.D.L.); Department of Dermatology, University of Essen, Essen, Germany (D.S.); University of Zürich Hospital, Zurich, Switzerland (R.D.); Cross Cancer Institute, Edmonton, AB, Canada (M. Smylie); Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (P.R.); Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), and Westmead and Blacktown Hospitals (M.S.C.) and Melanoma Institute Australia (M.S.C., G.V.L.), University of Sydney, and the Mater Hospital (G.V.L.), Sydney, and Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC (G.A.M.) - all in Australia; Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam (J.B.H.); Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid (I.M.-R.); Ludwig Center, Memorial Sloan Kettering Cancer Center (M.K.C., M.A.P., J.D.W.) and Weill Cornell Medical College (M.K.C., M.A.P., J.D.W.) - both in New York; Huntsman Cancer Institute, University of Utah, Salt Lake City (K.G.); Yale Cancer Center, Smilow Cancer Hospital of the Yale-New Haven Hospital, Yale University Sc
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: C Lance
authors.initials: CL
authors.lastname: Cowey
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lao
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Michael
authors.initials: M
authors.lastname: Smylie
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Pier F
authors.initials: PF
authors.lastname: Ferrucci
authors.forename: Andrew
authors.initials: A
authors.lastname: Hill
authors.forename: John
authors.initials: J
authors.lastname: Wagstaff
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Ivan
authors.initials: I
authors.lastname: Marquez-Rodas
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.forename: Kenneth
authors.initials: K
authors.lastname: Grossmann
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.forename: Lars
authors.initials: L
authors.lastname: Bastholt
authors.forename: Arvin
authors.initials: A
authors.lastname: Yang
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rollin
authors.forename: Christine
authors.initials: C
authors.lastname: Horak
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D000077594:Nivolumab; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D000077594:Nivolumab