title: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
abstract: BACKGROUND
  In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.
  
  
  METHODS
  In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.
  
  
  RESULTS
  Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.
  
  
  CONCLUSIONS
  The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).
authors.affiliation: From Memorial Sloan Kettering Cancer Center (M.A.P., J.D.W.), Weill Cornell Medical College (M.A.P., J.D.W.), and New York University, Perlmutter Cancer Center (A.C.P.) - all in New York; J. Graham Brown Cancer Center, University of Louisville, Louisville, KY (J.C.); Institute Gustave Roussy, Villejuif (C.R.), Paris-Sud University, Orsay (C.R.), and Institut Universitaire du Cancer, Toulouse (N.M.) - all in France; Huntsman Cancer Institute, Salt Lake City (K.G.); Beth Israel Deaconess Medical Center (D. McDermott) and Dana-Farber Cancer Institute (P.A.O., F.S.H.) - both in Boston; Washington University in St. Louis, St. Louis (G.P.L.); Greenville Health System, Greenville, SC (J.K.G.); St. Luke's Cancer Center, Bethlehem, PA (S.S.A.); University of New Mexico, Albuquerque (M.S.); Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland (M.S.E.); California Pacific Center for Melanoma Research, San Francisco (D. Minor); Duke University, Durham, NC (A.K.S.); Oregon Health and Science University, Portland (M.T.); Bristol-Myers Squibb, Lawrenceville, NJ (C.H.); and Bristol-Myers Squibb, Wallingford, CT (L.M.R., P.G.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Kenneth
authors.initials: K
authors.lastname: Grossmann
authors.forename: David
authors.initials: D
authors.lastname: McDermott
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Linette
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meyer
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Giguere
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: Montaser
authors.initials: M
authors.lastname: Shaheen
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
authors.forename: David
authors.initials: D
authors.lastname: Minor
authors.forename: April K
authors.initials: AK
authors.lastname: Salama
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rollin
authors.forename: Christine
authors.initials: C
authors.lastname: Horak
authors.forename: Paul
authors.initials: P
authors.lastname: Gagnier
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
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; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D000077594:Nivolumab; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D000077594:Nivolumab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf