title: Pembrolizumab versus Ipilimumab in Advanced Melanoma.
abstract: BACKGROUND
  The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.
  
  
  METHODS
  In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.
  
  
  RESULTS
  The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).
  
  
  CONCLUSIONS
  The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.forename: Catriona
authors.initials: C
authors.lastname: McNeil
authors.forename: Michal
authors.initials: M
authors.lastname: Lotem
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.forename: Ronnie
authors.initials: R
authors.lastname: Shapira-Frommer
authors.forename: Michele
authors.initials: M
authors.lastname: Kosh
authors.forename: Honghong
authors.initials: H
authors.lastname: Zhou
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
authors.forename: Scot
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab