title: Nivolumab plus ipilimumab in advanced melanoma.
abstract: BACKGROUND
  In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.
  
  
  METHODS
  We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
  
  
  RESULTS
  A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.
  
  
  CONCLUSIONS
  Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. wolchokj@mskcc.org
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Callahan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lesokhin
authors.forename: Neil H
authors.initials: NH
authors.lastname: Segal
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Ariyan
authors.forename: Ruth-Ann
authors.initials: RA
authors.lastname: Gordon
authors.forename: Kathleen
authors.initials: K
authors.lastname: Reed
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Burke
authors.forename: Anne
authors.initials: A
authors.lastname: Caldwell
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kronenberg
authors.forename: Blessing U
authors.initials: BU
authors.lastname: Agunwamba
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Hector David
authors.initials: HD
authors.lastname: Inzunza
authors.forename: William
authors.initials: W
authors.lastname: Feely
authors.forename: Christine E
authors.initials: CE
authors.lastname: Horak
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.forename: Jon M
authors.initials: JM
authors.lastname: Wigginton
authors.forename: Ashok
authors.initials: A
authors.lastname: Gupta
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab