PMID- 23724867
OWN - NLM
STAT- MEDLINE
DCOM- 20130725
LR  - 20220410
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Print)
IS  - 0028-4793 (Linking)
VI  - 369
IP  - 2
DP  - 2013 Jul 11
TI  - Nivolumab plus ipilimumab in advanced melanoma.
PG  - 122-33
LID - 10.1056/NEJMoa1302369 [doi]
AB  - 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.).
FAU - Wolchok, Jedd D
AU  - Wolchok JD
AD  - Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. 
      wolchokj@mskcc.org
FAU - Kluger, Harriet
AU  - Kluger H
FAU - Callahan, Margaret K
AU  - Callahan MK
FAU - Postow, Michael A
AU  - Postow MA
FAU - Rizvi, Naiyer A
AU  - Rizvi NA
FAU - Lesokhin, Alexander M
AU  - Lesokhin AM
FAU - Segal, Neil H
AU  - Segal NH
FAU - Ariyan, Charlotte E
AU  - Ariyan CE
FAU - Gordon, Ruth-Ann
AU  - Gordon RA
FAU - Reed, Kathleen
AU  - Reed K
FAU - Burke, Matthew M
AU  - Burke MM
FAU - Caldwell, Anne
AU  - Caldwell A
FAU - Kronenberg, Stephanie A
AU  - Kronenberg SA
FAU - Agunwamba, Blessing U
AU  - Agunwamba BU
FAU - Zhang, Xiaoling
AU  - Zhang X
FAU - Lowy, Israel
AU  - Lowy I
FAU - Inzunza, Hector David
AU  - Inzunza HD
FAU - Feely, William
AU  - Feely W
FAU - Horak, Christine E
AU  - Horak CE
FAU - Hong, Quan
AU  - Hong Q
FAU - Korman, Alan J
AU  - Korman AJ
FAU - Wigginton, Jon M
AU  - Wigginton JM
FAU - Gupta, Ashok
AU  - Gupta A
FAU - Sznol, Mario
AU  - Sznol M
LA  - eng
SI  - ClinicalTrials.gov/NCT01024231
GR  - K24 CA172123/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20130602
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Ipilimumab)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 31YO63LBSN (Nivolumab)
SB  - IM
CIN - N Engl J Med. 2013 Jul 11;369(2):187-9. PMID: 23724866
CIN - Nat Rev Clin Oncol. 2013 Jul;10(7):365. PMID: 23752732
EIN - N Engl J Med. 2018 Nov 29;379(22):2185. PMID: 31442371
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects/*therapeutic use
MH  - Antineoplastic Agents/*administration & dosage/adverse effects
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - CTLA-4 Antigen/*antagonists & inhibitors/immunology
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Ipilimumab
MH  - Male
MH  - Melanoma/*drug therapy/pathology
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - Nivolumab
MH  - Programmed Cell Death 1 Receptor/*antagonists & inhibitors
MH  - Skin Neoplasms/*drug therapy/pathology
MH  - Young Adult
PMC - PMC5698004
MID - NIHMS919205
EDAT- 2013/06/04 06:00
MHDA- 2013/07/26 06:00
PMCR- 2017/11/21
CRDT- 2013/06/04 06:00
PHST- 2013/06/04 06:00 [entrez]
PHST- 2013/06/04 06:00 [pubmed]
PHST- 2013/07/26 06:00 [medline]
PHST- 2017/11/21 00:00 [pmc-release]
AID - 10.1056/NEJMoa1302369 [doi]
PST - ppublish
SO  - N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 
      Jun 2.