Nivolumab plus Ipilimumab in advanced melanoma Journal Article


Authors: Wolchok, J. D.; Kluger, H.; Callahan, M. K.; Postow, M. A.; Rizvi, N. A.; Lesokhin, A. M.; Segal, N. H.; Ariyan, C. E.; Gordon, R. A.; Reed, K.; Burke, M. M.; Caldwell, A.; Kronenberg, S. A.; Agunwamba, B. U.; Zhang, X.; Lowy, I.; Inzunza, H. D.; Feely, W.; Horak, C. E.; Hong, Q.; Korman, A. J.; Wigginton, J. M.; Gupta, A.; Sznol, M.
Article 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. Copyright © 2013 Massachusetts Medical Society.
Journal Title: New England Journal of Medicine
Volume: 369
Issue: 2
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2013-07-11
Start Page: 122
End Page: 133
Language: English
DOI: 10.1056/NEJMoa1302369
PROVIDER: scopus
PUBMED: 23724867
PMCID: PMC5698004
DOI/URL:
Notes: --- - Cited By (since 1996):6 - "Export Date: 1 August 2013" - "CODEN: NEJMA" - "Source: Scopus"
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MSK Authors
  1. Jedd D Wolchok
    669 Wolchok
  2. Neil Howard Segal
    107 Segal
  3. Michael Andrew Postow
    187 Postow
  4. Naiyer A Rizvi
    157 Rizvi
  5. Margaret Kathleen Callahan
    103 Callahan
  6. Ruth-Ann Roman
    30 Roman
  7. Charlotte Eielson Ariyan
    78 Ariyan
  8. Alexander Meyer Lesokhin
    118 Lesokhin