Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
Hodi, F. Stephen M.D.; O'Day, Steven J. M.D.; McDermott, David F. M.D.; Weber, Robert W. M.D.; Sosman, Jeffrey A. M.D.; Haanen, John B. M.D.; Gonzalez, Rene M.D.; Robert, Caroline M.D., Ph.D.; Schadendorf, Dirk M.D.; Hassel, Jessica C. M.D.; Akerley, Wallace M.D.; van den Eertwegh, Alfons J.M. M.D., Ph.D.; Lutzky, Jose M.D.; Lorigan, Paul M.D.; Vaubel, Julia M. M.D.; Linette, Gerald P. M.D., Ph.D.; Hogg, David M.D.; Ottensmeier, Christian H. M.D., Ph.D.; Lebbe, Celeste M.D.; Peschel, Christian M.D.; Quirt, Ian M.D.; Clark, Joseph I. M.D.; Wolchok, Jedd D. M.D., Ph.D.; Weber, Jeffrey S. M.D., Ph.D.; Tian, Jason Ph.D.; Yellin, Michael J. M.D.; Nichol, Geoffrey M. M.B., Ch.B.; Hoos, Axel M.D., Ph.D.; Urba, Walter J. M.D., Ph.D.
[Article]
New England Journal of Medicine.
363(8):711-723, August 19, 2010.
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BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab - which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response - administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.
METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.
RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.
CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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