Improved survival with ipilimumab in patients with metastatic melanoma.
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.)
Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu
F Stephen
FS
Hodi
Steven J
SJ
O'Day
David F
DF
McDermott
Robert W
RW
Weber
Jeffrey A
JA
Sosman
John B
JB
Haanen
Rene
R
Gonzalez
Caroline
C
Robert
Dirk
D
Schadendorf
Jessica C
JC
Hassel
Wallace
W
Akerley
Alfons J M
AJ
van den Eertwegh
Jose
J
Lutzky
Paul
P
Lorigan
Julia M
JM
Vaubel
Gerald P
GP
Linette
David
D
Hogg
Christian H
CH
Ottensmeier
Celeste
C
Lebbé
Christian
C
Peschel
Ian
I
Quirt
Joseph I
JI
Clark
Jedd D
JD
Wolchok
Jeffrey S
JS
Weber
Jason
J
Tian
Michael J
MJ
Yellin
Geoffrey M
GM
Nichol
Axel
A
Hoos
Walter J
WJ
Urba
D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000473:pathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D000074324:Ipilimumab; C544395:gp100(209-2M) vaccine