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.)
Hodi
F Stephen
FS
Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu
O'Day
Steven J
SJ
McDermott
David F
DF
Weber
Robert W
RW
Sosman
Jeffrey A
JA
Haanen
John B
JB
Gonzalez
Rene
R
Robert
Caroline
C
Schadendorf
Dirk
D
Hassel
Jessica C
JC
Akerley
Wallace
W
van den Eertwegh
Alfons J M
AJ
Lutzky
Jose
J
Lorigan
Paul
P
Vaubel
Julia M
JM
Linette
Gerald P
GP
Hogg
David
D
Ottensmeier
Christian H
CH
Lebbé
Celeste
C
Peschel
Christian
C
Quirt
Ian
I
Clark
Joseph I
JI
Wolchok
Jedd D
JD
Weber
Jeffrey S
JS
Tian
Jason
J
Yellin
Michael J
MJ
Nichol
Geoffrey M
GM
Hoos
Axel
A
Urba
Walter J
WJ
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