Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

Abstract

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.)

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…Although different vaccination trials have reported a lack of a real advantage in the anti-tumor efficacy, 29 , 30 also in combination with the CTLA-4 blockade, 31 the gp100 209-217 (210M)-based vaccination, in combination with IL-2, showed clinical benefits in metastatic melanoma patients. 32 , 33 At TCR level, Schrama et al found the expansion of an oligoclonal gp100 210M-specific TCR repertoire from two patients receiving DTIC alone or in combination with low doses of IFN-α.…”

Emerging findings into molecular mechanism of brain metastasis

“…An anti‐CTLA‐4 antibody named ipilimumab was approved by the FDA for treating patients with advanced melanoma in 2011 118. When ipilimumab cooperated with SRS, a median survival was increased from 4.9 to 21.3 months, along with a 2‐year survival rate from 19.7% to 47.2% 119.…”

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…Within the last decade, treatment of metastatic melanoma (MM) has been revolutionized by a wide array of immunotherapies including checkpoint inhibitors against CTLA-4 1 and PD-1/PD-L1 2 , 3 as well as adoptive cell therapy (ACT). 4-6 However, despite great advances, treatment responses are restricted to a fraction of patients.…”