Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

Abstract

Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…First, cytotoxic agents that elicit immunogenic TCD, which converts the tumor itself into an endogenous vaccine and provides adequate DC stimulation, through release of danger signals, are ideal candidates for combination with adoptive immunotherapy strategies aimed at eliminating immune suppressor cells. For example, combining standard chemotherapy with ipilimumab, a human anti-CTLA-4 monoclonal antibody that blocks the CTLA-4 inhibitory signal on T-cells, proved extremely effective in a phase-III clinical trial on advanced melanoma patients, 128,129 as well as in a phase-II clinical trial on lung cancer patients. 130 Second, as chemotherapy increases the immune visibility of surviving or damaged tumor cells by upregulating HLA molecules and NK-related or TRAIL ligands, co-administration of immunostimulatory molecules (for example, TLR ligands, cytokines, and so on) may further facilitate immune recognition by DCs and NK, thus potentiating antitumor T-cell responses.…”

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…5 A second randomized trial assessed 502 patients with previously untreated metastatic melanoma who were randomly assigned to receive ipilimumab (10 mg/kg) and dacarbazine (850 mg/m 2 body-surface area) or dacarbazine (850 mg/m 2 ) and placebo. 9 In that trial, overall survival was increased in patients who received ipilimumab (11.2 months versus 9.1 months; P <0.001). The 3-year survival was also higher in patients receiving ipilimumab (20.8% versus 12.2%; hazard ratio for death, 0.72; P <0.001).…”

“…Ipilimumab has been evaluated in several phase I and II clinical trials and demonstrated an improvement in overall survival in patients with metastatic melanoma in two large prospective randomized phase III trials. 5,9,44,45 In a double-blind, randomized phase III trial, 676 patients with advanced-stage melanoma who expressed the HLA-A2 haplotype were treated with ipilimumab (3 mg/kg), ipilimumab (3 mg/kg) and an HLA-A2-restricted modified gp100 peptide vaccine, or vaccine alone. Patients who received ipilimumab in either treatment arm had improved overall survival compared to patients receiving vaccine alone (10 months versus 6 months; P = 0.0026).…”

“…7,8 Ipilimumab has been associated with significant improvement in overall survival in the metastatic setting. 5,9 Immunotherapy requires special attention to several caveats. Although therapeutic benefits can be durable, only a subset of patients respond.…”

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…In the first study, ipilimumab therapy led to a 4 month improvement in overall survival (HR 0.66; p = 0.0026) and an 11 % radiographic response rate compared to only 1.5 % of control patients [17]. In the second study, ipilimumab plus dacarbazine had higher median overall survival as well as improved survival at 1, 2 and 3 years compared to dacarbazine plus placebo [18]. Of note in both of these studies, median PFS did not differ between treatment arms although the PFS hazard ratio was reduced for ipilimumab receiving patients.…”