OBJECTIVE: To review the mechanism of action, pharmacokinetics, efficacy, safety, drug interactions, dosing, and economic considerations of ipilimumab. DATA SOURCES: A literature search using MEDLINE (1966-November 2010) was performed using the terms ipilimumab, metastatic melanoma, MDX-010, and MDX-101. Additional data were obtained from meeting abstracts, bibliographies, and media releases. STUDY SELECTION AND DATA EXTRACTION: English-language articles identified from the data sources were reviewed. Selected studies evaluated the pharmacology, pharmacokinetics, efficacy, and safety of ipilimumab for the treatment of metastatic melanoma. DATA SYNTHESIS: The incidence of melanoma in the US is increasing faster than any other type of cancer in men and more than any other type of cancer, except lung cancer, in women. For patients with metastatic melanoma, systemic therapies are limited by low response rates, short durations of response, and a 5-year survival rate <10%. Ipilimumab, a novel CTLA-4 inhibitor, is under investigation for the treatment of metastatic melanoma. Results of a randomized, controlled Phase 3 trial showed a first-ever overall survival benefit for patients with previously treated metastatic melanoma who received ipilimumab compared with the controls. The majority of adverse events reported with ipilimumab administration are considered to be low-grade immune-related events involving the skin and intestine and can be managed medically. Nonetheless, 10-17% of patients have immune-related adverse events of grade 3 or higher severity, with 2-3% of these events resulting in death. CONCLUSIONS: Ipilimumab is a novel CTLA-4 inhibitor that has been evaluated for the treatment of metastatic melanoma. On March 25, 2011, the Food and Drug Administration approved ipilimumab, making it the first agent indicated for unresectable or metastatic melanoma in more than a decade.

RECORD STATUS: This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database. CITATION: Pichon Riviere A, Augustovski F, Garcia Marti S, Glujovsky D, Alcaraz A, Lopez A, Bardach A, Ciapponi A, Rey-Ares L, Caccavo F. Ipilimumab para pacientes con melanoma metastásico. [Ipilimumab for patients with metastatic melanoma] Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rápida N° 265. 2012

RECORD STATUS: This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database. CITATION: IQWiG. Addendum zum Auftrag A13-44 (Ipilimumab, neues Anwendungsgebiet) . [Addendum to Commission A13-44 (ipilimumab)] Cologne: Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). IQWiG-Berichte 213. 2014

BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: 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.).

RECORD STATUS: None CITATION: Ipilimumab for previously treated unresectable malignant melanoma.. NIHR Health Technology Assessment programme.

RECORD STATUS: This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality of this assessment has been made for the HTA database. CITATION: NHSC. Ipilimumab (Yervoy) for prostate cancer – second line Birmingham: National Horizon Scanning Centre (NHSC). Horizon Scanning Review. 2011

Studies of ipilimumab have shown improved overall survival in patients with metastatic cutaneous melanoma. As a result, use of ipilimumab in patients with Stage IV melanoma is rapidly increasing. Patients with Stage IV melanoma often require urgent operations for complications from metastases, but little is known about the safety of surgical intervention for patients receiving ipilimumab. We performed a systematic review of the literature using PubMed. Our search terms were melanoma and ipilimumab. We excluded foreign language articles, review articles, and those not addressing cutaneous melanoma. We identified 194 publications matching the search criteria. Only six of those met the inclusion criteria. In these six publications, seven patients who had undergone surgical intervention during treatment with ipilimumab were described. There were no documented surgical complications. We reviewed our institutional experience and identified an additional three patients. No postoperative complications could be attributed directly to ipilimumab. There are limited data on the safety of surgical intervention during treatment with ipilimumab. Preliminary reports suggest there is no reason to withhold or delay surgery for patients receiving ipilimumab therapy.

Of 93 patients with pretreated, BRAF(V600) mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p < .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated 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.)