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      The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ,   9 , 10 , 9 , 8 , 3 , 5 , 11 , 7 , 12 , 11 , 3 , 4 , 13 , 14 , 8 , 15 , 16 , 1 , 1 , 17 , 18 , 15 , 19 , 16 , 17 , 20 , 2 , 1 , 16 , *
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          Abstract

          Background

          Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.

          Methods and Findings

          Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.

          Conclusion

          The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

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          Most cited references41

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          Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

          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. 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. 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. 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.)
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            Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

            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. 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. 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. 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.).
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              Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

              Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Bristol-Myers Squibb. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                14 January 2013
                : 8
                : 1
                : e53745
                Affiliations
                [1 ]Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
                [2 ]Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
                [3 ]Department of Dermatology, University Hospital Mainz, Mainz, Germany
                [4 ]Institute Gustave Roussy, Department of Dermatology, Villejuif, France
                [5 ]Department of Dermatology, University Hospital Kiel, Kiel, Germany
                [6 ]Department of Dermatology and Allergology, University of Munich LMU, Munich, Germany
                [7 ]Department of Internal Medicine (Gastroenterology, Endocrinology, and Pneumology), University Hospital Erlangen, Erlangen, Germany
                [8 ]Department of Dermatology and Allergy/Department of Pathology, Skin Cancer Center Hannover/Hannover Medical School, Hannover, Germany
                [9 ]Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
                [10 ]Department of Dermatology, Hospital Hornheide, Münster, Germany
                [11 ]Department of Dermatology/III. Medical Department, Technische Universität München, München, Germany
                [12 ]Department of Dermatology, University Hospital Graz, Graz, Austria
                [13 ]Department of Dermatology, Elbe Kliniken Buxtehude, Buxtehude, Germany
                [14 ]Department of Dermatology, University Hospital Frankfurt, Frankfurt, Germany
                [15 ]Department of Dermatology, University Hospital Essen, Essen, Germany
                [16 ]Department of Oncology/Hematology and Dermatology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
                [17 ]Department of Dermatology, University Hospital Charité Berlin, Berlin, Germany
                [18 ]Department of Dermatology, Hospital Quedlinburg, Quedlinburg, Germany
                [19 ]Department of Dermatology, Cantonal Hospital Graubünden, Chur, Switzerland
                [20 ]Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany
                The University of Queensland, Australia
                Author notes

                Competing Interests: The authors have read the journal’s policy and have the following conflict: Several authors are member of local and regional BMS-ipilimumab advisory boards. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: LMH SP DG CJV. Analyzed the data: LMH CJV. Contributed reagents/materials/analysis tools: SMG CL CR KK TB C. Berking TE MF CG RG AH RH GH AJ UK CK CM PM SP IS DS MS BS UT JU JV RvM PW TW DG RD. Wrote the paper: LMH CJV. Designed the figures: CL PW RvM C. Bockmeyer. Critically reviewed the manuscript: LMH CJV SG C. Berking GS RD.

                ¶ For the ipilimumab network.

                Article
                PONE-D-12-27215
                10.1371/journal.pone.0053745
                3544906
                23341990
                a78314c8-5bce-4b09-8438-25e471ecbce1
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 September 2012
                : 3 December 2012
                Page count
                Pages: 17
                Funding
                This study is an academic study without any external funding.
                Categories
                Research Article
                Medicine
                Clinical Research Design
                Retrospective Studies
                Dermatology
                Skin Neoplasms
                Malignant Skin Neoplasms
                Melanomas
                Non-Clinical Medicine
                Health Economics
                Cost Effectiveness
                Oncology
                Cancer Treatment
                Immunotherapy
                Social and Behavioral Sciences
                Economics
                Health Economics
                Cost-Minimization Analysis

                Uncategorized
                Uncategorized

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