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Ipilimumab safety profile: Summary of findings from completed trials in advanced melanoma.
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2011
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Inflammation-related AesImmunodeficienciesImmune RegulationImmunologyImmunoeditingImmunotherapeuticsDermatologyImmune SystemImmunotherapyInflammationMetronomic TherapyClinical TrialsTumor ImmunitySafety DataCancer ResearchMolecular OncologySkin CancerAllergyAutoimmune DiseaseMedicineMelanomaAutoimmunityT Cell ImmunityImmune FunctionCancer TreatmentAdvanced MelanomaCancer ImmunosurveillanceIpilimumab Safety ProfileImmune Checkpoint InhibitorOncology
8583 Background: Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, has shown overall survival benefit in a phase III trial of patients with pretreated advanced melanoma (Hodi FS. NEJM 2010;363:711). Ipilimumab potentiates T cells by blocking the inhibitory function of CTLA-4; adverse events (AEs) associated with ipilimumab likely reflect this mechanism of action and are primarily inflammation-related. To further describe the safety profile of ipilimumab, a program wide review of observations from melanoma clinical trials was undertaken. Methods: A retrospective review was performed of safety data from 14 completed phase I-III trials of ipilimumab in patients with advanced melanoma. Safety data were pooled from 1498 patients treated with ipilimumab at various doses, alone and in combination with various agents, and AEs in the following categories were analyzed: all AEs; drug-related AEs; inflammation-related AEs, all serious AEs (SAEs); and drug-related SAEs. Results: Gastrointestinal (mostly diarrhea and/or colitis) and dermatologic (mostly rash, pruritus) inflammation-related AEs were the most common, with toxicities less frequently involving the liver and endocrine glands; neurological manifestations were rare. Inflammation-related AEs affecting other organ systems in <1% of patients included uveitis, pneumonitis, pancreatitis, autoimmune nephritis, myasthenia gravis, and others. Most inflammation-related AEs occurred during induction (initial 4 doses given once every 3 weeks). Conclusions: Of 1,498 patients studied, inflammation-related AEs occurred in 64.2% and resulted in death in <1% of patients. Although inflammation-related AEs associated with ipilimumab can be life threatening, these were generally mild and managed using product specific treatment guidelines that emphasize vigilance and appropriate use of immunosuppressive therapy and may require long-term hormone replacement. On-study AEs, n (%). Grade All AEs Drug-related AEs Inflammation-related AEs All SAEs Drug-related SAEs Any 1,452 (96.9) 1,271 (84.8) 962 (64.2) 597 (39.9) 319 (21.3) 3-4 689 (46.0) 379 (25.3) 266 (17.8) 470 (31.4) 241 (16.1) 5 50 (3.3) 13 (0.9) 9 (0.6) 49 (3.3) 13 (0.9)