The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network
Authors: Caroline J Voskens, Simone M Goldinger, Carmen Loquai, Caroline Robert, Katharina C Kaehler, Carola Berking, Tanja Bergmann, Clemens L Bockmeyer, Thomas Eigentler, Michael Fluck, Claus Garbe, Ralf Gutzmer, Stephan Grabbe, Axel Hauschild, Rüdiger Hein, Gheorghe Hundorfean, Armin Justich, Ullrich Keller, Christina Klein, Christine Mateus, Peter Mohr, Sylvie Paetzold, Imke Satzger, Dirk Schadendorf, Marc Schlaeppi, Gerold Schuler, Beatrice Schuler-Thurner, Uwe Trefzer, Jens Ulrich, Julia Vaubel, Roger von Moos, Patrik Weder, Tabea Wilhelm, Daniela Göppner, Reinhard Dummer, Lucie M Heinzerling
Journal: PLoS One (2013)
MeSH terms: Antibodies, Monoclonal / adverse effects, Antibodies, Monoclonal / immunology, CTLA-4 Antigen / immunology, Melanoma / drug therapy, Melanoma / pathology, Skin Neoplasms / drug therapy, Case Reports, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal / therapeutic use, Antineoplastic Agents / adverse effects, Antineoplastic Agents / immunology, Antineoplastic Agents / therapeutic use, Endocrine System / drug effects, Female, Gastrointestinal Tract / drug effects, Humans, Ipilimumab, Kidney / drug effects, Liver / drug effects, Male, Middle Aged, Neoplasm Metastasis, Nervous System / drug effects, Pancreas / drug effects, Respiratory System / drug effects, Retrospective Studies, Skin / drug effects, Antibodies, Monoclonal, Antineoplastic Agents, CTLA-4 Antigen, Ipilimumab

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.