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ipilimumab (Yervoy)

Indications: - metastatic cutaneous melanoma - may be useful in combination with gemcitabine + cisplatin for treatment of metastatic urothelial carcinoma [8] - used in combination with nivolumab for treatment of renal cell carcinoma [9] - treatment of colorectal cancer deficient with microsatellite instability or mismatch repair deficiency [9] - in combination with nivolumab (Opdivo) for neoadjuvant treatment of colorectal adenocarcinoma with mismatch repair deficiency [10] Dosage: - intravenous administration - single dose up to 20 mg/kg - also given in multiple doses up to 10 mg/kg - 3 mg/kg every 3 weeks [4] Pharmacokinetics: - half-life of ipilimumab is 359 hours Adverse effects: - autoimmune reactions are common - colitis, diarrhea most commonly in association with nivolumab - autoimmune hepatitis - endocrine dysfunction - hypothalamic insufficiency - pituitary insufficiency, hypophysitis - T cell-mediated pituitary destruction [11] - adrenal insufficiency - thyroid insufficiency - inflammatory arthritis [7] - sicca syndrome [7] - fatigue - skin rash, mucositis - severe or fatal reactions in 13% Toxicity: - discontinue ipilimumab - high-dose intravenous glucocorticoids [5] - methylprednisolone Mechanism of action: - blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA4) - ipilimumab apparently decreases Bacteroidales species in stool [6] Comparative biology: - fecal transplantation into mice from patients treated with ipilimumab enhances responses of mice to anti-CTLA4 therapy [6]

Interactions

drug adverse effects of checkpoint inhibitor(s)

General

checkpoint inhibitor; immune checkpoint inhibitor; PD-1/PD-L1 inhibitor antineoplastic monoclonal antibody

References

  1. FDA NEWS RELEASE: March 25, 2011 FDA approves new treatment for a type of late-stage skin cancer http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm
  2. Weber JS et al Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008 Dec 20;26(36):5950-6. Epub 2008 Nov 17. PMID: 19018089
  3. FDA MedWatch 4/6/2011 Yervoy (ipilimumab): Risk Evaluation and Mitigation Strategy (REMS) - Severe Immune-Mediated Adverse Reactions http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249770.htm
  4. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015 Apr 19; [e-pub] PMID: 25891173 http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 - Postow MA et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015 Apr 20 PMID: 25891304 http://www.nejm.org/doi/full/10.1056/NEJMoa1414428
  5. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  6. Vetizou M, Pitt JM, Daillere R et al Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Nov 27;350(6264):1079-84 PMID: 26541610
  7. Cappelli LC et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017 Jan; 76:43 PMID: 28000525 Free Article
  8. Fuerst ML with critique by Bowman IA Metastatic Urothelial Cancer: 'PD-1/PD-L1 Inhibitors Poised to Impact Standard of Care'. Patients with tumors with mutations in genes involved in repairing DNA damage were most likely to respond. MedPage Today. ASCO Reading Room 06.14.2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/73490 - Galsky MD, Wang H, Hahn NM et al Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. European Urology 2018; 73 (5): 751-759. PMID: 29248319 https://www.europeanurology.com/article/S0302-2838(17)31033-3/abstract
  9. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune Checkpoint Inhibitor Toxicities. Mayo Clinic Proc. July 2019. 94(7):1321-1329 PMID: 31272574
  10. Davenport L 'Unprecedented' Responses to Neoadjuvant Treatment in dMMR Colon Cancer. Medscape. Sept 11, 2022 https://www.medscape.com/viewarticle/980548
  11. NEJM Knowledge+ - Hodi FS, O'Day SJ, McDermott DF et al Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. PMID: 20525992 PMCID: PMC3549297 Free PMC article. Clinical Trial. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1003466 - Barroso-Sousa R, Barry WT, Garrido-Castro AC et al Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol. 2018 Feb 1;4(2):173-182. PMID: 28973656 PMCID: PMC5838579 Free PMC article.