Ipilimumab

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Compound Name:IpilimumabMolecular Target:CTLA-4 (cytotoxic T-lymphocyte-associated antigen)Molecular Structure:Chimeric IgG1?, recombinant monoclonal antibodyLicensed Indication:Melanoma that is metastatic or unresectableManufacturer and/or Distributor:Bristol-Myers SquibbInitial FDA Approval:2011Summary:Ipilimumab (Yervoy) is a fully human IgG1k monoclonal antibody that binds to the T-cell surface molecule CTLA-4 (cytotoxic T-lymphocyte-associated antigen) and blocks its interaction with its ligands, CD80 and CD86. This prevents the delivery of a negative signal to the T cells, and thus augments their activation and proliferation. This is thought to enhance an active immune response by T cells directed at cancer cells. Ipilimumab is administered as an intravenous infusion in 4 doses over 9 weeks. Ipilimumab was approved by the FDA on March 25, 2011 for the treatment of unresectable or metastatic melanoma. Additionally, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer. On September 2015, the FDA granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. The approval of ipilimumab for treatment of melanoma was based on a trial of 676 previously-treated patients with unresectable or metastatic disease. Overall median survival improved from 6 months in the control group to 10 months in the ipilimumab groups. Interestingly, approximately 20% of the ipilimumab-treated patients have shown long-term survival (>3 years) in follow-up studies. Phase III study in 951 patients, EORTC 18071, has also indicated that adjuvant therapy with ipilimumab for patients with high-risk stage III melanoma decreases the relative risk of cancer recurrence by 25% compared to placebo. The T-cell activation and proliferation set off by ipilimumab can lead to the targeting of various organ systems by an immune-mediated attack that can be severe or even fatal. These adverse reactions include hepatitis, enterocolitis, dermatitis, neuropathy, and endocrinopathies, particularly of the thyroid. Management of immune-mediated adverse reactions includes permanent discontinuation of ipilimumab and initiation of high dose corticosteroids. Milder adverse reactions include fatigue, diarrhea, pruritus, rash and colitis.References

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1. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012 Apr 1;18(7):2039-2047.  http://www.ncbi.nlm.nih.gov/pubmed/22271879 

2. Thompson JA, Hamid O, Minor D, Amin A, Ron IG, Ridolfi R, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial. J Immunother. 2012 Jan;35(1):73-77.  http://www.ncbi.nlm.nih.gov/pubmed/22130164 

3. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res. 2011 Nov 15;17(22):6958-6962.  http://www.ncbi.nlm.nih.gov/pubmed/21900389 

4. Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother. 2012 Jan;35(1):89-97.  http://www.ncbi.nlm.nih.gov/pubmed/22130166 

5. Wolchok J, Hodi F, Weber J, Allison J, Urba W, Robert C, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Annals of the New York Academy of Sciences. 2013;1291(1):1-13.  http://www.ncbi.nlm.nih.gov/pubmed/23772560

6. Callahan M, Postow M, Wolchok J. Immunomodulatory therapy for melanoma: ipilimumab and beyond. Clinics in dermatology. 2013;31(2):191-199.  http://www.ncbi.nlm.nih.gov/pubmed/23438382

7. Maio M, Di Giacomo A, Robert C, Eggermont AM. Update on the role of ipilimumab in melanoma and first data on new combination therapies. Current opinion in oncology. 2013;25(2):166-172.  http://www.ncbi.nlm.nih.gov/pubmed/23299197

8. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. http://www.ncbi.nlm.nih.gov/pubmed/25840693

9. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. https://www.ncbi.nlm.nih.gov/pubmed/27717298

10. Copur MS, Ramaekers R, Crockett D. Ipilimumab Adjuvant Therapy in Melanoma. N Engl J Med. 2017 Jan 26;376(4):398-9. https://www.ncbi.nlm.nih.gov/pubmed/28125194

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