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Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2011.
In March 2011, ipilimumab (YERVOY™; Bristol-Myers Squibb) gained US FDA approval for the treatment of adult patients with stage III to IV melanoma unresponsive to previous therapy. That's certainly good news for patients, who have few options once the melanoma spreads to other areas of the body (stage IV disease, metastatic melanoma).
Regulatory pathways that limit the immune response to cancer are becoming well characterised. Ipilimumab is a fully human monoclonal antibody that activates the body's immune system to fight melanoma by inhibiting the cytotoxic T lymphocyte (T-cells)-associated antigen 4 (CTLA-4) molecule.
CTLA-4 is a molecule on T-cells, a type of white blood cell, that plays a critical role in regulating natural immune responses. The presence of CTLA-4 suppresses the immune system's response to disease, so blocking its activity stimulates the immune system to fight the melanoma.
Three previous early-phase (phase II) clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51% for people with stage III or IV melanoma, which is almost double the number not on this treatment.
Ipilimumab has also being tested in advanced (phase III) trials by itself and in combination with vaccines, other immunotherapies (such as interleukin-2) and chemotherapies (such as dacarbazine). Overall response rates ranged from 13% with ipilimumab plus vaccine in patients with stage IV disease to 17% and 22%, with ipilimumab plus dacarbazine or interleukin-2, respectively, in patients with metastatic disease. Responses have been long-lasting, with more than one-third of ipilimumab-treated patients with advanced melanoma experiencing a long-term survival benefit, a rare success story in the treatment of this disease.
Recently published results of a randomized, controlled phase III trial have shown a first-ever significant overall survival benefit with ipilimumab compared with a cancer vaccine comprising HLA-A*0201–restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100) in patients with metastatic melanoma, previously treated unsuccessfully with aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered intravenously with or without gp100 (2mg peptide by deep SC) every 3 weeks for up to four treatments.
Based on these results, the US FDA granted marketing approval for ipilimumab as second-line treatment for metastatic melanoma in adult patients. The FDA noted in its approval announcement that the common adverse effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhoea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe and some fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. Because of the unusual and severe adverse effects associated with ipilimumab, the therapy was approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide has also been provided to patients to inform them about the therapy's potential adverse effects.
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. These are:
In the event of any of these adverse events, ipilimumab should be discontinued and treatment initiated with systemic corticosteroids, i.e. prednis(ol)one or equivalent. Upon improvement, corticosteroids should be tapered gradually.
Vitiligo has been reported as an adverse effect of ipilimumab. Vitiligo has been thought to be a good prognostic factor in metastatic melanoma.
The recommended dose of ipilimumab is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.
For any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy, the scheduled dose of ipilimumab should be withheld. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, ipilimumab should be resumed at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier.
Ipilimumab should be discontinued permanently for any of the following reasons:
None have been reported.
No formal drug-drug interaction studies have been conducted with ipilimumab.
No data are currently available on overdosage with ipilimumab.
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