5 mg per 1 mL concentrate solution for infusion
Approved indication: metastatic melanoma
Australian Medicines Handbook section 14.2.1
Patients with metastatic melanoma have a poor prognosis. Although chemotherapy may be given for progressive disease the response rate is low.
Ipilimumab is a recombinant human monoclonal antibody. It binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) on activated T-cells. This enhances immune responses which could lead to tumour regression.
In a phase II study, 155 patients were given ipilimumab after previous treatment of their unresectable melanomas had failed. They were given an intravenous infusion (10 mg/kg) every three weeks (at weeks 1, 4, 7 and 10) then every 12 weeks. The overall response rate was 5.8%. There were no complete responses but nine patients had a partial response to treatment. With a median follow-up of 10 months, the median overall survival was 10.2 months.1
A double-blind dose-finding trial investigated previously-treated patients with advanced melanoma. The 217 patients were randomised to receive doses of 0.3 mg, 3 mg or 10 mg/kg for induction and maintenance therapy. The overall response rate increased with the dose. While nobody responded to the lowest dose, the response rate was 4.2% with 3 mg/kg and 11.1% with 10 mg/kg. The median overall survival was 8.6 months with 0.3 mg/kg, 8.7 months with 3 mg/kg and 11.4 months with 10 mg/kg.2
The 3 mg/kg dose was used in a phase III double-blind trial. In this study, 137 previously-treated patients were randomised to receive ipilimumab alone while 403 were randomised to also receive a peptide vaccine to induce an immune response. Another group of 136 patients were randomised to receive the vaccine alone. The patients were followed up for up to 55 months. Median survival was only 6.4 months with the vaccine alone. This was significantly less than the 10.1 months with ipilimumab alone and the 10 months in the combined treatment group. After 24 months, 21.6% of the ipilimumab group and 23.5% of the combined treatment group were still alive.3
Another trial involved 502 patients with previously untreated metastatic melanoma. They were randomised to receive dacarbazine or dacarbazine plus ipilimumab (10 mg/kg). The median survival was 9.1 months with dacarbazine and 11.2 months with the combination. After 24 months the survival rate was 17.9% with dacarbazine and 28.5% with the combination.4
Stimulating an immune response can provoke severe adverse reactions in any organ system. Gastrointestinal effects are common with ipilimumab and immune-mediated enterocolitis can be fatal. Immune-mediated hepatitis, dermatitis, neuropathy and endocrinopathy can also be life-threatening. In the phase III study of previously treated patients, 2.1% died because of the effects of their treatment (8 patients in the combination group, 4 in the ipilimumab group, 2 in the vaccine group).3 While immune reactions may respond to systemic corticosteroids, a study found that prophylactic oral budesonide does not affect the rate of severe diarrhoea.5
Ipilimumab should be infused over 90 minutes. A steady state is reached by the third dose and the terminal half-life is approximately 15 days. Although some of the trials used a higher dose, the recommended dose is 3 mg/kg.
Ipilimumab improves survival in patients with metastatic melanoma. This improvement comes at the risk of severe adverse reactions which may be delayed in onset and can be persistent. However, there could possibly be a relationship between the immune-mediated adverse effects and the likelihood of the melanoma responding. Further research is needed to assess the role of the drug in other presentations of the disease, particularly as some trials excluded patients with brain metastases. At present ipilimumab is only approved as monotherapy for patients with unresectable or metastatic melanoma who have failed or are intolerant to previous therapy.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010;21:1712-7.
- Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155-64.
- Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
- Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26.
- Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009;15:5591-8.