Ipilimumab for Melanoma Treatment

In August 2013, ipilimumab (Yervoy,^®) was made available to patients on the Pharmaceutical Benefits Scheme (PBS) for the treatment of unresectable and metastatic melanoma. Melanoma is the least common form of skin cancer, accounting for approximately 2.3% of all skin cancers, however it is the most serious form, responsible for 75% of skin cancer deaths. Exposure to ultraviolet light from the sun or solariums is the primary cause of all skin cancers, and in areas with a high level of exposure to UV light, such as Australia, there is an increased risk of melanoma. Australia, followed by New Zealand, has the highest incidence of melanoma in the world and the rate of incidence is increasing. Between 1986 and 2006, Melanoma rates in Australia doubled, with more than 12,000 new cases diagnosed each year. It is the third most common form of cancer in Australians, accounting for approximately 10% of cancers, and is the most common cancer in young Australians, aged 15-39 years.

If detected early, melanoma can be effectively treated through surgical removal, and the risk can be minimised by adhering to sun safe practices. However, unresectable advanced melanoma and metastatic disease are aggressive and have traditionally been difficult to treat. The prognosis for advanced disease is poor, with a median survival of approximately six to nine months.

In the past, systemic chemotherapy treatment options for advanced melanoma have been limited and generally considered ineffective, these include interferon-alpha-2b, dacarbazine, fotemustine and temozolomide. With a poor prognosis and low response rates to chemotherapy, there is a high clinical need for more effective advanced melanoma treatments, particularly in a country with such a high incidence as Australia.

Ipilimumab is a recombinant human monoclonal antibody, which acts by binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) on T-cells, blocking CTLA-4’s inhibitory signals and allowing T-cell activation and proliferation. This results in an enhanced immune response against the tumour which can lead to its regression.

Ipilimumab is administered at a dose of 3mg/kg over 90 minutes every three weeks for a total of four doses. The dose for this protocol was based on a phase III study which compared ipilimumab in combination with gp100, an experimental peptide vaccine used to induce an immune response, to gp100 alone and ipilimumab alone in patients with unresectable metastatic melanoma. Patients were treated once every three weeks for a total of four doses. A total of 676 patients were randomised to the study, of which 403 patients received ipilimumab 3mg/kg and gp100, while 137 received ipilimumab 3mg/kg alone and 136 received gp100 alone. Median survival for the vaccine alone was 6.4 months, compared to 10.1 months for the ipilimumab alone group and 10 months for the combination group. There was no difference in overall survival between ipilimumab used alone or with the addition of gp100. The study demonstrated long term effects of ipilimumab, showing estimated overall survival rates of 46% at one year and 24% at two years.

61% of patients who received ipilimumab, alone or in combination, received all four doses. Patients were able to receive further re-induction treatment for disease progression if after the initial induction treatment they had confirmed partial or complete response, or if there was stable disease for three months after completing treatment. Dosing for re-induction remains the same at 3mg/kg infusion every three weeks for four doses.

Common adverse events experienced by patients included fatigue, diarrhoea, decreased appetite, vomiting, abdominal pain and dyspnoea. Due to the heightened activity of the immune system, approximately 60% of patients who received ipilimumab experience immune related adverse effects. In many cases these were mild to moderate, however 10-15% of these adverse events were more severe and potentially life threatening grade three or four toxicities. There were fourteen fatalities related to the use of the study drug, seven of which were associated with immune related adverse events. Immune related adverse effects include pruritus, rash, diarrhoea, colitis, endocrine, neurological and hepatic adverse events.

These events may occur at any time after the first infusion, in some cases weeks to months after the last dose. At baseline and prior to each dose of ipilimumab, liver and thyroid function tests should be monitored, and patients should be regularly assessed for signs of immune related events during and after treatment is complete. Dose reductions are not recommended for this protocol. If patients experience immune related adverse events, doses may be omitted, however an omitted dose cannot be replaced, and some patients may not receive all four doses. Detailed guidelines to manage immune related adverse events have been developed, which depending on the type, severity and duration of event may involve symptomatic management, use of high-dose corticosteroids or other immunosuppressive therapy, hormone replacement, omission of a dose or permanent discontinuation of ipilimumab.

Patient education prior to therapy is very important to ensure they are monitoring for adverse events and understand these are potentially life threatening. Any adverse events experienced or any worsening of symptoms should be reported and medical intervention should be initiated as soon as indicated.

Due to the high cost of ipilimumab (approximately $30,000 per dose) and the relatively small clinical trials, PBS listing is conditional. The drug company Bristol-Myers Squibb must supply evidence to the Pharmaceutical Benefits Advisory Committee to verify the overall survival benefits of ipilimumab in Australian clinical practice. Patients must be registered on the Yervoy Australian Condition of Listing program in order to receive the drug. Data will be collected on patients receiving ipilimumab in Australia to determine if the survival benefits in practice correlate to what was observed in clinical trials.