Melanoma is a malignant cancer that begins in the melanocytes of the skin. It is often referred to as our national cancer as Australia has the highest incidence of melanoma in the world. Whilst melanoma is not the most common form of skin cancer, it accounts for around 75% of skin cancer related deaths. This is due to its tendency to grow quickly and spread to other parts of the body, combined with its relative resistance to traditional therapies.
Early detection is the key to securing a favourable prognosis. If detected early, while the melanoma is still localised in the epidermis, surgical excision (ensuring clear margins) is generally curative. However, the outcome for patients with metastatic or unresectable melanomas is usually poor. The five year survival rate for patients with distant metastases is only around 10%.
Ipilimumab (Yervoy®) offers a new approach to melanoma treatment. Ipilimumab is a monoclonal antibody specific for cytotoxic T-lymphocyte antigen 4 (CTLA-4). CTLA-4 is a receptor protein expressed on the surface of T-lymphocytes, and is responsible for downregulating the response of these cells. By blocking the inhibitory effect of CTLA-4, ipilimumab acts to enhance the body’s immune response to melanoma.
Melanoma cells express proteins on their surfaces which may be processed by antigen presenting cells (APCs) and then presented to T-lymphocytes. Once the T-lymphocytes recognise these melanoma antigens, they may become stimulated to induce an immune response.
For full activation of the T-lymphocytes and subsequent immune cascade, a second signal is required. A class of peripheral membrane proteins known as B7 can be found on the surface of APCs. These B7 proteins function to either upregulate or downregulate the ensuing immune response, depending upon which receptor they bind to on the T-lymphocyte. However, the strength of this immune response depends upon the complex interplay between cluster of differentiation 28 receptors (CD28) and CTLA-4 receptors. When B7 proteins bind to CD28 receptors, the immune response is enhanced; conversely, the effect is inhibited when B7 binds to CTLA-4 receptors.
Ipilimumab works by binding to the CTLA-4 receptor on T-lymphocytes, preventing the interaction of B7 with CTLA-4. The net result is that more B7 is available to bind with the CD28 receptors, leading to an enhanced immune response to the melanoma antigens.
Efficacy data coming out from the long-term follow up of clinical trial patients is promising. Patients treated with a combination of ipilimumab and dacarbazine displayed higher survival rates at one year (47.3% versus 36.3%) compared with patients treated with dacarbazine plus placebo. The survival rate remained higher after three years (20.8% versus 12.2% p value <0.001). It also appears that these improved survival rates remain if ipilimumab therapy is continued.
The side effect profile of ipilimumab is predictable in that it includes a number of adverse events related to T-lymphocyte activation and proliferation. These range from relatively mild conditions that can be treated with oral or intravenous steroids, to severe and potentially life threatening reactions. Severe adverse reactions may affect any organ system, but more commonly present as enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy and endocrinopathy.
Any severe immune-mediated reaction requires permanent discontinuation of ipilimumab and initiation of high dose systemic corticosteroids. Due to the possibility of such serious adverse events, it is imperative that patients are monitored for any signs of immune reactions and receive baseline and pre-dose liver function tests and thyroid function tests.
The recent Pharmaceutical Benefits Scheme listing of ipilimumab has been welcomed by patient groups and oncologists in Australia. With an annual cost in the region of $100,000 per patient, therapy had previously been out of reach for many people. However, the Pharmaceutical Benefits Advisory Committee has taken the unusual step of collecting information on patients receiving ipilimumab.
This ongoing surveillance is intended to identify whether the improved survival rates seen in clinical trials match what actually happens in the community. Given the high cost of this medicine and the relatively small number of patients involved in the clinical trials, this would appear to be a prudent step by the Government.
- Bristol-Myers Squibb Company. Yervoy (ipilimumab). Princeton, USA.
- Collins, M, Ling V, Carreno B. The B7 family of immune-regulatory ligands. Genome Biol 2005; 6(6): 223.
- Melanoma Institute Australia. Melanoma Institute Australia. Crows Nest, Australia.
- Robert C, Thomas L, Bondarenko I, O’Day S, M D JW, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364(26): 2517-26.
- Yervoy (ipilimumab) Australian approved product information. Mulgrave: Bristol-Myers Squibb Australia Pty Ltd. Approved 27 June 2011, amended 31 July 2013.