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Keytruda - The Next Step in Advanced Melanoma Treatment?

General | October 5, 2014 | Author: The Super Pharmacist

general

Keytruda - The Next Step in Advanced Melanoma Treatment?

Advanced Melanoma

Melanoma is a condition affecting approximately 230,000 people worldwide, and is associated with approximately 50,000 deaths. It is responsible for the vast majority of skin cancer-related deaths. A melanoma is a type of tumour developing from melanocytes that are normally present to produce pigments (melanin) in the skin in order to protect this tissue from damage as a result of UV light exposure. Melanomas may initially resemble moles (raised blemishes in skin) in their early stage. Unless they are detected and treated at this point, they may become larger, asymmetrical and more resistant to treatment. Advanced melanoma is treated with surgery to remove them, and with drug therapy to reduce existing tumours and prevent the development of new ones. The most effective form of the latter is antibody therapy. As the incidence of melanoma is estimated to double by 2024, the availability and efficacy of its treatment will become more and more relevant for more and more patients1.

Pharmacotherapy for Melanoma

advanced melanomaAntibody therapy (also known as immunotherapy) is the administration of drugs that bind certain molecules or cellular receptors in the body that play a role in tumour development or the repression of natural mechanisms that exist to combat cancer progression. In the case of melanoma, research has found that the most effective antibody is against the CTLA-4 receptor, located on cytotoxic T lymphocytes, an immune cell type that can identify and kill cancer cells2. However, these lymphocytes may be negatively regulated, or 'switched off' by molecules (or ligands) that bind the CTLA-4 receptor2. This 'instructs' the cell to stop its cytotoxic, or cell-destroying, reactions. These are normally produced by dendritic cells, to control and direct natural immune processes. Cancer cells, including melanoma cells, can also produce the CTLA-4 ligand, which protects them from destruction by cytotoxic T lymphocytes even if they are detected2. However, molecules acting to 'block' the CTLA-4 ligand from its receptor, without activating negative regulation, have been developed2. These are often derived from the natural immune molecules that are specifically designed to bind others, known as antibodies. These include ipilimumab, one of the most effective immunotherapies in achieving response and remission in cases of advanced melanoma3. Ipilimumab has been found to achieve five year survival rates in approximately 50% of patients in follow-up studies of its clinical trials4. However, this drug is also linked to some drawbacks and issues, including:

Consistency

advanced melanomaIpilmumab has demonstrated efficacy in blocking CTLA-4 activation in laboratory and clinical trials, but in practical melanoma treatment, it is difficult to develop a dose-regimen that elicits the expectant cancer cell death, as this has been observed to differ drastically from patient to patient5. In addition, ipilmumab may function best as part of a combination with other immunotherapy and/or chemotherapy, which again may take time and resources to work out the right dose for each individual patient5,6. In a trial comparing the efficacy of ipilimumab alone and the drug in combination with another form of melanoma therapy, dacarbazine (randomised to 32 patients each), 20% of the combination group achieved 36-month survival, compared to 9% for the ipilimumab monotherapy group.

Cost

A full course of this treatment may cost up to $120,0007. This may present an issue for many patients eligible for ipilmumab treatment, especially in healthcare markets without state-sponsored health services.

Side-effects

Ipilmumab is associated with a relatively high incidence of adverse reactions, mainly concerned with the release of inflammation into many body tissues. These side-effects range from moderate to severe skin itching, rash, pneumonitis (or lung tissue inflammation), diarrhoea, and colitis (as a result of gastrointestinal inflammation)8. These are 'knock-on effects' of cytotoxic T lymphocyte positive regulation, which may result in the direct or indirect production of pro-inflammatory immune molecules. These occur at a rate of between approximately 4% and 12% for gastrointestinal adverse effects, and approximately 3-4% for skin reactions, depending on dose4. This may result in the inability of patients who also suffer from conditions such as Crohn's disease or lung disorders to begin a course of ipilmumab.

Keytruda for advanced melanoma treatment

advanced melanomaKeytruda is still in the early stages of market release and post-market surveillance, but already shows potential in addressing some of the problems linked to ipilimumab therapy, particularly those relating to its side-effect profile. However, as a relatively new drug, Keytruda is likely to be associated with a cost at least similar to that of existing pharmacotherapy for advanced melanoma. Early studies into PD-1 receptor and ligand blockage via antibody binding demonstrated promising results in trials involving many types of cancer, including melanoma2,9. PD-1 inhibition has also been shown to be associated with the incidence of fewer side-effects in comparison with CTLA-4 blockage2. In addition, CTLA-4 blocking may be associated with increased PD-1 ligand expression in and around tumours2. Therefore, PD-1 receptor binding may be a more efficacious and direct method of cancer treatment. Keytruda (pembrolizumab or lambrolizumab) is a novel alternative to ipilimumab. This is another type of antibody, but unlike the more established treatment, it acts against another type of receptor called the programmed-death 1 (PD-1) receptor2. Again, cancer cells may mimic dendritic cells in releasing the PD-1 ligand, which negatively regulate cytotoxic T cells in a manner similar to that mediated by the CTLA-4 ligand2.

Keytruda in Clinical Trials

A phase I, open-label, non-placebo-controlled trial, randomised 157 patients with ipilimumab-resistant advanced melanoma to either 2mg/kg or 10 mg/kg Keytruda (then referred to as pembrolizumab) every three weeks, and then evaluated for disease progression and adverse effects eight months afterward10. Overall response was similar in both groups. The rates of side-effects were also similar in both groups. The most common of these were itchiness, rash and fatigue10. This was an indication that Keytruda was safe and effective at these doses, although it should be noted that the trial was funded by Merck, the company claiming the rights to manufacture and sell this drug10. Another one-way trial of 135 patients receiving 2 or 10mg/kg lambrolizumab every 2 to 3 weeks found that the response rate was 38% for the 2mg/kg group and 52% for the 10mg/kg group11. The most common side effects were itching, rash, fatigue and diarrhoea, which was low-grade in most cases11.

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REFERENCES:

  1. Tronnier M, Mitteldorf C. Treating advanced melanoma: current insights and opportunities. Cancer management and research.2014;6:349-356.
  2. Dranoff G. Immunotherapy at large: Balancing tumor immunity and inflammatory pathology. Nature medicine.2013;19(9):1100-1101.
  3. Dequen P, Lorigan P, Jansen JP, van Baardewijk M, Ouwens MJ, Kotapati S. Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma. The oncologist.2012;17(11):1376-1385.
  4. Lebbe C, Weber JS, Maio M, et al. Survival follow-up and ipilimumab retreatment for patients with advanced melanoma who received ipilimumab in prior phase II studies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO.2014.
  5. Kim DW, Trinh VA, Hwu WJ. Ipilimumab in the treatment of advanced melanoma - a clinical update. Expert opinion on biological therapy.2014:1-10.
  6. Maio M, Di Giacomo AM, 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.
  7. Couzin-Frankel J. Cancer Immunotherapy. Science.2013;342(6165):1432-1433.
  8. Thompson JA, Hamid O, Minor D, 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. Journal of immunotherapy (Hagerstown, Md. : 1997).2012;35(1):73-77.
  9. Robert C, Soria JC, Eggermont AM. Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. European journal of cancer (Oxford, England : 1990).2013;49(14):2968-2971.
  10. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet.2014;384(9948):1109-1117.
  11. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. The New England journal of medicine.2013;369(2):134-144.
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