February 2014
circuit
clinical initiatives, research and current updates in treatment New and Emerging Therapies for Metastatic Melanoma Jodie Lyons, APHS Pharmacy Holy Spirit Northside Melanoma is the third most common cancer in Australia, with over 12,000 new cases diagnosed and 1,500 deaths per year.1 Australia has the world’s highest incidence of melanoma, with the majority of cases diagnosed early and treated with surgical excision. Historically, metastatic melanoma has been considered one of the most difficult cancers to treat, and a true ‘cure’ remains elusive. However, a range of new drug therapies are altering treatment goals and promising patients long term survival.1 A better understanding of both the activation of the immune system and the role of activation of pathogenic pathways has led to the identification of several targets for drug therapy, such as BRAF, MEK, and Ras proteins.
Ras
P Proliferation Differentiation Migration Survival/Apoptosis
Raf
P P
MEK1/2
ERK1/2 Figure 1 Targeting melanoma - The Ras-Raf → MEK-ERK pathway.28 CTLA-4 Inhibitors Ipilimumab (Yervoy®) is a monoclonal antibody targeted at cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T cell activation which serves as a ‘brake’ on the activated immune system. Ipilimumab prevents this, allowing a T-cell mediated immune response against the tumour.2
Given its mechanism of action, evaluation of the effectiveness of ipilimumab requires a unique perspective, as the patterns of response differ from those with molecularly targeted agents or cytotoxic chemotherapy. Rather than the traditional pattern of improvement after treatment, patients may have a transient worsening of the disease (up to and including the appearance of new lesions) before the disease stabilises or regresses. Response may also take considerably longer to become apparent, with continued disease regression frequently observed well after completion of initial induction therapy (as late as 5.5 months after initial ipilimumab infusion).2,3 The danger with this is that if those assessing the patients are unfamiliar with immune-related response criteria, the patient may be prematurely discontinued on treatment which may have otherwise eventually led to a response or prolonged disease stabilisation.3 Current guidelines suggest not conducting initial post therapy tumour assessment until week 12, after induction therapy is complete.2 Ipilimumab’s PBS listing is based on a 676 patient phase III trial in those with previously treated metastatic stage III or IV melanoma. Patients were randomised to receive ipilimumab (at 3mg/kg) with gp100 (an investigational vaccine), ipilimumab monotherapy, or gp100 vaccine monotherapy. The rate of overall survival for ipilimumab at 1 year was 45.6%, independent of age, sex, metastasis, stage of disease and baseline serum LDH levels.4,5 In addition, 60% of patients who had achieved a partial or complete response remained free of relapse at 2 years, with ongoing responses observed at up to 44 months.5 Of the patients who did progress or relapse, a further course of re-induction therapy led to a partial or complete response in 67%.5 The ongoing PBS listing for ipilimumab is dependent upon the drug being able to replicate the clinical trial results in a real world setting. As a result of its mode of action, immune related adverse events (irAE) have been observed in 60% of patients treated with ipilimumab, with 10-15% of these classified as grade 3 or 4.5 The likelihood of these types of effects is greatest during the 10 week induction period, however they can occur weeks or months afterward. Liver function tests (LFTs) and thyroid function tests should be undertaken at baseline and before each dose of ipilimumab, as well as at completion of symptom checklists. The most frequently encountered irAE are: • Gastrointestinal – diarrhoea and colitis in 31% of patients (identified as having led to cases of bowel perforation, sepsis and death).5,6 • Hepatic – hepatitis in 2% - 9% of patients (at least one death recorded due to liver failure).5,7 • Dermatological – pruritis, vitiligo or alopecia seen in 40% of patients (StevenJohnson syndrome and toxic epidermal necrolysis also recorded in 2.5% of patients).5,8 • Endocrinopathies – wide ranging, potentially affecting the pituitary, thyroid or adrenal glands. • Neurological – rarely Guillain Barre syndrome.5,10 Ipilimumab irAE management guidelines identify and provide management recommendations based on the severity of presenting symptoms, classifying patients by whether or not they are safe to proceed with scheduled treatment.2
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