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Disease focus: Melanoma

Looking at the challenges, goals and developments for the pharmaceutical industry within specific disease areas: melanoma
Melanoma

Melanoma is the most dangerous form of skin cancer. It is caused by malignant transformation of melanocytes – the skin's pigment-producing cells. Unlike most other solid tumours, this disease affects younger, middle-aged people. Although melanoma can be treated if detected at an early stage, in advanced disease when the cancer has spread to other parts of the body it is very difficult to treat and survival outcome is poor. However recent advances in understanding the immunology of melanoma are offering the medical community fresh hope for treating this challenging malignancy.

In Europe, almost 68,000 individuals are diagnosed with melanoma each year. The diagnosis of melanoma has increased at an alarming rate. The past three decades have seen a 237 per cent increase in the prevalence of advanced melanoma, making it the fastest growing malignancy in men and the second-fastest growing in women. Unfortunately, metastatic melanoma is one of the most aggressive forms of cancer, with 75 per cent of patients dying within a year.

The most important preventable cause of melanoma is too much ultraviolet (UV) sunlight exposure. Artificial UV sources, such as sun beds, also raise melanoma risk. People who burn easily in the sun are particularly at risk.

Melanomas are less common in dark-skinned people, occurring most often in fair-skinned people who tan poorly. Often they have blonde or red hair, blue or green eyes, and freckle easily. Other risk factors include having a large number of moles, especially larger moles known as 'dysplastic naevi'. The risk is also raised if another family member has melanoma or if someone has had a previous melanoma.

Disease management
Melanomas that are detected and treated early can be cured using surgical excision. Advanced disease, in which the melanoma has spread beyond the surface of the skin to other organs, such as the lymph nodes, lungs, or brain, has a significantly worse prognosis, with an average survival time of six to nine months. Adjuvant treatments, those given after surgery in order to try to prevent recurrence, have traditionally included dacarbazine chemotherapy, with or without the addition of interferon alpha, interleukin-2, and/or radiotherapy. Dacarbazine has a response rate of 5-15 per cent and improves progression-free survival by a few months at best. There is no randomised clinical trial data that shows an improvement in overall survival, the gold standard endpoint for clinical trials.

In advanced disease, none of these interventions has been shown to have a significant effect on overall survival. Advanced patients are therefore usually referred for enrolment into clinical trials of new compounds. Due to the very poor prognosis and lack of effective treatments for stage III unresectable and stage IV metastatic melanoma, there remains a significant unmet medical need.

Chronology of Melanoma drugs approved in the past 30 years

Year
Type of Treatment
Drug
1975 (FDA)
Chemotherapy
dacarbazine (DTIC)
1995 (FDA)
Immunotherapy
interferon (IFN) alpha-2b
1998 (FDA)
Immunotherapy
interleukin-2
Evaluated but not approved
Chemotherapy
temozolomide
2011 (FDA & EMA)
Immunotherapy/Monoclonal antibody
ipilimumab (YERVOY™)
Filed (FDA & EMA), not yet approved
BRAF Inhibitor
vemurafenib
In development
MEK inhibitor
AZD6244
In development for melanoma
c-KIT tyrosine kinase inhibitor
imatinib (Gleevac, US; Glivec, Europe)
In development
c-KIT tyrosine kinase inhibitor
dasatinib
In development
c-KIT tyrosine kinase inhibitor
nilotinib
In development
Vaccines
OncoVEX GM-CSF
In development
Vaccines
MAGE-A3 ASCI
In development for melanoma
Monoclonal antibody/VEGF inhibitor

bevacizumab (Avastin)

Recent advances
Fortunately, recent advances in understanding the molecular pathology and immunology of melanoma are starting to tackle this unmet need. At least nine major pharmaceutical companies are developing scores of potential new treatments for melanoma.

According to analysts GlobalData, the melanoma market was valued at $351m in 2009 and is forecast to grow at a compound annual growth rate of 16.8 per cent to reach $1.4bn by 2017. Other analysts predict a more rapid growth to $1.1bn by 2015. This growth will primarily be driven by an increase in melanoma incidence, an increase in patients seeking treatment and an influx of novel and efficient drugs.

One of the most promising recent developments has been the emergence of the new field of immuno-oncology, in which the body's immune system is used to attack cancer cells, rather than the traditional approach of trying to destroy tumour cells using chemotherapy.

The approach is exemplified by the Bristol-Myers Squibb immunotherapy, ipilimumab (YERVOY). This first-in-class received European Commission approval for the treatment of adult patients with previously-treated advanced melanoma on July 13, 2011, making it the first new treatment to be EU-approved for this indication in more than two decades. It is also the first and only therapy for metastatic melanoma to demonstrate a significant improvement in overall and prolonged survival in more than 30 years.

Current standard of care

No standard of care exists for people with advanced melanoma and current guidelines recommend that patients should be treated within a clinical trial examining new treatment modalities.

Treatment recommendations for the various stages are:

  • Early stage/localised melanoma (stage 0–II): Surgery (wide excision), chemotherapy and radiotherapy

  • Regionally advanced melanoma (stage III): Wide local excision with or without the removal of lymph nodes. Surgical removal of solitary metastases, such as central nervous system tumours.

Advanced melanoma (unresectable stage III & IV melanoma):

  • Treat in clinical trials. If there is none available, then palliative therapy with dacarbazine or other chemotherapy, plus cytokines (interferons, interleukin-2) for patients with several metastases.

Ipilimumab, a fully human monoclonal antibody, indirectly targets the tumour by stimulating the patient's immune system to recognise and destroy cancer cells. It specifically blocks cytotoxic T lymphocyte antigen 4 (CTLA-4), which plays a role in suppressing the normal immune response.

By blocking this suppression, ipilimumab allows the patient's immune system to respond to melanoma cancer cells. In a randomised, double-blind phase III study published in the New England Journal of Medicine in June 2010 the one- and two-year estimated survival rates for patients treated with ipilimumab were 46 per cent and 24 per cent, respectively, versus 25 per cent and 14 per cent in the comparator arm. Some patients in the ipilimumab arm have remained alive for up to four-and-a-half years.

Wider promise
The potential of up-regulating the immune system is not limited to melanoma. The use of ipilimumab is being investigated in other cancers, including prostate, pancreatic and lung cancer. On the wider melanoma front, there are many other new agents in the pipeline.

Roche and Plexxikon have submitted applications to the US Food and Drug Administration and European Medicines Agency for marketing approval of vemurafenib for the treatment of metastatic melanoma. Vemurafenib selectively targets the BRAF V600E mutation, which occurs in about half of all cases of melanoma. Other BRAF inhibitors are also being developed by other companies. Unfortunately resistance to these small molecule targeted agents eventually develops.

Clinicians remain optimistic that novel targeted therapies and immunotherapies, including novel vaccine strategies, alone or in combination with existing agents, will probably change the standard of care for this difficult to treat malignancy in the near future.

The Author
Ian Mason is a freelance medical writer.

To comment on this article, email pme@pmlive.com

27th September 2011

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