Personalised Medicine At A Glance: Metastatic Melanoma
For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine in January 2015 and updated in February 2017
Melanoma is a cancer arising from specialised cells found in the skin called melanocytes. These cells produce the dark melanin pigment responsible for skin colour. Exposure to ultraviolet light (eg from the sun) increases production of melanin, giving the DNA of skin cells some protection against the adverse effects of this form of radiation and darkening skin colour. But overexposure can lead melanocytes themselves to become malignant.
Melanoma that has spread from the skin to other parts of the body was until recently very difficult to treat. But rapid progress in understanding the biological basis of the disease has led to more effective drug therapy that can be tailored to the molecular characteristics of the tumour affecting an individual patient. So melanoma treatment has now become one of the most impressive examples of personalised medicine. There is particular excitement about a new class of immunomodulatory agents called checkpoint inhibitors. These are discussed in the last section below.
In Europe each year, there are over a hundred thousand new cases of melanoma of the skin and more than twenty thousand deaths from the disease. Although still infrequent compared with cancers of the lung, colon, breast and prostate, melanoma is an increasing problem.
Types of treatment
As with all tumours, initial treatment is tailored to the patient’s individual circumstances and the size and spread of the cancer. Surgical removal of melanomas that are small and confined to one site on the skin usually resolves the problem. The cancer is cut out along with a surrounding margin of healthy tissue, with the width of the margin depending on the diameter of the melanoma. But melanomas that are large or penetrate deep within the skin, and those that are ulcerated, are more likely to recur. Radiotherapy sometimes has a place in treating extensive but still localised disease.
Melanoma that has spread to other parts of the body and its internal organs (i.e. metastatic disease) generally cannot be cured. Cytotoxic chemotherapy, using drugs such as dacarbazine, was tried but with disappointing results. But major advances in two new types of systemic therapy – the use of drugs targeted against the genetic mutations that cause uncontrolled growth of melanoma cells, and the development of agents that encourage our immune system to fight the disease – have brought remarkable improvements in survival. Patients and doctors now have a choice of drug treatments as first-line therapy for metastatic melanoma, and a choice of agents that can be held in reserve for use if the cancer fails to respond to initial treatment or escapes from drug control.
Drugs targeting tumour mutations
Genetic mutations found in many melanomas cause the tumour cells to grow out of control. Identifying these genetic defects – which vary from one patient to another – has proved very helpful in designing more effective drug treatments based on blocking the abnormal growth signalling that causes uncontrolled proliferation.
Particularly important to melanoma was the discovery of the MAPK (mitogen-activated protein kinase) pathway which transmits a growth signal from the surface of a cell to its nucleus. Among the messenger molecules are RAS, RAF and MEK. If a mutation arises in a gene responsible for one of the proteins involved in this signalling cascade, the pathway may become overactive. Growth messages are transmitted when they are not appropriate, causing excessive cell division.
Gene mutations that activate BRAF (a subtype of the RAF component of the MAPK pathway) are found in about 50% of melanomas. The second most common abnormalities are activating mutations in NRAS (a subtype of the RAS element of the pathway) which are found in roughly 20%. If individual patients have one type of mutation, they are unlikely to have the other.
By identifying the mutations that have caused a particular patient’s cancer, we can personalise treatment. Drugs that target NRAS mutations are still under investigation. But drugs that target BRAF are already in routine use.
Patients whose cancers have BRAF mutations can be treated with the BRAF inhibitors vemurafenib or dabrafenib. These drugs combat abnormal activation of the MAPK pathway and melanomas are likely to shrink. However, cancer cells eventually develop ways of bypassing these inhibitors and growth of the melanoma resumes.
This process can be delayed by using a combination of drugs. Combining the BRAF inhibitor dabrafenib with another drug, trametinib, postpones the return of cancer progression. Trametinib inhibits a different signalling molecule, MEK, which acts downstream from RAF in the signalling cascade. Use of the new combination increases survival time in patients with previously untreated metastatic melanoma while not worsening side effects.
Worthwhile progress has been made in melanoma patients who have BRAF mutations. Additional drugs will be needed to bring the abnormal MAPK pathway under long-term control. The search is also on for drugs to help patients whose melanomas arise from other gene abnormalities. But at least we know that the principle of personalising treatment based on tumour mutations works.
Drugs that boost our immune response
Although the response is generally too weak to overcome the disease, melanoma does activate our immune systems. A few years ago, researchers developed an antibody called ipilimumab which strengthens this natural response by inactivating a protein (CTLA-4) that inhibits the activity of T lymphocytes. The effect has been described as taking the brakes off the immune system. Once released from inhibition, the T lymphocytes are better able to recognise and destroy melanoma cells. This was a major step forward and extended survival. The immunomodulatory approach also has the advantage of being effective irrespective of the mutation status of the melanoma being treated.
Efforts to strengthen the immune response have recently been hugely boosted by the introduction of a new class of drugs – the immune checkpoint inhibitors. A characteristic of many cancers is that they find ways of evading the immune response. As with ipilimumab, the checkpoint inhibitors give our bodies a better chance of fighting back.
The first such agent was nivolumab; and this was followed by pembrolizumab. In a recent clinical trial, nivolumab was compared against ipilimumab. Nivolumab delayed progression of disease more effectively than ipilimumab without increasing toxicity. The use of nivolumab in combination with ipilimumab may further delay progression of melanoma, but at the cost of substantially increased side effects.
The checkpoint inhibitors target a receptor on the cell called programmed cell death-1 (PD-1). PD-1 binds to ligand called PD-L1. Not all melanomas express it to the same extent, and it may be that tumours expressing PD-L1 at a high level respond better to this class of drugs than tumours with little PD-L1 expression.
Testing for this biomarker – as with many of the treatments discussed above – may become another example of the importance of a personalised approach to medicine that decides the most appropriate treatment by taking into account the specific molecular characteristics of the cancer affecting an individual patient. It is already clear that the advent of the checkpoint inhibitors offers patients with metastastic melanoma a greater chance of prolonged disease remission than they have ever had before.