Immunotherapy and Beyond: Improved Treatments for Advanced Melanoma


By Mahrukh Hussain, MD

Until recently, people with advanced melanoma – the most dangerous form of skin cancer that leads to malignant tumors that can spread all over the body – faced a grim prognosis and a grueling treatment plan.

Once the tumor or tumors were surgically removed, most patients were prescribed a drug called interferon, which they would be given by IV every two weeks over the course of an entire year, requiring regular trips to the hospital for infusion. Interferon is a toxic treatment that causes debilitating flu-like symptoms in many people. It can also cause irreversible damage to the bone marrow, liver, and nervous system. For some people, the side effects were so harmful they had to stop treatment. Those who remained on the drug often had to curtail work or family activities during the long treatment course. Perhaps most discouraging, interferon therapy was not a cure, but instead used to extend life for months or years.

Today, treatment for advanced melanoma has improved dramatically, thanks to advances in genetic testing and immunotherapy – a strategy that harnesses the body’s own immune cells to fight off cancer.

New treatments for melanoma, approved by the Food and Drug Administration within the last year, are better targeted to the individual and are much less toxic. As a result, patients with melanoma have many fewer side effects while taking medication, which means they can continue working and enjoying daily life. Most promising: These gentler, more effective new drugs have been shown to prevent cancer from recurring – holding the potential for a cure.

What is immunotherapy?

Essentially, immunotherapy wakes up the body’s own immune system to recognize and destroy invading cancer cells. With advanced melanoma (Stage 3 or beyond), several types of immunotherapy can now be used effectively, often in combination.

Checkpoint Inhibitors: To keep the immune system from fighting off normal cells, our bodies have developed “checkpoints” – proteins on immune cells that need to be turned on or off to start an immune response. Melanoma cells can be crafty, co-opting these checkpoints to avoid being detected and attacked by the immune system. New melanoma therapies target checkpoint proteins.

Anti PD-1 Therapy: This strategy blocks a pathway that shields invading cancer cells from immune system cells, called T cells, that would normally fight them off. Through drugs such as pembrolizumab and nivolumab, doctors remove the shield that protects tumors from immune system destruction, shrinking tumors and allowing people to live longer. These drugs are delivered via IV every two to three weeks over the course of a year. Side effects tend to be relatively mild.

CTLA-4 Inhibitor: Another protein on T cells that is often targeted is CTLA-4. A drug called ipilimumab, given by IV every three weeks for a total of four treatments, blocks CTLA-4, freeing up the patient’s immune response. In patients whose melanoma has spread to other parts of the body, this drug has been shown to help them live longer. But side effects can be more serious than with anti PD-1 therapy; ipilimumab can cause the immune system to start attacking other parts of the body, so it’s important for patients to report health concerns promptly to their health care team.

Targeted Agents: Roughly half of all patients with melanoma have a mutation in a particular gene known as the BRAF gene, which causes melanoma cells to grow out of control. Doctors can biopsy your cancer cells to see if you have this mutation or a related gene mutation involving MEK proteins. If you do, you may be a candidate for a BRAF inhibitor – drugs that directly attack the BRAF protein. (If you don’t have the mutation, you won’t benefit from this therapy.)

Using targeted agents (such as vemurafenib, dabrafenib, or encorafenib) in patients with a BRAF mutation has been shown to shrink or slow tumor growth in some patients, and help some people live longer. In some cases, these drugs can also help cancer from returning. The good news for patients is that unlike checkpoint inhibitors, which must be administered by IV, these targeted agents can be taken as pills or capsules, once or twice daily – resulting in much less disruption to daily life. Side effects tend to be relatively mild (though some people do develop more serious issues such as heart rhythm or liver problems).

Often, oncologists will prescribe both a BRAF inhibitor and a MEK inhibitor, which can also be taken by pills or capsules. Studies indicate that combining both drugs is more effective in shrinking tumors and for preventing cancer recurrence for longer periods of time.

Catching melanoma early

While these new treatments bring new hope to patients with advanced melanoma, recent advances also hold promise for those in the early stages of the disease (Stages 1 and 2).

When caught early, before it has spread, melanoma can often be cured by surgery. But some people have certain gene expression patterns in their cancer cells that put them at higher risk for having their cancer spread or come back. New genetic testing now allows doctors to test the cancer cells of a patient with early melanoma to see whether the patient is at low risk (Class 1) or high risk (Class 2) of having the cancer spread. Equipped with this knowledge, oncologists can decide whether a patient with early-stage disease should get additional treatment or be followed more closely after surgery to look for signs of recurrence.

To find out more about other melanoma treatments, visit MAPMG’s Staying Healthy pages.

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