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At the beginning of the 21st century, only 10-15% of patients with advanced melanoma lived for 5 years, and some estimates were even lower. Today, almost half of patients with newly diagnosed advanced melanoma treated with combination immune therapy will live 5 years or longer, and the percentage continues to increase. The credit for the improved outlook in large part goes to two types of drugs: (1) targeted agents that neutralize or block the activity of abnormal proteins produced by genetic mutations in tumors; and (2) immunotherapy, which unlocks the anticancer potential of the human immune system.

None of these drugs are a cure for melanoma, and some patients still do not benefit from the treatment. Melanoma survival rates, however, continue to improve as doctors and researchers learn more about the biology and behavior of the disease and about how to use the new therapies to provide the best outcome possible for each patient.

Targeted Therapy

About half of all melanomas have a mutation in a gene known as BRAF. The drug vemurafenib (Zelboraf) was the first approved drug that blocks the abnormal protein produced by BRAF mutations. BRAF-positive melanomas often respond to vemurafenib, but the responses tend to be short lived. The same is true of other BRAF inhibitors. Additionally, the drugs are associated with several types of side effects, especially skin problems, including a type of nonmelanoma skin cancer.

Researchers discovered that giving a second drug that targets a gene known as MEK improves responses to BRAF inhibitors and reduces the side effects. Today three different combination therapies that simultaneously target BRAF and MEK have been approved for treating melanoma:

• Dabrafenib (Tafinlar)/trametinib (Mekinist)

• Encorafenib (Braftovi)/binimetinib (Mektovi)

• Vemurafenib/cobimetinib (Cotellic)

The three combination therapies are approved only for melanomas that have BRAF mutations that have been detected by an FDA-approved test.

Vemurafenib is still approved for treatment by itself, but is used only in certain situations, such as for melanomas that have progressed on combination treatment or for patients who cannot take or tolerate one of the combination therapies.

Immunotherapy

This type of therapy came about as a result of ground-breaking research that led to a Nobel Prize. Researchers discovered that the human immune system has a series of "checkpoints" that moderate the activity of the immune system to prevent damage to normal cells and tissues. Cancer cells essentially hijack the checkpoints and continually slow down or turn off the immune system's anticancer activity.

Two types of drugs, known as immune checkpoint inhibitors (ICIs), have demonstrated the ability to block cancer cells' interaction with checkpoints and allow the immune system to mount a more vigorous anticancer response. Ipilimumab (Yervoy) blocks a protein known as CTLA-4, which helps keep the immune system in check. Pembrolizumab (Keytruda) and nivolumab (Opdivo) target a protein known as PD-1, another type of "off switch" for immune cells.

Ipilimumab, pembrolizumab, and nivolumab are all approved for use by themselves as initial treatment for advanced melanoma. In reality, pembrolizumab and nivolumab are used most often because they are better tolerated and may induce more potent anticancer responses.

Nivolumab and ipilimumab also are approved for use in combination as the first treatment for advanced melanoma. Not all melanomas respond to immunotherapy, but the likelihood of achieving a long-lasting response, sometimes lasting for years, is higher with combination therapy.

Melanomas with or without BRAF mutations respond to immunotherapy, so ICIs can be used as the initial treatment for most patients with advanced melanoma. That flexibility allows cancer doctors to use ICI and targeted drugs in sequence for BRAF-positive melanoma.

Patients with BRAF-positive tumors should talk with their doctors about which type of therapy is most appropriate in their situation: a targeted combination followed by immunotherapy or vice versa. Immunotherapy is most often used as initial treatment for advanced melanoma, but either approach is acceptable.

Recently, the FDA approved a new immunotherapy combination, nivolumab and relatlimab (Opdualag), for advanced melanoma. Relatlimab blocks the activity of yet another checkpoint -- this one known as LAG-3. Patients should talk with their doctors about whether this combination is an appropriate option for them.

Clinical Trials

A clinical trial is another reasonable option for someone with advanced melanoma. Multiple trials of new therapies and new treatment strategies (such as combinations or sequencing) are ongoing. When discussing potential treatments with your doctor, be sure to ask about currently available clinical trials and whether one might be appropriate for you.

Read previous installments in this series:

For Your Patients: What Is Melanoma?

For Your Patients: Is What You're Seeing Harmless or Is It Melanoma?

For Your Patients: Is It Melanoma or Something Else?

For Your Patients: What to Know about Treating Early-Stage Melanoma

For Your Patients: New Options, Better Outcomes for Advanced Melanoma

"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.