Historic Progress. New Options. More Hope.
While melanoma is one of the most dangerous forms of skin cancer, promising new treatment options are improving quality of life and increasing survival rates for patients with advanced melanoma.
If you’ve been diagnosed, your treatment choices depend on the stage of the disease, the location of the tumor and your overall health. Options include:
Ask your doctor to clearly explain the options that might work best for you, including details about the benefits and risks.
Surgical removal of the melanoma
Treating early melanoma
Stage 0 “in situ” and stage I
Tumors discovered at an early stage are confined to the upper layers of the skin and have no evidence of spread. These melanomas are treated by excisional surgery. Usually, this is the only treatment required. The first step was a biopsy, where the physician removed part or all of the lesion and sent it to a lab for analysis, where the melanoma was diagnosed and staged. For the excisional surgery, the surgeon removes more tissue from the site.
Melanoma in situ (stage 0) is localized to the outermost layer of skin (the epidermis). Stage 0 melanoma is the least challenging to treat and cure. Stage I melanoma has invaded the second layer of skin (the dermis). In both stage 0 and stage I melanoma cases, the physician uses a scalpel to remove any remaining tumor plus a “safety margin” of surrounding normal tissue. The margin of normal skin removed depends on the thickness and location of the tumor. After surgery the margins are checked to make sure they are cancer-free. If the margins are cancer-free, no further surgery is necessary.
Surgeons may, under certain circumstances, recommend removal of melanoma by Mohs surgery. The procedure is done in stages over a few days to remove all of the cancer cells in layers while sparing healthy tissue and leaving the smallest possible scar. One layer at a time is removed and examined until the margins are cancer-free. New advances in this technique make it easier for the surgeon to spot melanoma cells in the margins.
If a melanoma measures 0.8 mm or more in thickness or has other traits such as ulceration that make it more likely to spread to the lymph nodes, a sentinel lymph node biopsy (SLNB) may be performed at the same time as the surgery to remove the primary tumor.
Treating intermediate, high-risk melanomas
Since the risk of spreading to local lymph nodes is higher in stage II melanomas, a sentinel lymph node biopsy is often recommended in addition to surgery to remove the original tumor. If melanoma is found in the sentinel node, your physician may examine the rest of the nodes in this lymphatic basin and remove any that contain cancer cells.
Treating advanced melanomas
Stage III and stage IV
Advanced melanomas are those that have spread beyond the original tumor, most often reaching the lymph nodes and/or distant organs and becoming more difficult to treat.
In recent years, new immunotherapies and targeted therapies have achieved positive results in many patients with stage III and stage IV melanoma.
Patients with stage III melanoma now have options for supplemental or “adjuvant” treatment – medicines that enhance the effectiveness of surgery, with the goal of preventing or delaying relapse and extending survival, ideally achieving a cure.
After surgery to remove the tumor and in many cases the lymph nodes, stage IV patients have quite a few frontline treatment options that have had considerable success. In many cases, if the first treatment proves ineffective or stops working, other therapies are available. These therapies work by shrinking tumors and halting or slowing disease progression to help extend life by months to years and perhaps even leading to a cure.
Revolutionary treatment options
Pioneering breakthroughs in immunotherapy — the use of medicines to stimulate a patient’s immune system to destroy cancer cells — have led to significant progress in treating patients with advanced melanoma.
Immunotherapies boost the body’s ability to fight melanoma and other cancers by using synthetic versions of natural immune system proteins, or by enabling the release of cells that attack tumors. These therapies are effective when used alone or in combinations.
Checkpoint blockade therapy
To assure that T cells attack only bacteria and disease and not the body itself, the immune system uses checkpoints, molecules that suppress T cells. T cells are the white blood cells that help protect the body from infection. Checkpoints help keep T cells from attacking normal cells in the body.
Checkpoint blockade immunotherapies are given intravenously to melanoma patients to stop checkpoint molecules from inhibiting T cells. This enables the immune system to release waves of T cells to attack and kill cancer cells.
The following checkpoint blockade therapies are being used for patients with advanced melanoma:
Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) blocker
Approved by the FDA in 2011 for patients with stage IV melanoma, ipilimumab was the first checkpoint blockade therapy that helped shrink many tumors markedly and extend life for patients with advanced melanoma. Since then, newer immunotherapy drugs have proven even more effective as single therapies (monotherapies), some with less serious side effects.
How it works
Ipilimumab targets CTLA-4, a protein on the T cell that functions as a “brake” to regulate immune system activation. Blocking CTLA-4 allows T cells to attack and destroy tumors.
While ipilimumab is no longer the frontline choice for treating stage IV melanoma, it is often paired with another checkpoint blockade drug, nivolumab, as a combination frontline therapy for stage IV patients, or can be administered if anti-PD-1 treatment has failed.
In 2014, the FDA approved two additional checkpoint blockade drugs for use in patients with melanoma that has spread beyond the lymph nodes or for melanomas that cannot be removed by surgery (stage IV).
How they work
PD-1 (programmed death-1), a protein receptor on T cells that binds to a complementary protein called PD-L1 on the surface of other cells, helps keep the immune system in check. Both drugs block PD-1 to release the brakes on T cells and allow them to attach melanoma cells.
These drugs can be used alone (monotherapies), or nivolumab can be used in combination with ipilimumab or relatlimab. They can be used as the first treatment option, before other medicines have been tried, and as a second option when other treatments have failed or stopped working.
In 2017, the FDA approved nivolumab for therapy after tumor removal (known as adjuvant therapy) in stage III patients who have melanoma in the lymph nodes.
In February 2019, the FDA also approved the checkpoint blockade therapy pembrolizumab for the adjuvant treatment of stage III melanoma that has metastasized to the lymph nodes after tumor removal. The approval was based on phase 3 research demonstrating that pembrolizumab significantly prolonged recurrence-free survival (RFS) in patients with resected, high-risk stage III melanoma. Depending on the patient, either nivolumab or pembrolizumab can now be considered the frontline option for adjuvant treatment of stage III melanoma in patients who do not have a defective BRAF gene. (In those who do have defective BRAF, the combination targeted therapy dabrafenib-trametinib (Tafinlar®-Mekinist®) can also be considered a frontline option.)
In December 2021, the FDA expanded the approval of pembrolizumab to the adjuvant treatment of stage IIB and IIC melanoma, which have the same high risk for recurrence or death as stage III melanomas. The approval was based on phase 3 research demonstrating that pembrolizumab reduced the risk of disease recurrence or death by 35 percent compared to placebo in patients with surgically removed stage IIB or IIC melanoma. This approval essentially doubles the number of melanoma patients now eligible for adjuvant immunotherapy.
Unprecedented results by pairing therapies
In 2016, the FDA approved the combination of nivolumab and ipilimumab as a frontline therapy for patients with metastatic or inoperable melanoma. In 2022, the FDA approved a second combination, nivolumab and relatlimab, as a frontline therapy for patients with metastatic or inoperable melanoma.
How they work
By pairing nivolumab and ipilimumab, two successful checkpoint blockade therapies, researchers have created another treatment option that has proven even more effective in shrinking tumors and prolonging life than either drug therapy used on its own, though adverse reactions with the combination medicine are also stronger than with either medicine alone.
Similarly, pairing nivolumab and relatlimab proved to be a more effective treatment option than nivolumab therapy alone. Relatlimab, only FDA-approved in this combination, blocks the LAG-3 protein receptor on T cells, thus preventing T cells from binding to a complementary protein on the surface of tumor cells. Just like PD-1 inhibition, this releases the breaks on the immune system and allows T cells to attack melanoma cells.
Oncolytic virus therapy
In 2015, the FDA approved the oncolytic virus therapy talimogene laherparepvec (Imlygic®), also known as T-VEC, to treat the skin and lymph nodes of patients with advanced melanomas that cannot be surgically removed.
How it works
This new class of immunotherapy, injected directly into tumors, uses a lab-altered virus, known as an oncolytic virus, that is specifically programmed to infect and kill cancer cells exclusively. At the same time, an immune-boosting protein in the virus accelerates the body’s immune response to the tumors. The medicine’s most immediate effect is to shrink the size of injected tumors, but the secondary goal is for the drug to work systemically, attacking the cancer throughout the body.
Similar viruses are now being studied, with the goal of producing more options for melanoma patients whose diseases have spread or returned.
Adoptive cell transfer
How it works
This experimental new avenue uses white blood cells called tumor-infiltrating lymphocytes (TILs) to attack melanoma. The treatment is currently being explored in clinical trials on patients with advanced melanomas that have not responded to other treatments. Most often, the lymphocytes found to be attacking the melanoma are extracted from the patient, cultured in massive numbers in a lab and then returned to the patient.
Older forms of immunotherapy once used in high-risk stage II, III and IV melanoma patients have since been replaced as frontline treatments by newer, more effective treatment options.
How they work
These early forms of immunotherapy worked by boosting the immune system’s ability to fight disease. They are less used today because of the superior results of the newer therapies.
Personalized cancer treatment
The development of revolutionary targeted therapies marked the beginning of a new era of personalized medicine for melanoma patients, allowing tumors to be treated with minimal damage to healthy cells.
Targeted therapies use drugs and other agents to attack melanoma by inhibiting the action of defective genes and molecules – including BRAF and MEK – that play a role in accelerating the growth and spread of melanoma cells. When successful, these treatments halt or slow the progression of the disease and help patients live longer.
In the past decade there has been notable success using BRAF- and MEK-targeted therapies to treat advanced melanoma.
What is BRAF?
BRAF is known as a “switch gene.” It produces a protein that normally regulates skin cells, allowing them to multiply only when needed. But genetic changes (mutations) to BRAF can keep it switched on abnormally, driving out-of-control tumor growth.
About half of all melanoma patients have the BRAF mutation. Targeted therapies have had significant success in improving outcomes for patients with advanced melanoma who have the BRAF mutation.
In 2011, vermurafenib became the first targeted therapy approved for advanced melanoma patients. For varying amounts of time, it shut off the BRAF gene’s production of the BRAF protein.
How they work
These targeted drugs interrupt and deactivate the tumor growth pathway driven by the genetic change in BRAF, delaying the progression of the disease, shrinking tumors and extending the life of patients.
If testing confirms that a patient has advanced melanoma, the lab will generally perform a BRAF mutation test to determine whether the tumor has the defective gene. These results show whether therapies targeting BRAF can be used in treatment.
What is MEK?
MEK is an enzyme that works together with BRAF to regulate cell growth. Drugs that inhibit MEK can also help treat melanomas that arise because of mutations in the BRAF gene.
BRAF-targeted therapies are often remarkably effective for a period of time, but in most patients, the melanoma eventually develops a resistance to treatment and begins to grow again. Medications targeting MEK were developed to address this resistance and halt the advancement of the disease.
How they work
To delay melanoma treatment resistance and increase survival, researchers developed targeted drugs that inhibit MEK.
Combination targeted therapies
Better health outcomes by pairing therapies
A melanoma patient with defective BRAF who goes on targeted therapy will almost always be treated with drugs that inhibit both BRAF and MEK, because pairing these targeted drugs has been found to work better than the BRAF therapies alone. Patients treated with combination therapies have faster, more dramatic and sustained tumor shrinkage, slower disease progression and live longer on average, while also experiencing fewer serious side effects. The combos work so effectively that the use of the single-drug targeted therapies has been virtually eliminated.
How they work
The principle behind combination therapy is that even when the BRAF inhibitor meets with resistance, the MEK inhibitor can be effective in slowing or stopping disease progression.
*Learn more about the combination immunotherapy and targeted therapy: Atezolizumab-Cobimetinib-Vemurafenib (Tecentriq®-Cotellic®-Zelboraf®).
Since immunotherapies and targeted therapies produce vastly superior results, chemotherapy is no longer a frontline therapy. It is most often used if targeted therapies and/or checkpoint blockade therapies fail. It may sometimes be used in conjunction with these other therapies.
How it works
Chemotherapy is a systemic approach to stopping tumor growth using certain medicines that either kill cancer cells or stop them from multiplying. It has never been proven to extend life for melanoma patients as a single therapy, however, and can have serious side effects.
Radiation is rarely used to treat a primary melanoma tumor, but may be used to treat melanomas that have spread to the brain or other distant sites to shrink tumors and decrease pain, improve comfort and mobility. It can also be used on the surgical site after surgery to help assure that all tumor cells have been killed, and is being studied in combination with treatments such as checkpoint blockade therapies to enhance outcomes.
How it works
Radiation is a localized treatment that directs high-energy X-ray beams to penetrate and destroy the tumors or keep them from growing. Radiation is most often used for:
- Melanomas at high risk of recurrence: Radiation can be used after surgery to lower the chance of recurrence after removal of certain types of melanomas.
- Melanomas that have returned: If the melanoma has come back on the skin or lymph nodes, in certain cases, doctors may treat with radiation to reduce or eliminate the tumor and potentially prevent spread to distant sites.
- Melanomas that have spread: Radiation may be used to help make checkpoint blockade therapies or targeted therapies work more effectively.
If you have been diagnosed with advanced melanoma, you may be eligible to participate in a clinical trial – a carefully controlled research study using new or experimental treatments.
Before making a decision, it’s important to discuss the possibilities, risks and benefits of clinical trials with your doctor. For more information about clinical trials that are being conducted now, along with results of recent trials, visit the Find Studies page on the U.S. National Institutes of Health website.
On the horizon
While more melanoma treatment options exist today than ever before, there are even more new approaches currently being explored. In fact, there are new tools, including genomic testing, that are helping doctors make more informed decisions to improve health outcomes and the patient experience. Building on today’s strong forward momentum in understanding and treating melanoma, researchers are hard at work refining the therapeutic combinations and strategies to improve outcomes. Someday, advanced melanoma may be transformed from a deadly disease to a chronic, manageable or even curable condition.
Allan C. Halpern, MD
Ashfaq A. Marghoob, MD
Ofer Reiter, MD
Last updated: January 2022