Treatments for Stage III and Stage IV Melanoma

When melanoma cells spread to the lymph nodes (stage III) or more distant parts of the body (stage IV), including organs, the disease is considered advanced, and additional therapy usually follows surgical removal of the original (primary) skin tumor. (This may also be the case with  stage II patients whose melanomas are considered at high risk of spreading to the lymph nodes or beyond.) Today, patients with metastatic melanoma can benefit from an array of treatments approved by the FDA in recent years that can extend their lives by months or years, with a rising number of patients going into long-term remission. With several effective treatments available, the decisions patients and their physicians make about which treatments to use are more important than ever, a vital part of the treatment process. A variety of factors may influence this decision.

Below, you’ll find the key treatments now available for advanced melanoma patients. Ask your physician to explain the possibilities and the reasons for selecting one treatment over another. For more extended definitions of individual treatments, please refer to our Skin Cancer Treatment Glossary.

Select a treatment to learn more about it.

  • Immunotherapy

    Some of the most important recent advances in melanoma treatment are increasingly effective new forms of immunotherapy. Using synthetic, mass-produced versions of natural immune system proteins, or by inhibiting proteins that block normal immune functions, immunotherapies boost the body’s ability to fight disease. New agents are adding years to many patients’ lives.

    Checkpoint Blockade Therapy
    The most successful form of melanoma immunotherapy to date is checkpoint blockade therapy, which now boasts four treatments approved by the FDA since 2011 — three individual drugs and a combined drug. They are significantly extending lives for many metastatic melanoma patients. These medicines, all injected intravenously, have produced a bona fide revolution in melanoma treatment the past several years, giving real hope to patients.

    The first successful checkpoint blockade therapy was ipilimumab (Yervoy®), approved in 2011 for patients with stage IV melanoma. Ipilimumab blocks CTLA-4 (cytotoxic T lymphocyte-associated protein 4), a protein receptor that functions as an immune checkpoint or “brake” to regulate the immune system. It can inhibit activation of T cells, thereby preventing them from destroying the tumor. By blocking CTLA-4, ipilimumab allows more T cells to be produced when needed to fight a cancer. It is often referred to as anti-CTLA-4 therapy.

    A monoclonal antibody (a purified class of antibodies cloned and mass-produced in the lab from one specific type of cell or cell line), ipilimumab has yielded dramatic, sustained responses akin to “cures” in certain patients, with some surviving more than five or even 10 years. In a study of 1,861 patients treated with ipilimumab, about 22 percent lived three years or longer, and 84 percent of those survivors were estimated to be alive after five years and 10 years. One recent report, in fact, suggested that 20 percent of patients who received ipilimumab are alive after eight years. In contrast, only about 4 to 6 percent of patients on an earlier form of immunotherapy, interleukin-2, achieved long-term survival, and chemotherapy has never demonstrated a survival advantage.

    In 2014, the FDA approved two additional immune checkpoint-blockading drugs, pembrolizumab (Keytruda®) and nivolumab (Opdivo®). Both drugs inhibit another molecule (programmed death-1, or PD-1) that suppresses T cells. PD-1 can directly interact with tumor cells by binding to a molecule called programmed death ligand-1 (PD-L1), and cancer cells may use PD-L1 to hide from attack by T cells. But the anti-PD-1 drugs can release the T cells to fight the cancer.

    Both pembrolizumab and nivolumab are approved for use in patients whose melanoma has metastasized or cannot be removed by surgery. As of 2016, based on results showing they are more effective than ipilimumab or other therapies, both pembrolizumab and nivolumab can be used as frontline treatments — before other drug treatments have been tried — or as second-line treatments after other treatments have failed or stopped working.

    A 2016 study of 655 patients on pembrolizumab offered some of the most impressive results ever with advanced melanoma patients. Average survival was 23 months, and more than 40 percent of patients — whether they had been previously treated with other drugs or not — were alive three years after starting treatment, with 85 patients remaining cancer-free. The fact that the therapy worked as well for previously treated patients as for previously untreated patients is especially good news for those whose initial drug therapies have failed to work or stopped working.

    Nivolumab has produced comparable results. A 2016 report on the longest ongoing study of the drug shows 17-month average survival, with 42 percent of patients surviving three years and 34 percent surviving five.

    Both pembrolizumab and nivolumab have resulted in higher response rates, longer periods without the disease advancing and longer survival, as well as fewer, less serious side effects than those seen with ipilimumab. These agents have thus largely replaced ipilimumab as preferred options for frontline treatment, with ipilimumab still being used as a second-line therapy, as well as in conjunction with PD-1 inhibitors or other treatments.

    Other PD-1 inhibitors for advanced melanoma such as pidilizumab (CT-011) are being tested, along with the related experimental inhibitors MPDL3280A (atezolizumab) and BMS-936559, which block PD-L1, the ligand that binds PD-1 to T cells and deactivates them. By blocking PD-L1, these inhibitory drugs keep it from interacting with PD-1, and thus release the T cells to fight the melanoma.

    In late 2015, the FDA approved use of ipilimumab at an earlier stage, for stage III patients after their tumor and local lymph nodes are removed. This is the first time a checkpoint blockade therapy is being used as an adjuvant therapy — a supplementary treatment designed to prevent or slow recurrence and possibly prevent metastasis beyond the lymph nodes. It is also the first therapy to significantly improve upon what was once the sole existing adjuvant immunotherapy for melanoma, high-dose interferon alfa-2b (IFN-alfa-2b).

    The FDA based its acceptance of adjuvant ipilimumab on results from a phase 3 trial showing a 25 percent improvement in delaying recurrence in stage III patients treated with ipilimumab vs. placebo (27.6 months on average before the disease came back in the ipilimumab patients, vs. 17.1 months in the placebo patients). This is somewhat longer than achieved with IFN-alpha-2b.

    Now, longer-term follow-up of the study has produced even more important results. In October, 2016, researchers for the European Organization for Research and Treatment of Cancer (EORTC) published findings in the New England Journal of Medicine demonstrating that ipilimumab increased survival in these patients, reducing risk of death by 28 percent compared to placebo treatment. Five-year survival (overall survival, or OS) rates were 65.4 percent for patients in the ipilimumab group vs. 54.4 percent for those in the placebo group. All patients had previously gone through surgery to remove their primary tumors.

    This makes ipilimumab the first proven life-extending treatment for stage III melanoma patients in history.

    Both pembrolizumab and nivolumab are currently in early testing as adjuvant treatments.

    Combined Checkpoint Blockade Therapies
    Building on the success of the individual checkpoint blockade therapies, investigators have pursued different avenues in combining them to even greater effect. In 2015, the FDA approved one such combination therapy, ipilimumab-nivolumab, for patients with metastatic or inoperable melanoma, and findings to date show it is indeed more effective than either ipilimumab or nivolumab alone. The ongoing phase 3 CheckMate-067 trial has found that the combination reduces disease progression by about 58 percent in previously untreated patients, compared with 45 percent reduction with nivolumab alone and 19 percent with ipilimumab alone. About 17 percent of patients on the combination therapy appear to have gone into complete remission. Of the initial 53 patients treated with the combination therapy, an astonishing 68 percent have survived three years or longer.

    One thing to be aware of is that patients on the combination therapy have a higher percentage of side effects and complications, such as thyroid or kidney damage, that can be serious enough to discontinue the therapy. However, some investigators suggest that for patients who have such serious reactions — even if they have to be hospitalized and go on steroids for weeks or months to recover from the side effects — the ultimate life-extending benefits may be worth the risk of using the combination therapy rather than the single-agent therapies. Much of this depends on the age, health and hardiness of the patient. Until longer follow-up and survival data emerge, choosing between a solo therapy or the combination therapy will remain an important decision for doctors and patients.

    Oncolytic Virus Injections
    In late 2015, the FDA approved the first drug in an entirely new class of immunotherapies for melanoma: injectable oncolytic virus therapy. The drug, talimogene laherparepvec (Imlygic®), often shortened to T-VEC, is approved for local treatment of inoperable metastatic lesions in the skin or lymph nodes that recur after initial surgery.

    An oncolytic virus is one designed to specifically target, infect and kill cancer cells. Imlygic is a version of the herpes simplex virus genetically modified to select cancer cells but not healthy cells for infection, while also secreting an immune-boosting protein added to the drug that can strengthen the body’s immune response against melanoma. Over many months, a massive amount of the virus is injected directly into detectable skin tumors, where it replicates inside the tumor cells, causing them to rupture and die. At the same time, the immune-boosting protein in the drug kick-starts the immune system to attack the injected tumors.

    The question remains whether the immune system attacks only the injected tumors or goes on to attack tumors throughout the body, but in the clinical trials, the therapy increased durable response rates (up to six months) for patients with advanced disease, shrinking tumors in about 16 percent of patients. While these benefits are fairly limited, and while the drug has not proven to extend survival or prevent metastases to the organs, T-VEC represents a new avenue for treatment that researchers hope to improve upon significantly. This agent is also being tested in combination with other therapies.

    Similar oncolytic viruses are now being tested, with the goal of producing more dramatic results for melanoma patients who have recurrences.

    Adoptive Cell Transfer
    The use of white blood cells called tumor-infiltrating lymphocytes (TILs) is another, still experimental, avenue for immunotherapy in advanced melanoma patients. Of special note is a technique from the National Cancer Institute called adoptive cell transfer (ACT), which involves harvesting TILs from the patient’s blood. Scientists identify and isolate the most effective melanoma-killing T cells from these TILs. They then grow them in large numbers in the lab and reinject them into the patient in the hope that they will massively attack the patient’s melanoma cells. The doctors may add high doses of the immunotherapy interleukin-2 to make these tumor-fighting cells mature and multiply, and may also use certain drugs to eliminate immune factors (and even bone marrow) that might inhibit the tumor-fighting cells. (This is called lymphodepletion.) In clinical trials with metastatic melanoma patients who had not responded to previous treatment, the patients’ response rates have been far higher than those seen with chemotherapy.

    In the latest trials, total-body irradiation was added to enhance lymphodepletion, and response rates up to 72 percent were observed in 93 patients, with 11 achieving complete remissions lasting 18 to 75 months or more.

    Reduced Roles for Earlier Immunotherapies
    As recently as five years ago, injectable interferon alfa-2b for adjuvant use (intended to prevent recurrence or metastatic spread) in high-risk stage II and stage III patients and interleukin-2 (for stage IV patients) were the only approved immunotherapies for advanced melanoma. However, adjuvant interferon in low-, intermediate- and high-dose regimens (the high-dose regimen is the only one approved in the U.S.) has proven to have little or no effect on patients’ survival, and interleukin-2 has improved survival for an extremely limited percentage of patients. With the success of the revolutionary checkpoint blockade immunotherapies and targeted therapies, high-dose interferon and interleukin-2 have been relegated to backup or complementary roles, used after other therapies, to reinforce other therapies or as a treatment arm in clinical trials testing other drugs.

    In 2011, the FDA approved a new variation of high-dose interferon alfa-2b called peginterferon alfa-2b (Sylatron®) as an adjuvant therapy to treat stage III melanoma patients, but it has not been demonstrated to improve patients’ length of survival either.

  • Targeted Therapy

    Targeted therapies, among the most revolutionary treatments for advanced melanoma, use drugs or other substances to identify and attack specific types of cancer cells, or to block the action of certain genes, enzymes, proteins or other molecules that promote the growth and spread of cancer cells. This allows the cancerous cells to be treated without killing healthy cells.

    In the past few years, there have been several notable successes in targeted melanoma therapy. The first was vemurafenib (Zelboraf®), FDA-approved in 2011, a drug taken by mouth that inhibits a defective (mutated) version of a gene called BRAF. BRAF produces a protein that normally regulates skin cells, causing them to multiply only when growth is needed. However, specific mutations in BRAF called v600E (found in about half of all melanoma patients), and less frequently, two other defective versions of BRAF called v600K and v600D, produce an abnormal version of the protein that stays switched on. This leads to out-of-control cellular growth, i.e., cancer. Vemurafenib can bind to the defective protein and deactivate it. Studies have shown that it produces rapid, striking antitumor activity in patients with BRAF V600E- and V600K-mutated melanoma, delaying disease progression and increasing patients’ survival compared with standard chemotherapy (median 13.6 months’ survival for vemurafenib patients vs. 9.7 months for chemotherapy patients). And some patients go much longer before recurrence. However, most patients eventually develop resistance to the treatment, and the melanoma starts to grow and advance again.

    In hopes of delaying resistance and increasing survival, scientists developed two other targeted treatments, one directed at BRAF and another targeting a related molecule called MEK. The FDA approved the BRAF inhibitor, dabrafenib (Taflinar®), and the MEK inhibitor, trametinib (Mekinist®),both taken by mouth, in 2013. Like vemurafenib, these newer targeted therapies can be used only in patients who have the defective BRAF gene.

    Used in combination, dabrafenib and trametinib produce more rapid responses and higher response rates in metastatic melanoma patients than either agent or vemurafenib alone. The idea behind this combination therapy is that even when the BRAF inhibitor meets with resistance in inhibiting melanoma, the MEK inhibitor further slows progression of the disease by blocking MEK, at least delaying the melanoma’s advance.

    In 2014, the FDA approved the use of combination dabrafenib and trametinib for patients who have inoperable or metastatic melanoma with a BRAF V600E or V600K mutation. Due to its superior results, the combination therapy is now considered the frontline treatment over vemurafenib or dabrafenib alone. This drug combination has reduced resistance, increased tumor shrinkage and extended the length of time before the melanoma starts growing again, leading to longer survival. The latest studies show that a remarkable 51 percent of BRAF-mutated metastatic melanoma patients on combination dabrafenib-trametinib are still alive at two years, with median survival of 25.6 months, vs. 45 percent of patients on dabrafenib alone and 38 percent of patients on vemurafenib alone (median survival 18 months).

    In November of 2015, the FDA approved a second targeted combination BRAF/MEK inhibitor therapy for advanced melanoma. Combining the established BRAF blocker vemurafenib with a new oral MEK blocker called cobimetinib (Cotellic®), the therapy is approved for stage IV BRAF-mutated patients with melanoma that is inoperable or has metastasized throughout the body. This new combination therapy works similarly to dabrafenib-trametinib. Like dabrafenib, vemurafenib blocks the mutant BRAF gene, while cobimetinib, like trametinib, blocks MEK. By inhibiting these two different parts of the signaling pathway that promotes metastasis, the new combination therapy delays advance of the disease about five months longer on average (12 months vs. seven months) than vemurafenib alone. Patients on this combination therapy also live longer on average than those on vemurafenib alone, with approximately 65 percent of patients alive 17 months after starting treatment, compared with about 50 percent of those taking vemurafenib only.

    With both of the combination therapies, dabrafenib-trametinib and vemurafenib-cobimetinib, producing comparably superior results to vemurafenib or dabrafenib alone, they have become the standard frontline targeted options for treating BRAF-mutant melanoma, although single-drug therapy may still be useful in certain situations.

  • BRAF and MEK Inhibitors Vs. Immune Checkpoint Blockade Therapies

    With the rapid evolution of immunotherapies and targeted therapies for advanced melanoma in the past five years, the choice of frontline treatment has continually shifted. With FDA approval of the BRAF inhibitor vemurafenib (Zelboraf®) in 2011, targeted anti-BRAF therapy became the standard frontline treatment for advanced melanoma patients with the defective BRAF gene. For patients who did not have the defective gene, the checkpoint blockade immunotherapy ipilimumab (Yervoy®), also approved in 2011, became the frontline treatment.

    Then, when the combination targeted therapy dabrafenib-trametinib was approved in 2013, proving more effective than either vemurafenib or dabrafenib alone, combination dabrafenib-trametinib came to be accepted as the preferable frontline treatment for patients with the mutant BRAF gene. Ipilimumab remained the first option for those who did not have the mutant gene, and the second-line therapy for patients in whom the targeted therapy failed or stopped working.

    The field shifted again in 2014, when the new PD-1-inhibiting checkpoint blockade therapies pembrolizumab (Keytruda®) and nivolumab (Opdivo®) were approved. Studies soon showed them to be safer and more effective than ipilimumab, and they eventually replaced ipilimumab as the frontline therapy for advanced melanoma patients who did not have the mutant BRAF gene. Then, combination nivolumab-ipilimumab was approved in 2015, proving somewhat more effective than pembrolizumab, nivolumab or ipilimumab alone.

    Later that year, the FDA approved the targeted combination therapy vemurafenib-cobimetinib (Cotellic®), comparable to the combination targeted therapy dabrafenib-trametinib, adding to patients’ available options.

    Most recently, research has shown that the approved checkpoint blockade therapies pembrolizumab, nivolumab and combination nivolumab-ipilimumab are all effective whether or not patients have the mutant BRAF gene, and are often more effective than any of the targeted BRAF therapies.

    Depending on their situation and personal preferences, advanced melanoma patients now most often choose from among five treatments as their frontline therapy: the single agent checkpoint blockade therapies nivolumab or pembrolizumab, combined nivolumab-ipilimumab or the targeted combination therapies dabrafenib-trametinib or vemurafenib-cobimetinib. A variety of factors may influence the decision. For example, the targeted therapies tend to begin working faster, often eliminating many or all tumors at a rapid pace. Thus, if the patient is in a desperate state and needs rapid elimination of tumors to survive, combination dabrafenib-trametinib or combination vemurafenib-cobimetinib might be the frontline choice for patients with the mutant BRAF gene.

    However, this therapy most often begins to fail sooner than the immunotherapies, so if rapid elimination of tumors is not as important, the patient and physician might opt for one of the checkpoint blockade immunotherapies, which offer the best chance of long-term survival. The most effective of all these therapies at present is combination nivolumab-ipilimumab (by a small margin over pembrolizumab or nivolumab alone), which may make it the first choice, particularly if rapid response is needed in a patient with advanced melanoma. However, it is a riskier therapy than either pembrolizumab or nivolumab alone, with a greater chance of serious side effects that might stop the therapy, so for older or frailer patients with poorer immune systems, either pembrolizumab or nivolumab alone might still be the first choice.

    Ultimately, of course, making these decisions remains up to you and your doctor, based on your health and other factors. The good news is that today, if your first therapy doesn’t work or stops working, other effective therapies now exist that often can be tried next. Researchers are continually homing in on which combinations, methods and sequences are most suitable to slow or eliminate melanoma most effectively, maintain the best possible quality of life for patients and extend their lives as long as possible. Many other new approaches are also on the horizon, currently in active laboratory study or clinical trials. The hope is to turn metastatic melanoma into a manageable or even curable condition.

  • Chemotherapy

    A number of chemotherapy drugs active in fighting cancer cells have been used to treat melanoma, either one at a time or in combination. However, with new immunotherapies and targeted therapies producing much better results, the chemotherapies have been phased out as frontline treatments. They are sometimes used to supplement the other treatments. To date, dacarbazine (DTIC), given by intravenous injection, is the only chemotherapy approved for melanoma by the U.S. Food and Drug Administration (FDA). DTIC may be combined with carmustin (BCNU) and tamoxifen, or with cisplatin and vinblastine. Temozolomide, an oral drug closely resembling DTIC, is FDA-approved for brain cancers but also used off-label (without specific FDA approval) for melanomas that have spread to the brain or nervous system.

  • Radiation Therapy

    Radiation, directing high-energy X-ray beams at the cancer cells to destroy them, is being combined experimentally with some of the medications used for advanced melanoma, and results so far are promising. External beam radiation therapy (EBRT) focuses radiation from outside the body on the skin tumor.

    While rarely used to treat a primary melanoma tumor, radiation therapy can also sometimes be used after surgery to lower the chance of recurrence in a site where lymph nodes have been removed, especially if many nodes were cancerous. In addition, it may be used on occasion to help treat melanoma that has come back after surgery in the skin or lymph nodes. Radiation therapy has a definite role in treating spread of melanoma to the brain and in relieving symptoms and pain in specific areas where the melanoma has already spread, by shrinking or slowing the tumor’s growth. Radiation therapy is now being studied in combination with immune checkpoint inhibitors to see if it can enhance the antitumor immune response.

  • Clinical Trials

    Many patients, especially those with advanced disease, participate in clinical trials to obtain new treatments that may be more effective than standard therapy but are still experimental and not generally available.

    Patients who have stage III and IV melanoma might consider enrolling in a clinical trial of a new or experimental treatment. There are risks involved in enrolling in a clinical trial, but there can be benefits as well. Discuss the possibilities with your doctor. More treatment possibilities exist than ever before, giving ever greater hope to people with advanced melanoma.

Next Steps: Improving Long-Term Survival

The advances in understanding melanoma and the immune system have set the stage for continual improvements in the treatment of advanced disease. A substantial proportion of patients have already derived significant long-term benefits and are now living years longer than in the past.

The next goal will be to determine which combinations and methods are most suitable to shrink melanoma most effectively, maintain the best possible quality of life for patients and extend patients’ lives as long as possible. Many other novel approaches are also on the horizon, currently either in active laboratory study or clinical trials; the hope is to turn metastatic melanoma from a deadly disease into a manageable chronic condition.

Medical Reviewer: Susan Swetter, MD, Stanford University Medical Center and Cancer Institute