For patients with Stages III and IV disease, surgery is usually followed with an additional adjuvant therapy. Ask your physician to explain the possibilities and grounds for selection of one treatment over the other.
Select a treatment to learn more about it.
A number of drugs active in fighting cancer cells are being used to treat melanoma, either one at a time or in combinations. Currently, Dacarbazine (DTIC), given by injection, is the only chemotherapy approved by the 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 for melanomas that have spread to the brain or nervous system.
Another class of drugs, based on a different principle, has come into use more recently. They are anti-angiogenic, which means that they prevent new blood vessels from forming. The reason this is important is that they cut off the blood supply that would otherwise nourish the cancer cells and enable them to grow. These drugs are still experimental for melanoma, and a good deal of research into improving and combining them with others is going on. Studies are under way with the anti-angiogenic drug thalidomide, combined with the chemotherapeutic agent, temozolomide. Angiostatin and endostatin are two other drugs in this class that have shown some degree of activity against melanoma in preliminary studies.
Isolated Limb Perfusion Method: This palliative treatment, which relieves symptoms, is sometimes used when melanoma metastases have reached an arm or leg. “Isolated” means that the chemotherapy is “perfused” (shunted directly) to the blood flowing through the affected limb, but to no other part of the body, to limit toxic effects. The drug melphalan is the chemotherapy most frequently used, often combined with other agents.
This is one of the most exciting and changing fields in medicine, based on drugs that act on the body's immune system. A number of newly developed treatments are now being tested with some success. Among the immunotherapies, several types of experimental melanoma vaccines are now viewed as promising. Unlike the influenza vaccine, given when you are well to prevent disease, these are given to people who already have melanoma. Clinical trials of various types of vaccine are under way with patients whose disease is in Stages III and IV. The vaccines are intended to stimulate the immune system so that it reacts more strongly against a patient's melanoma cells, destroying the cancer or slowing the progression. These vaccines are not a part of routine treatment at this time, so patients with advanced melanomas may wish to discuss this possibility with their physicians.
Another type of immunotherapy (also known as biologic therapy) makes use of chemicals that occur naturally in the body. One therapy you are likely to hear about is injectable interferon (IFN) alpha-2b, the only drug with FDA approval to treat “high-risk” Stage II and Stage III melanomas. High-risk melanomas are tumors that have a high chance of recurring (such as those that are ulcerated or over 4 mm thick) or have spread to the nearby lymph nodes. At first, IFN alpha-2b appeared to increase overall 5-year survival. After further study, it proved to give patients a longer period without relapse, extending their disease-free interval to an average of 9 months, but did not lengthen overall survival. It has significant flu-like side effects.
In 2011, the FDA approved a new drug, peginterferon alfa-2b (also known as Sylatron), to treat Stage III melanoma patients – those found to have microscopic or palpable metastatic disease that has reached the lymph nodes. The drug, injected subcutaneously, was the first adjuvant, or additional, therapy for Stage III patients approved since high-dose IFN alfa-2b in 1995. This approval followed on the heels of a trial in which melanoma patients taking Sylatron remained relapse-free an average of nine months longer than patients not taking the drug (34.8 months vs. 25.5 months). There was no difference in overall survival.
Tumor necrosis factor (tumor-killing) factor is another of these naturally occurring substances. Both of these — especially interferon alpha-2b — are produced by white cells (lymphocytes) when they come in contact with tumor cells, viruses or other harmful substances, and have been shown to kill a number of tumors, including melanomas. They have some anti-angiogenic properties as well. However, both drugs have significant side effects that can limit their use. And while interferon alpha-2b is FDA-approved, tumor necrosis factor is not.
Lymphokines, immune chemicals naturally produced by the white blood cells in small quantities, are being used for Stage IV patients. They may also be produced by white blood cells that have been specially stimulated by antigens, a basic part of the immune system, to make them better “killers” of malignant cells. The best known of these therapies uses the injectable lymphokine interleukin-2 (IL-2), with or without the addition of interferon alpha or other biotherapies and chemotherapies. It enters melanoma cells and attacks them. High-dose IL-2 (“Proleukin”) was the first FDA-approved immunotherapy used to treat Stage IV metastatic melanoma. It is associated with very significant side effects when given in high doses, but has been found to increase disease-free and overall survival in some patients. About 10-16 percent of carefully selected patients on IL-2 regimens respond to the drug, with 6 percent having complete responses (remissions), and about 60 percent of the complete responders have significantly extended lives.
Tumor-infiltrating lymphocytes (TILs) also play a part in some new therapies for advanced melanoma. 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, then isolating from them the cells expressing T cell receptors that can recognize melanoma-specific antigens; in other words, the most aggressive melanoma-killing lymphocytes are identified and isolated. These are then grown in large numbers in the lab and reinjected into the patient in the hope that they will massively attack the patient’s melanoma cells. High doses of IL-2 may be added to make these tumor-fighting cells mature and multiply, and certain drugs are used to eliminate immune factors 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.
Checkpoint Blockade Therapy
The most successful form of melanoma immunotherapy to date is “checkpoint blockade therapy,” which now boasts three recently FDA-approved drugs and a combined drug that are significantly extending lives for many metastatic melanoma patients.
The first successful checkpoint blockade therapy was ipilimumab (YervoyTM), approved in 2011 for patients with advanced melanoma. Ipilimumab blocks CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), a protein receptor that functions as an immune checkpoint or “brake” in the immune system; it can inhibit activation of T-cells, thereby preventing them from destroying the tumor. Ipilimumab is designed to block CTLA-4 so that more T-cells can be produced when needed to fight a cancer. It is often referred to as an 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 5 or even 10 years. In a study of 676 people with advanced, inoperable melanoma (reported in June, 2010 at the American Society for Clinical Oncology annual meeting), 24 percent of patients given ipilimumab alone or combined with another immune-stimulating treatment were alive after two years, vs. only 14 percent of those given the other immune-stimulating treatment alone. In a later 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 5 years and 10 years. One recent report, in fact, suggested that 20 percent of patients who received ipilimumab are alive after 10 years. In contrast, only about 4-6 percent of patients were ever found to achieve long-term survival with Interleukin-2, and no overall survival advantage was ever demonstrated with chemotherapy.
Two additional immune checkpoint-blockading drugs, pembrolizumab (Keytruda®) and nivolumab (Opdivo®), were FDA-approved in 2014. 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 these 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
- and who have had disease progression after treatment with ipilimumab
- and who, if they have an abnormal BRAF gene, have had disease progression following treatment with a targeted BRAF inhibitor (vemurafenib or dabrafenib).
Other PD-1 inhibitors for advanced melanoma are in the wings, and a related inhibitor dubbed MPDL3280A blocks PD-L1, the ligand that binds PD-1 to T cells and deactivates them. Thus far, PD-1/PD-L1 blockades have resulted in even higher response rates, progression-free survival, and overall survival rates, as well as a more favorable side effect profile than that seen with ipilimumab. Many researchers have begun asserting that they should become front-line therapies, rather than be reserved for patients who have already failed treatment with ipilimumab or a BRAF inhibitor. Several randomized trials comparing ipilimumab with anti-PD-1 therapy are ongoing, and to date, the studies show that the anti-PD-1 therapies are even more effective than ipilimumab.
In October 2015, the FDA gave accelerated approval to combination nivolumab–ipilimumab for patients with metastatic or inoperable melanoma, based on the CheckMate -069 trial, which found that the combination therapy demonstrated a 60 percent reduction in disease progression compared to ipilimumab alone. Approved for patients who do not have the mutated BRAF gene, this is the first combination immunotherapy ever approved for patients with cancer. Median progression-free survival was 8.9 months with the combination regimen, vs. 4.7 months for ipilimumab alone, with 17 percent of patients on the combination therapy going into remission.
In a new development that could be a huge boon to patients, the checkpoint blockade therapies could soon start to be used earlier, before Stage IV, when they may save even more lives. Recently the FDA accepted an application for ipilimumab to be used for Stage III patients at high risk of recurrence, after their tumor and local lymph nodes are removed. Here, it would be used as an “adjuvant” therapy – a supplementary treatment to prevent recurrences and metastasis beyond the lymph nodes. Acceptance of the application was based on results from a Phase III trial showing a 25 percent improvement in recurrence-free survival in Stage III patients treated with ipilimumab versus placebo. This trial is the first to show that the checkpoint blockade drugs may be given earlier in the course of disease, when they can do more good and potentially cure more patients.
The FDA is scheduled to make a decision on ipilimumab as a Stage III adjuvant therapy by October 28 of 2015.
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 (ZelborafTM), FDA-approved in 2011, which inhibits a defective 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, a specific mutated version of BRAF called v600E (found in about half of all melanoma patients) – and in smaller subsets of patients, the related mutant gene versions V600K and V600D – produces an abnormal version of the protein that stays switched on. This leads to out-of-control growth, i.e., cancer. Vemurafenib can bind to the defective protein and deactivate it. Studies have shown that it produces striking and rapid antitumor activity in patients with BRAF V600E- and V600K-mutated melanoma, delaying disease progression and increasing patients’ overall survival (OS) compared to standard chemotherapy (median OS of 13.6 months for vemurafenib patients vs. 9.7 months for chemotherapy patients).
While this is a significant increase in survival, and while some patients go much longer before recurrence, most patients eventually develop resistance to the treatment, and the melanoma starts to grow and advance again.
BRAF is part of the mitogen-activated protein kinase (MAPK) pathway, a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. When BRAF is defective, this signal helps promote melanoma growth. In hopes of delaying resistance and increasing survival, two other treatments directed toward BRAF and a related molecule called MEK, downstream of BRAF in the MAPK pathway, were approved: the BRAF inhibitor dabrafenib (Taflinar®) and the MEK inhibitor trametinib (Mekinist®). All three of these targeted therapies can be used only in patients who have the defective BRAF gene. The idea is that even when the BRAF inhibitors vemurafenib and dabrafenib meet with resistance in inhibiting melanoma, trametinib will inhibit its progression at MEK further down the MAPK cascade, at least delaying the melanoma’s advance.
In 2014, the FDA also approved the use of dabrafenib and trametinib in combination for patients with inoperable or metastatic melanoma with a BRAF V600E or V600K mutation. The hope is that these different drugs and drug combinations will increase tumor shrinkage and extend the length of time before the melanoma starts growing again.
Indeed, 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 addition, a Phase III study of a new BRAF/MEK inhibitor combination – the BRAF inhibitor vemurafenib plus an experimental MEK inhibitor called
cobimetinib– found that patients with advanced melanoma lived almost four months longer on average than patients on vemurafenib alone. Based on these results, cobimetinib has been submitted to the FDA, and could be approved sometime in 2015. All these findings have driven researchers to anticipate a time in the near future when the combination BRAF-MEK inhibitors will become standard treatment for BRAF-mutant melanoma, phasing out the single-drug therapies.
BRAF and MEK Inhibitors vs. Immune-Checkpoint Blockade Therapies
Although the likelihood of a melanoma shrinking when treated with BRAF and MEK inhibitors is high, the response to this targeted treatment often lasts for a limited period. Ipilimumab is less likely to shrink metastases, and it usually takes weeks to months before improvements are seen. However, in patients who respond, ipilimumab offers greater potential for long-term control of the melanoma and more prolonged survival. The new anti-PD-1 immune-checkpoint blockade therapies – nivolumab (Opdivo) and pembrolizumab (Keytruda®) – appear to offer even longer-lasting effects comparable to ipilimumab, and may bring about a more rapid response, shrinking the melanoma.
Combining Targeted Therapy and Immunotherapy
Both targeted drugs and immunotherapy are now important treatment options, though the best ways to use them are not yet clear. Because of the substantial melanoma-killing activity of BRAF and MEK inhibitors, it may be particularly attractive to combine them with ipilimumab or other checkpoint-blockade immunotherapies. It is hypothesized that by killing melanoma cells, BRAF and MEK inhibitors will increase activation of immune cells to attack any remaining melanoma cells. However, initial attempts to combine a BRAF inhibitor (vemurafenib) with immune-checkpoint blockade therapy (ipilimumab) was deemed unsafe, so this combination should not currently be used in standard practice. Clinical trials are now evaluating combinations of these drugs used in different ways -- for example, using them in sequence rather than concurrently.
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. Some patients have already derived significant long-term benefits. One recent report suggested that 20 percent of patients who received ipilimumab are alive after 10 years. (In contrast, only about 4-6 percent of patients were ever found to achieve long-term survival with Interleukin-2, and no overall survival advantage was ever demonstrated with chemotherapy.) Similarly, early clinical trials have described an improved likelihood of significant tumor shrinkage using combinations of these new drugs, specifically dabrafenib combined with trametinib or ipilimumab with nivolumab.
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.
A gene is the basic unit of genetic material. It is the code or "blueprint" by which our body's proteins are made. Alterations in these codes can result in uncontrolled cell growth as in cancer.
On the other hand, selected genes can be altered so as to correct genetic defects or enhance the cancer-fighting potential of cells. There is hope that making changes in genes will lead to successes in treating a wide range of illnesses, so this kind of therapy frequently gets newspaper headlines. However, keep in mind that this treatment is in the very early stages of research, and its effectiveness is yet to be proven conclusively.
One form of gene therapy is based on creating alterations in the white blood cells or in the tumor-infiltrating lymphocytes (TILS) so that they will attack the melanoma. This is achieved by removing these cells from the patient, growing them outside the body and treating them so as to increase their number. The next step is the addition of genetic material that produces one of the many growth factors which make the lymphocytes more aggressive as cancer-fighters. These more aggressive lymphocytes are returned to the patient's body in an effort to stimulate the immune system to kill the melanoma and its metastases.
The focus of current research is the identification of genes for specific melanoma antigens. These are molecules found on the cell wall that stimulate the production of antibodies, which are a part of the body's immune defense system. An antibody attaches itself to only one type of antigen. By injecting the gene for the melanoma antigens, the hope is to increase their number and produce a broad attack by the patient's immune system.
Many patients, especially those with advanced disease, are participating in clinical trials to obtain new treatments that 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. More treatment possibilities exist than ever before, giving new hope to people with melanoma.