The BRAF gene makes a protein that is involved in cell division. BRAF is mutated in 50% to 60% of people with melanoma, making it the most commonly mutated gene in this group of aggressive skin cancers. BRAF mutations can occur in all melanoma subtypes, but are most common in skin with intermittent sun exposure. Most tumors with this abnormal gene can be treated with vemurafenib (Zelboraf™). Vemurafenib is often used in combination with other drugs that inhibit a protein called MEK.
Melanomas can be tested for BRAF abnormalities by a laboratory procedure called polymerase chain reaction or PCR. This process makes many copies of DNA fragments so that even a small amount of DNA from a person can be tested for genetic abnormalities. The most common BRAF mutation is called V600E; this abnormality can be targeted with a drug called vemurafenib.
There are several manufacturers of genetic tests that can detect BRAF mutations in melanoma tumor samples. Testing may be performed onsite at a medical facility or at a specialized laboratory. Your doctor can recommend which tests are appropriate for you.
BRAF is an oncogene. When mutated, oncogenes can cause or contribute to tumor growth. Like many genes, the BRAF gene provides instructions for making a protein. Normally, the BRAF protein helps transmit signals that regulate cell growth, division, and movement. However, when the BRAF gene is mutated, it makes an abnormal BRAF protein that is too active. This abnormal protein makes cells divide abnormally fast, potentially leading to tumor formation.
The BRAF protein is a serine-threonine protein kinase. This protein is regulated by signals received by cells. When activated, the BRAF protein in turn activates a cellular process called the MAP kinase pathway. This pathway is involved in cell division. The only protein known to be directly activated by the BRAF protein is another kinase, which is called MEK. This means that MEK inhibitors also have the potential to counteract the effects of BRAF mutations.
BRAF mutations are infrequently found in non-small cell lung cancer, or NSCLC, as well as in cancers of the colon and rectum, ovary, and thyroid gland.
The U.S. Food and Drug Administration (FDA) has approved three treatments specifically for melanomas with BRAF mutations. Vemurafenib and dabrafenib directly target a mutated form of the BRAF protein, and trametinib inhibits a protein called MEK. Ongoing clinical trials are testing the effectiveness of other targeted therapies, as well as drug combinations that inhibit several different protein targets at once.
FDA-approved targeted treatments and immunotherapies
The FDA has approved treating melanomas that have BRAF mutations with vemurafenib. This drug is also known as PLX4032, or Zelboraf, and is made by Roche. In clinical trials with Zelboraf, melanoma tumors stopped growing for several months. In addition, during the course of the trials, melanoma patients treated with Zelboraf were 63% more likely to survive than those treated with conventional chemotherapy. The latter treatment kills rapidly dividing cells rather than targeting specific genetic abnormalities. Vemurafenib is a BRAF inhibitor that blocks only the most common mutated form of the BRAF protein, which is called BRAF V600E.
In May 2013, the FDA approved dabrafenib for all melanoma patients with the BRAF V600E mutation. The drug was developed by GlaxoSmithKline as Tafinlar. Its approval was based on the results of randomized clinical trials in which patients who took dabrafenib showed significantly improved progression-free survival compared to patients who received chemotherapy with dacarbazine.
Trametinib is a drug that inhibits a protein called MEK, which is, in turn, activated by mutant BRAF. It is made by GlaxoSmithKline as Mekinist. In a large clinical study, trametinib significantly prolonged progression-free survival in patients with metastatic melanoma. In May 2013, the FDA approved Mekinist as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. The FDA did not recommend that Mekinist be given to patients who have previously been treated with BRAF inhibitors.
A combination of these two drugs was approved for the treatment of melanoma in 2014. The approval was based on results of clinical trials that showed a response rate of 76% in patients who received both drugs, and 54% in patients who received Tafinlar only.
Immunotherapy is a treatment approach in which drugs or cells are used to redirect a patient’s own immune system to recognize and kill tumor cells. Recently, great successes were seen with antibody-based drugs that work by releasing the molecular “brakes” that prevent immune cells from eliminating tumor cells. These antibodies work either by unleashing the activity of the immune cells directly, or by removing obstacles from the tumor cells. The three remaining treatments in this section are all examples of immunotherapies.
High-dose bolus interleukin-2 (IL-2) was approved by the FDA for the treatment of metastatic melanoma in 1998. IL-2 is a so-called “immunomodulatory agent” that stimulates the immune system to attack cancer cells. IL-2 has been shown to achieve rates of tumor reduction of about 10-15%, but about half the patients who respond to IL-2 have a complete response—disease remission for more than 10 years. However IL-2 is among the most toxic of cancer treatments, with marked side effects and a significant risk of life-threatening adverse events. IL-2 treatment can be considered only for patients who are in otherwise excellent health and only after extensive discussion of the risks and benefits of this treatment.
Interferon alfa-2b—which, like IL-2, is an immunotherapy agent—is approved by the FDA as an adjuvant treatment for patients with stage II melanoma and primary tumors more than 4-mm thick, or with stage III melanoma. (An adjuvant treatment is given after a primary treatment to keep the cancer from returning.) Interferon alfa-2b has been shown to delay recurrence in these patients, but in most clinical studies it has not improved overall survival durations.
The FDA has approved ipilimumab for all patients with advanced melanoma, regardless of whether BRAF is mutated. This drug is made by Bristol-Meyers Squibb as Yervoy. In clinical trials, ipilimumab has increased survival in a small subset of melanoma patients. Ipilimumab is an immunotherapy drug that inhibits a protein called CTLA-4, which normally helps control immune system cells called T cells. By blocking CTLA-4, ipilimumab stimulates T cells and thus boosts the immune system response against melanoma cells in the body. However, ipilimumab does not specifically target tumors with BRAF mutations.
Pembrolizumab, previously known as MK-3475, is better known by its brand name Keytruda. It was approved in 2014 for metastatic melanoma patients who have not responded to Yervoy. In clinical trials, at least half of the patients responded to Keytruda. Keytruda blocks a protein called PD-1, which is found on the surface of immune cells known as T cells. PD-1 usually inhibits the function of T-cells, so blocking it can increase T cell activity, thereby promoting immune system function.
Nivolumab (Opdivo) was approved for the same condition as Keytruda in 2014. It is also an antibody drug that targets PD-1, and is very similar to Keytruda.
Investigational targeted treatments and immunotherapies
New BRAF and MEK inhibitors:
Other Targeted Drugs:
Some melanoma tumors with BRAF mutations also have abnormalities or activation of other genes, including PTEN, AKT, CCND1, or others. Clinical trials are underway to test combinations of drugs to treat melanomas that have BRAF mutations as well as mutations in other genes. Among investigational drugs that are tested in trials in combination with inhibitors of BRAF or MEK are inhibitors of PI3K and/or AKT (MK2206 and BKM120, PX-866, SAR260301), inhibitors of HSP90 (STA-9090), inhibitors of CDK4 (LEE011), and many others.
Immunotherapy is a treatment approach in which drugs or cells are used to redirect a patient’s own immune system to recognize and kill tumor cells. Recently, great successes were seen with antibody-based drugs that work by releasing the molecular “brakes” that prevent immune cells from eliminating tumor cells. These antibodies work either by unleashing the activity of the immune cells directly, or by removing obstacles from the tumor cells. The treatments listed below are all examples of immunotherapies.
A combination of these two checkpoint drugs has been studied in clinical trials with outstanding results. In a phase I trial, 65% of patients treated for metastatic melanoma have experienced significant tumor reduction. The combined treatment has more side effects than either drug alone, but these side effects are mostly manageable.
MPDL3280A is an antibody drug that targets a protein called PD-L1. PD-L1 is sometimes found on tumor cells and protects them from being killed by immune cells. PD-L1 binds to PD-1 on immune T cells and inhibits their killing activity. MPDL3280A is being tested in clinical trials, and preliminary results are promising for melanoma, as well as other cancer types.
A number of clinical trials are exploring combinations of BRAF and MEK inhibitors with immunotherapies, such as checkpoint blockade or adoptive cell transfer. There is a strongly held opinion in the cancer community that these types of combination treatments are the most promising ones.
Another immune system-based approach, adoptive T cell therapy, makes use of immune system cells called T cells, which can target and kill tumor cells. First, T cells are harvested from a patient’s tumor. Many copies of the T cells are produced in the laboratory, and then billions of the cells are transferred intravenously back into the patient’s bloodstream. These T cells specifically target and kill tumor cells, but are not numerous or strong enough to eradicate the entire tumor. To help the body make even more copies of these tumor-specific T cells in the bloodstream, the patient is given chemotherapy to deplete ordinary T cells prior to the tumor-specific T cells’ reintroduction, and then given a high dose of the protein IL-2 to stimulate T cell growth after the T cells’ reintroduction. This therapy is still highly investigational.