About half of all melanomas have changes mutations in the BRAF gene. Melanoma cells with these changes make an altered BRAF protein that helps them grow. Some drugs target this and related proteins, such as the MEK proteins. If you have melanoma that has spread beyond the skin, a biopsy sample of it will likely be tested to see if the cancer cells have a BRAF mutation.
Targeted Cancer Therapies Fact Sheet - National Cancer Institute
Dabrafenib can also be used along with the MEK inhibitor trametinib; see below after surgery in people with stage III melanoma, where it can help lower the risk of the cancer coming back. Less common but serious side effects can include heart rhythm problems, liver problems, kidney failure, severe allergic reactions, severe skin or eye problems, bleeding, and increased blood sugar levels.
Some people treated with these drugs develop new squamous cell skin cancers. These cancers are usually less serious than melanoma and can be treated by removing them. Still, your doctor will want to check your skin often during treatment and for several months afterward.
You should also let your doctor know right away if you notice any new growths or abnormal areas on your skin. Some tumor cells and certain cells in the inflammation-ridden environment that surrounds many tumors are able to manipulate this checkpoint program by improperly turning it on, masking them from attack by T cells and other immune cells. This drug, a monoclonal antibody , targets a checkpoint protein on T cells called CTLA-4, releasing them to attack tumors. The approval was based on improved overall survival in a large phase III trial that enrolled patients whose cancers were no longer responding to FDA-approved or other commonly used therapies.
At the European Cancer Congress in , researchers presented an analysis of 12 clinical trials that included approximately 1, patients with advanced melanoma who were treated with different doses of ipilimumab. The median survival was The drug became the first PD-1 inhibitor to be approved by the FDA, which based its approval on positive results from an early-stage trial published in September In that trial, approximately one-fourth of patients with advanced melanoma who had previously received ipilimumab experienced tumor shrinkage. Results from a different phase III clinical trial published in November showed that, among patients with advanced melanoma whose tumors did not have BRAF mutations, nivolumab improved overall and progression-free survival compared with dacarbazine.
The rates of treatment-related side effects and serious side effects were similar in both groups. PD-1 inhibitors may have the greatest potential of the currently available therapies, Dr. Schuchter added. The only FDA-approved combination, thus far, is trametinib plus dabrafenib for patients with metastatic melanoma whose tumors have BRAF mutations.
The combination was initially approved based on early results from a late-stage trial that showed a substantially higher rate of tumor responses and longer duration of tumor responses with the combination than with dabrafenib alone. Updated results showed a modest but statistically significant improvement in progression-free survival with the combination treatment. In another phase III trial that compared the trametinib-dabrafenib combination with vemurafenib alone, patients who received the combination had better overall and progression-free survival, according to results published in November In addition to improvements in progression-free survival, Dr.
Schuchter said, the combination treatment also dramatically reduces the risk of skin-related side effects often seen when BRAF or MEK inhibitors are used alone. In the trial that compared trametinib plus dabrafenib with vemurafenib alone, for example, 18 percent of patients treated with the BRAF inhibitor alone developed non-melanoma forms of skin cancer, squamous cell carcinoma or keratoacanthoma , compared with only 1 percent of patients treated with the BRAF-MEK inhibitor combination.
Findings from several recent clinical trials suggest that other combinations could receive regulatory approval in the near future. For example, results from a large clinical trial of patient with melanoma whose tumors had BRAF mutations showed the combination of vemurafenib plus the investigational MEK inhibitor cobimetinib improved median progression-free survival compared with vemurafenib alone 9. And, as was the case with the dabrafenib-trametinib combination, patients treated with both drugs were less likely to experience serious skin-related side effects, although there was an increased risk of some other side effects, including diarrhea and visual impairment.
Targeted therapies are not the only drugs being tested in combination. In an early-phase clinical trial presented at the American Society of Clinical Oncology annual meeting, for example, patients with advanced disease who received ipilimumab plus nivolumab had a median overall survival of 40 months, nearly twice that seen in clinical trials that have tested either agent alone.
Sznol cautioned, however, that the trial was small and the results need to be validated in a larger study. With multiple effective options available to patients with advanced melanoma, a pressing issue facing clinicians and patients is which treatments to use and when. Schuchter said.
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For patients with BRAF mutations who have more extensive disease and are experiencing symptoms patients with advanced melanoma can be asymptomatic for extended periods , starting with a BRAF inhibitor rather than a checkpoint inhibitor may be the preferred option, she explained, because these drugs can produce more immediate tumor responses and, consequently, symptom relief.
NCI, for example, is planning a trial in patients whose tumors have BRAF mutations that will compare initial treatment with a targeted therapy combination against an immunotherapy combination. According to Dr. Streicher, the trial is currently under review and should launch in Several researchers noted that the common side effects of this new generation of cancer therapies are not any worse than those seen with chemotherapy or radiation. But they are different from the side effects that clinicians and their staffs are used to seeing. Managing the side effects of these new drugs, Dr.
But in addition to their skin-related side effects, patients treated with these agents can experience high fevers, diarrhea, and joint pain—which have led some clinical trial participants to halt treatment. Some patients treated with these drugs have also developed melanoma that was distinct from their original cancer.
Similarly, many patients treated with checkpoint inhibitors experience only minor side effects. But these therapies can also cause severe skin rashes, diarrhea, and an inflammation of the colon called colitis. The drugs can also cause serious immune-related reactions.
The Clinical Trial Landscape for Melanoma Therapies
In an early-stage trial of nivolumab, for example, several patients died as a result of lung inflammation. With all of the new therapies, patient education is critical, Dr. Schuchter stressed. Although IL-2 worked in only a small percentage of patients, when it did work the results were often dramatic, with complete tumor regressions in some patients that have lasted for several decades. The work done in Dr. Rosenberg and his colleagues from the CCR Surgery Branch have since been at the forefront of another approach to immunotherapy called adoptive cell transfer ACT , which has demonstrated considerable success in patients with melanoma.
The availability of ACT-based therapies is currently limited to early-stage clinical trials. With increasing interest from the pharmaceutical and biotechnology sectors, however, these therapies are quickly moving toward testing in the later-stage trials typically required to gain regulatory approval and broader clinical use. Menu Contact Dictionary Search. Understanding Cancer.
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