In the last few years, patients with the grim diagnosis of metastatic melanoma have gained reasons to feel more hopeful about their chances of beating the disease. Melanoma has become a poster child for new cancer treatment options, with several targeted and immune therapies approved by the U.S. Food and Drug Administration (FDA) and many more in clinical development.
Targeted therapies are so named because they are directed towards specific mutated targets (proteins) that are found in tumors and actually cause cancer development. Hundreds of such mutations have been identified in various cancers, but not all are ‘targetable’ yet. However, about half of melanomas have mutated BRAF proteins, for which three drugs are approved: vemurafenib, dabrafenib, and trametinib. The first two hit mutant BRAF directly; the last one inhibits MEK proteins, which carry cancer-promoting signals from mutated BRAF. The response rate (response = tumor shrinkage) to these inhibitors in patients with BRAF mutations is impressive.
Unfortunately, many melanoma patients whose tumors ‘melt away’ after treatment with a BRAF or MEK inhibitor eventually experience recurrence in 6 to 8 months, that is, the disease returns. To prevent this from happening, new therapies are being developed. It was found in clinical trials that combining dabrafenib and trametinib together produced more responses—and more durable responses—than with either drug alone. The great news is that this combination garnered a fast-track consideration from the FDA and will likely be approved for melanoma treatment within the next few months.
Another option for patients includes enrollment in clinical trials that test combinations of BRAF inhibitors with other drugs. These ‘other drugs’ are also precision targeted and hit other proteins that are abnormally active in melanomas with BRAF mutations. These drugs are experimental drugs, which means patients can only have access to them through participation in clinical trials. The trials explore the addition of inhibitors of proteins, such as PIK3, mTOR, CDK4, and MDM2, to the BRAF inhibitors. These proteins, when activated, aid mutant BRAF in the development of melanoma and thus present rational targets.
Many patients who do not have mutations in BRAF can also benefit from experimental targeted treatment options. About 20% of melanoma patients have mutations in a gene called NRAS. This particular protein is difficult to target directly, though a large initiative sponsored by the National Institutes of Health (NIH) will aim to develop inhibitors of NRAS and its relatives (the RAS family of proteins) because they are mutated in several different cancers. For now, there are drugs in clinical trials that target the derangements induced by mutated NRAS; these include drugs that inhibit the protein MEK, along with CDK4 or MDM2.
One type of treatment garnering a lot of attention lately is known as immune therapy, or immunotherapy. Immune therapies do not target specific, abnormally active proteins in melanoma cells; instead, they promote the ability of the patient’s own immune system to recognize melanoma cells, engage these cells, and kill them.
Stimulation of the immune system is currently carried out in several ways. The first involves removing molecular ‘brakes’ on either tumor cells or on immune cells themselves that prevent the killing of tumor cells. An antibody-based drug known as ipilimumab (Yervoy) is FDA-approved for melanoma, but the response rate to it is not great. However, when responses to the drug do occur, they are usually long-lasting.
Newer drugs in the same category include nivolumab and lambrolizumab, which seem to work much better than Yervoy. Both of these drugs target a protein known as PD-1, which is found on immune cells and prevents them from recognizing and killing tumor cells. Elimination of PD-1 has been shown to not only stop tumor growth, but ‘melt’ tumors altogether. Several drugs targeting PD-1 are in fairly advanced clinical testing for melanoma, kidney, and lung cancer. Moreover, combining Yervoy with nivolumab seems to be even more effective than using nivolumab alone.
Another promising immune therapy is a drug called MPDL3280A, also currently in trials for melanoma. This one targets the ‘brake’ found on tumor cells named PD-L1 (a protein that binds PD-1 and blocks the killing activity of immune cells).
A second type of immune therapy actively being investigated is known as adoptive cell transfer. It involves isolating immune cells from a patient’s tumor (surgically removed) or from blood, making many copies of them under certain conditions in the laboratory, then infusing them back into the patient where they can attack tumors. This approach is still highly experimental and requires enrollment in clinical trials, but has already shown tremendous promise.
A strong card in the immunotherapy deck is using it to treat patients whose tumors do not have directly targetable mutations (such as tumors not having changes in either BRAF or NRAS). Moreover, BRAF inhibitors and other targeted inhibitors could be combined with immune therapy. There is evidence that treating tumors with BRAF inhibitors first may make them more susceptible for immune attack. Clinical trials exploring combined administration of targeted and immune therapies are ongoing and are recruiting patients.
The Cancer Commons website has information on the mutations found in melanoma (listed as ‘biomarkers’) and lists trials suitable for each molecular subtype, as well as immune therapy trials.