Wild Card: Treating Triple Wild-Type Melanoma

When it comes to the treatment of later-stage melanoma, there’s a lot of focus on the mutations that drive the disease.

BRAF, MEK, c-KIT — if one of these mutations is at the heart of your melanoma, you may be eligible to take a targeted drug specifically designed to squelch the effect of the mutation. It’s a strategy that has stirred excitement in recent years for its ability to prolong progression-free and/ or overall survival in some eligible patients.

But what if you don’t have any mutations that can be treated with approved targeted drugs? Will you find yourself taking chemotherapy, instead, which may be less effective and cause more serious side effects?

There may be other options, says Michael Postow, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. While chemotherapy may be right for some patients, there are also a number of newer treatment options, including immunotherapies and even some targeted therapies, available on the market or in clinical trials for patients regardless of whether their tumors harbor any of the most common driver mutations.

Most often, targeted treatments and immunotherapies are given if a melanoma progresses or recurs after surgery, or if the cancer was advanced or non-operable when diagnosed. Stage 3 and 4 melanomas are the cases most likely to be treated with these types of drugs.

Since BRAF mutations are common in melanoma and are treatable with targeted drugs, patients with advanced disease are typically tested for this biomarker, and the information is used to guide them and their physicians in creating treatment plans, Postow says. Patients who test negative for BRAF mutations will likely not be helped by drugs that target BRAF, but rather than losing hope about treatment, that simply means they should consider other options, he says.

Since there are many methods for fighting melanoma these days, Postow concludes, “it doesn’t always matter what your mutation status is.”

WHAT’S IN A DRIVER MUTATION?

Driver mutations like those in BRAF are changes in genes that may support the development of melanoma, and researchers have discovered a number of them.

Most driver mutations are in oncogenes. Before they mutate, oncogenes are known as proto-oncogenes, and they help cells grow. In its normal state, such a gene switches on and off as necessary so that cells don’t grow out of control. When they mutate, or when there are too many copies of them, proto-oncogenes become oncogenes. They get stuck in the “on” position, which can cause cells to grow out of control and lead to the development of cancerous cells. Mutations in the oncogenes BRAF (present in 37 to 50 percent of melanomas), NRAS (13 to 25 percent), MEK (6 to 7 percent), KIT (2 to 8 percent), CTTNB1 (2 to 4 percent), GNA11 (1 percent) and GNAQ (1 percent) may drive melanoma.

Mutations in the tumor suppressor gene NF1 may drive about 12 percent of melanomas. Tumor suppressor genes slow down cell production, correct DNA mistakes and tell cells when to die. All of these processes can prevent cancer. Mutations in these genes can cause them to get stuck in the “off” position, which can allow cancer to develop more freely.

Drugs that target mutations in BRAF, MEK and KIT have been approved by the U.S. Food and Drug Administration for the treatment of melanoma, and other common driver mutations, such as NRAS and NF1, are being studied and may have approved targeted treatments soon.

Of course, there are side effects associated with these drugs. For example, when Mekinist (trametinib), a MEK inhibitor, and Tafinlar (dabrafenib), a BRAF inhibitor, are given together, they can cause fever, fatigue, rash, nausea, diarrhea, swelling of the hands and feet, cough, headache and joint pain.

But what does all this mean for patients who don’t have any of these mutations?

When a patient doesn’t have mutations in three of the major known driver genes in melanoma, doctors might call that triple wild-type, triple-negative or pan-negative disease. A wild-type gene is one that doesn’t have mutations. There is some debate as to which three genes, when normal, constitute triple wild-type melanoma, but often this refers to melanomas without mutations in BRAF, KIT or NRAS. Alternatively, it can refer to wild-type BRAF, NRAS and NF1.

Regardless of how you define triple wild-type melanoma, patients who fit into the category may still eventually find themselves on a road toward targeted therapy.

“Most patients who are triple wild-type may have other drivers that we’re just not testing for routinely,” Postow says. Identifying them and developing medications that effectively target them could give these patients more options, and researchers are pursuing that avenue now.

EXPANDING TARGETED THERAPY OPTIONS

A handful of clinical trials are exploring Akt-inhibiting drugs for Akt-mutated but BRAF and NRAS wild-type melanomas. ALK mutation may also be a driver of melanoma, and clinical trials are exploring inhibition of the Akt protein in BRAF and NRAS wild-type melanomas.

Another experimental therapy may target melanomas driven by fusion proteins. Most genes tell cells which proteins to make. When two or more genes join and produce a protein, it’s called a fusion protein. Some fusion proteins, which occur in 4 to 8 percent of melanomas that lack BRAF, NRAS and KIT mutations, could drive melanoma growth. According to early studies, melanomas driven by these proteins might respond to experimental treatment with Nexavar (sorafenib), a targeted drug known as a kinase inhibitor which is approved to treat certain kidney and liver cancers. Fusion protein-driven melanomas may also respond to the MEK inhibitor Mekinist. The MEK gene is closely related to the BRAF gene, and MEK inhibitors are often used in combination with BRAF inhibitors to bolster their effects against melanoma.

“We have lots of potential targets,” says Ryan Sullivan, an oncologist at Massachusetts General Hospital. “It’s probably a good idea to have your tumor genotyped more completely than just looking at BRAF, NRAS and KIT. If you have an actionable mutation, it can be a transformative therapy.”

IMMUNOTHERAPY

Cancer cells, by their nature, can escape the immune system’s typical disease-fighting mechanisms. Immunotherapy drugs trigger the immune system to recognize and better fight these stealthy cancer cells. Whether someone benefits from this type of drug is not necessarily related to mutational status.

“Patients who have BRAF mutations and who go on immunotherapy tend to have the same response rate of progression-free survival, and probably overall survival, as patients who don’t have a BRAF mutation,” Sullivan says. “That’s true for ipilimumab (Yervoy), high-dose interleukin-2, combination ipilimumab and nivolumab (Opdivo), and it’s probably true for single-agent anti-PD-1 antibodies.”

PD-1 inhibitors, which include Keytruda (pembrolizumab) and Opdivo, block a protein on the surface of immune cells, called PD-1, that acts as a checkpoint that prevents the immune system from attacking cancer cells that express a molecule called PD-L1. PD-L1 latches onto PD-1 proteins on the surface of immune cells, and this allows the cancer to slip through the gates of the immune system. When PD-1 is blocked, the immune cells are able to recognize cancer cells as a threat and attack them. “Certainly, PD-L1 expression can happen in the triple wild-type, no matter how you define it,” Sullivan says.

Desmoplastic melanoma, for example, doesn’t typically have any of the major driver mutations, such as BRAF, NRAS or KIT. “It tends to arise from sun-damaged skin, so it has an enormous amount of mutations and responds pretty well to PD-1 therapy,” Sullivan says.

Even people whose tumors don’t appear to express PD-L1 could benefit from PD-1 inhibitors, Sullivan adds. A tumor might express such low levels of PD-L1 that it tests negative, but the cancer could still respond to PD-1 blockers. “And PD-L1 is inducible, so a negative isn’t necessarily still a negative and a positive isn’t necessarily still a positive several months later.”

Yervoy blocks another protein on the surface of T-cells, CTLA-4, and outcomes with the drug are not affected by whether a patient’s cancer expresses a BRAF mutation, Postow points out.

Data are mixed as to whether someone with an NRAS mutation might have a better response to immunotherapy. Data that Sullivan and his colleagues collected on 229 patients showed that those with NRAS mutations were more likely to benefit from immunotherapy. But more recent studies, he says, have contradicted that finding.

Side effects of PD-1 inhibitors can include cough, fatigue, nausea, skin rash, itching, diarrhea and joint pain. CTLA-4 inhibitors can cause side effects including diarrhea, fatigue, itching and rash.

ADOPTIVE CELL TRANSFER

Experimental cell therapies serve as an immune system redesign.

This approach first causes lymphodepletion with the chemotherapies cyclophosphamide and fludarabine, and then infuses the immune system with T cells that are custom-made to recognize and fight melanoma. Melanoma tumors already contain these types of T cells, known as tumor-infiltrating lymphocytes (TIL), but typically in numbers too small to fight the cancer. When a tumor is removed, TILs can be extracted from the tumor tissue and grown in a lab, then injected back into the body of the patient. When the new, larger number of T cells are injected, it is as if the patient is getting a new immune system. Some studies show that 40 to 70 percent of people treated with lyphodepletion followed by adoptive cell transfer respond to it. About 40 percent have a long-lasting, potentially curative response.

Side effects can be expected with this approach because it involves chemotherapy, and because the immunotherapy IL-2 is injected into patients along with the laboratory-bred T cells. Side effects common to both regimens can include nausea and vomiting, diarrhea, drops in blood counts that can lead to infection or bruising, and fatigue.

Chemotherapy can also spark mouth sores and hair loss, and IL-2 can bring fever or flu-like symptoms, rash and swelling of the extremities.

Researchers are currently recruiting patients, regardless of mutational status, for clinical trials of adoptive cell transfer in combination with other drugs.

GENE MUTATIONS AND TREATMENT DECISIONS

The bottom line is that, while people with BRAF and KIT mutations are candidates for certain medications that others are not, immunotherapy outcomes are generally not drawn along the lines of gene mutations.

“At the end of the day,” Sullivan says, “you’re going to recommend some sort of immunotherapy and, if the patient is healthy, combination therapy or maybe treatment as part of a PD-1 based clinical trial.”

“It’s not about BRAF-mutant or BRAF wild-type,” Postow adds. “It’s all just about patients.”