If you’re diagnosed with advanced, malignant melanoma — a type of skin cancer — and surgery alone isn’t enough to control it, immunotherapy is an important treatment option. Immunotherapy enhances your own immune system’s ability to repress melanoma that has spread from the original tumor to other parts of your body.
Below, three experts in melanoma and immunotherapy explain how it works, who might benefit and what to expect if you undergo this evolving form of treatment.
Deciding on Immunotherapy
“It’s often the first choice among several options that we have available for patients with advanced disease,” says Dr. Suraj Venna, medical director at the Inova Melanoma and Skin Cancer Center in northern Virginia, where immunotherapy is the focal point for treating patients with advanced melanoma. “That’s really based on all the key research studies that have shown its superiority versus other treatments for melanoma.”
— What are the common side effects of the treatment?
— How often do I have to get this?
— How long am I going to be on treatments?
— How is this going to impact my day-to-day lifestyle?
Patients need to understand that immunotherapy drugs they see on TV commercials and elsewhere are given intravenously, Venna says. “They’re not oral medications. They’re distinct from chemotherapies. While most patients tolerate immunotherapy well, there are patients who develop fatigue, side effects like rashes and diarrhea.”
A subset of patients can develop rare, more serious side effects. “We call these immune-related adverse events, which occur in a minority of patients,” Venna says. “The immune drugs can cause inflammation of many internal organs. You can get inflammation of the lining of the heart (cardiomyositis), inflammation of the gut ( colitis), inflammation of the liver (hepatitis) and so on. You can have inflammation of the brain (encephalitis).”
Most of these immune-related side effects are reversible with treatments like steroids, Venna says. However, side effects like thyroiditis may require patients to stay on thyroid replacement medications permanently.
The risk of these side effects must be balanced with the risk posed by the threat of the disease itself. “When we’re talking about melanoma, the quoted five-year survival for most stage 4 patients is 10% to 15%,” Venna points out. “It’s sort of like all bets are off, and we have to go full force. And for most patients, they would agree that these rare side effects certainly would not outweigh all this.”
History of Immunotherapy
Dr. Steven Rosenberg, chief of the surgery branch at the National Cancer Institute, is a pioneer in cancer immunotherapy. Rosenberg heads NCI’s clinical program that seeks to translate research advances into effective immunotherapies for cancer patients.
Melanoma was among the first diseases for which the Food and Drug Administration approved use of an immunotherapy drug, Rosenberg notes. That drug was interleukin-2. Also called IL-2, it causes the body’s own lymphocytes — cancer-fighting cells called T-lymphocytes, or T-cells — to grow.
More than 30 years ago, Rosenberg and colleagues first demonstrated the ability of IL-2 to quash aggressive tumors in patients whose melanoma had wildly spread. “We also showed it could cause regression in patients with metastatic renal ( kidney) cancer who had been through all available treatments,” Rosenberg says. Until these findings, he says, these conditions were uniformly fatal once they metastasized, or spread, from the local site. This was a turning point in the fight against cancer.
In light of these findings, followed by similar successful results from multi-institutional studies, the FDA approved IL-2 for active use in U.S. patients with renal cancer in 1992, and for those with melanoma in 1998. But that was only the beginning. Rosenberg and his team soon discovered a way to further boost the effects of IL-2.
This “second generation version” of immunotherapy works by increasing the number of cancer-busting T-cells. His group was the first to publish research demonstrating how immunotherapy using tumor-infiltrating T-cells works. His group showed that by removing a patient’s tumor, isolating the tumor-infiltrating T-cells within it, growing those T-cells in the laboratory and then returning the increased population back to the patient, these immune warrior T-cells would recognize melanoma and make it regress.
As immunotherapy continued its development in clinical trials, evidence grew to support its effectiveness. For example, among 93 patients with metastatic melanoma who were treated with both tumor-infiltrating T-cells and IL-2, 20 patients (or 22%) had complete tumor regression, according to a study led by Rosenberg. That group of patients had a 100% survival rate at three years and a 93% survival rate at five years following treatment.
Follow-up studies showed that patients who received the immunotherapy drug combination had significantly higher rates of tumor regression than those who received IL-2 alone.
Latest in Immunotherapy
Patients now have access to next-generation immunotherapy options — drugs called checkpoint modulators. These new drugs are successfully fighting this type of skin cancer in a different way.
So-called checkpoints are part of the immune system to prevent itself from attacking normal cells in the body. To begin an immune response against foreign invaders like cancer cells, checkpoint proteins located on immune cells must be “off .” Melanoma cells sometimes evade detection from the immune system by activating checkpoint proteins, thus blunting the body’s normal immune response.
Drugs called immune checkpoint inhibitors restore the immune response against melanoma. These intravenous medications include the following:
— PD-1 inhibitors. Keytruda (pembrolizumab) and Opdivo (nivolumab) are medications that block the checkpoint protein called PD-1, located on the immune system’s T-cells. As a result, the body has a stronger immune response against melanoma cells. This can cause tumors to shrink.
— CTLA-4 inhibitors. Yervoy (ipilimumab) targets another checkpoint protein called CTLA-4, also located on T-cells.
Combining checkpoint inhibitors may bring an added survival benefit. Patients taking the combination of nivolumab with ipilimumab in the CheckMate-067 clinical trial were more likely to be alive after five years than patients taking a single checkpoint inhibitor combined with a placebo, according to recent findings.
Five year survival rates using checkpoint inhibitors:
— Opdivo (nivolumab): 44%
— Yervoy (ipilimumab): 26%
— Combination therapy: 52%
It’s worth noting that these findings are just based on Phase 3 clinical trial data presented Sept. 28, 2019, at the annual meeting of the European Society for Medical Oncology in Barcelona, Spain.
Immunotherapy combined with genetic modification of T-cells is a likely next frontier in treatment for advanced melanoma. Rosenberg has done pioneering work with chimeric antigen receptor T-cell therapy, or CAR-T, in treating lymphoma, a type of blood cancer.
Overall, “immunotherapy, in my view, is the likeliest approach we have to making progress in cancer over the next decade,” Rosenberg says. “Not only for melanoma, but for other cancers as well.”
Immunotherapy Versus Other Therapy Options
When patients undergo surgery to remove a melanoma tumor on their skin, a lymph node biopsy may also be done if doctors have any suspicion that cancer may have spread. Stage 3 melanoma is diagnosed if lymph nodes cells are found to contain cancer.
“If you are stage 3, it’s basically surgery and then consideration of alternative, or adjuvant, treatments after the surgery,” says Dr. Charlotte Ariyan, a melanoma expert and surgeon at Memorial Sloan Kettering Cancer Center in New York City.
The three main follow-up approaches for later-stage melanoma are:
— Close observation.
— Targeted therapy.
Close observation (sometimes called watching and waiting) is an option for some patients depending on their risk, such as the chances of cancer recurring, which is lower for patients with stage 3A versus stage 3C melanoma. Additional therapy is clearly indicated for patients at higher risk, Ariyan says.
Targeted drugs are technically a type of chemotherapy. However, because targeted therapies work with more precision than the traditional chemotherapy that was previously used for melanoma, full-body side effects (like losing all your hair) are less likely, Ariyan explains.
Targeted drugs focus on specific genetic changes, or mutations, in melanoma cells. A tumor biopsy and testing of those cells reveal whether your melanoma has specific abnormal proteins for drugs to act on. Melanomas most frequently involve changes in patients’ BRAF gene or their MEK gene. About half of patients with melanoma have the BRAF mutation.
Unlike immunotherapy, targeted drugs are oral drugs, so patients can take pills at home. Some may be used in combination. These are some of the more common targeted drugs for treating advanced melanoma:
— BRAF inhibitors. BRAF inhibitors aim to shrink or slow the growth of melanoma tumors. Drugs include vemurafenib (Zelboraf), dabrafenib (Tafinlar) and encorafenib (Braftovi).
— MEK inhibitors. MEK inhibitors are sometimes combined with BRAF inhibitors to improve the treatment response. Drugs include trametinib (Mekinist), cobimetinib (Cotellic) and binimetinib (Mektovi).
Targeted drugs have a range of side effects including skin changes and rash, sun sensitivity, fever, headaches and more.
The decision between immunotherapy and targeted therapy is a very individual one, Ariyan says. “First of all, a person has to have that mutation to even be considered for (targeted therapy),” she says. “It also goes into: Are there certain conditions the patient has that would make the side-effect profile worse with one drug versus the other?”
Lifestyle is another factor. Immunotherapy requires patients to come into the cancer center and receive the drugs intravenously on a regular basis, such as once every two weeks, three weeks or monthly.
Long-term side effects are a significant decision factor. Some immunotherapy side effects, like thyroiditis, are permanent, Ariyan notes. Targeted drugs also have side effects, she says, “but usually, when you stop the pills, those go away.”
Signs of Success
How quickly patients see results from immunotherapy depends on how the treatment is used, for instance as a single agent or in combination, Ariyan says. “These type of responses can take a little longer than chemotherapy, but can also be very rapid as well,” she says. “Obviously, it’s been quite dramatic for us to see people respond who we never thought would respond — who didn’t respond to traditional treatment in the past.”
In 2018, the Nobel Prize in Physiology and Medicine was awarded to Dr. James Allison — formerly an immunologist at Memorial Sloan Kettering and now at University of Texas MD Anderson Cancer Center — and Dr. Tasuku Honjo of Japan for their work in developing checkpoint inhibitors as cancer immunotherapy. The prize recognized that, in establishing this new approach to cancer therapy, Allison and Honjo have opened the door to new possibilities for patients with a cancer diagnosis.
At the Inova Center, Venna sees a spectrum of positive responses to melanoma immunotherapy. “You can think of success as disease stabilization,” he says. “Patients are having repeat scans and nothing is evolving.” Treatment gains control over what has been an out-of-control condition.
“We have patients with what we call partial responses, where with the treatment and subsequent scans, the tumor burden is shrinking,” Venna continues. “Then we have a subset of patients who have what we call a complete response, where there is no radiographic evidence of melanoma — as if it never existed in this person. That’s ultimately the goal, to get more patients in this complete response group and also to have a sustained response.”
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Correction 10/18/19: A previous version of this story gave incorrect information about a drug combination’s name in a clinical trial.