Monoclonal Antibodies Enter the Ring for Treatment of Melanoma Brain Metastases
Author: Erin O’Rorke
Editor: Becky Gold
As summer starts to come to a close, we need to continue to be wary of the sun! While it gives us warm and bright days that allow us to swim, hike, and play outdoors, it can also cause irreparable skin damage that can lead to cancers, such as melanoma. Unfortunately, melanoma is both very common and can be very lethal, and very few effective treatments exist for melanoma that has spread to other parts of the body besides the skin.
The article to be discussed is a phase 2 clinical trial titled “Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain,” which discusses the first trial of the aforementioned medications used in combination on patients with melanoma and asymptomatic, untreated brain metastases. The results showed promising rates of progression-free survival after an average of ~2 months on nivolumab/ipilimumab combination therapy, raising the question of whether or not we should change the standard treatment protocol for patients with melanoma metastases to the brain.
Melanoma is an aggressive, malignant form of skin cancer that has a high propensity to spread to the brain. Until recently, the prognosis of patients with melanoma malignant to the brain was poor, with a median overall survival of about 4-5 months. Treatment of melanoma has proven to be difficult, as it does not respond well to traditional chemotherapy and radiation treatments that are frequently used on similar types of cancer. This has prompted a large surge in melanoma research, unveiling novel medications that treat the cancer with higher success rates than previously seen with chemotherapy and radiation.
Many of the new medications being tested for melanoma treatment end in the same three letters: “-mab”. As an example, the two medications being discussed in this article are nivolumab and ipilimumab. “Mab” stands for monoclonal antibody, which is a protein designed by researchers in a lab. It is considered a type of immunotherapy, meaning that the antibody triggers the patient’s own immune system to attack and eliminate cancer cells.
Monocloncal antibodies are designed specifically to stick to a certain protein on the surface of cancer cells (in this case, a protein that is specific to melanoma cells). For example, nivolumab is an antibody designed to attach to a protein called PD-1 (which stands for Programmed Death 1), a protein commonly expressed on the surface of melanoma cells but not on healthy, non-cancerous human cells. Once the antibody has bound to its designated protein on the cancer cell, it signals the patient’s immune system to attack and kill the bound cancer cell. The “monoclonal” part truly means “one clone”, or that all of the antibodies in that medication are searching for the exact same protein.
Monoclonal antibodies have been popular in new cancer treatments (and treatments of many diseases other than cancer) because they are a form of “targeted” therapy, meaning that they will ideally only recognize and trigger death of cancer cells, and not healthy cells. This is an improvement from chemotherapy, which targets and kills any rapidly dividing cells in the human body (cancer cells, healthy immune cells, skin cells, hair follicles, cells lining the gut, etc.). It is also an improvement from radiation, which can be targeted to zap the cancerous tumor, but can also inadvertently damage healthy surrounding cells. Targeted therapies such as monoclonal antibodies can reduce the number and severity of side effects, and ideally provide a safer option for the treatment of cancer.
This study enrolled 94 patients with melanoma metastatic to the brain. These patients did not have neurologic symptoms, and had not had radiation or systemic glucocorticoid therapy to treat their brain metastases within 10 days prior to starting the trial. The patients were treated with combined nivolumab and ipilimumab, and researchers measured their progression-free survival and overall survival rates. They found that the 6-month and 9-month rates of progression-free survival were 64% and 83% respectively, and that the 6-month and 9-month overall survival rates were 92% and 83%, respectively. When compared to the previously established prognosis of 4-5 months after diagnosis of brain metastases, it is a clear improvement that 83% of the patients in this trial survived for at least 9 months. The side-effects in this study were similar to those seen when using the same medications to treat patients with melanoma not metastasized to the brain. This is promising news for patients with brain metastases, because it means that it is not any more dangerous for them to undergo this treatment than it is for melanoma patients without brain metastases.
Just under 100,000 patients are diagnosed with melanoma in the United States each year. When treated with traditional chemotherapy and radiation regimens, only 5% of patients with melanoma metastatic to the brain (stage IV) survive more than five years. Monoclonal antibodies such as nivolumab and ipilimumab could create an entirely different protocol for the treatment of such an aggressive and prevalent cancer, potentially saving thousands of lives each year. If clinical trials with these medications continue to show promising results, the new standard of treatment for patients with melanoma metastatic to the brain could potentially involve the initiation of immunotherapies—such as monoclonal antibodies—for disease control, before considering chemotherapy and radiation. This change could allow patients to avoid the relatively low success rates and often devastating complications that accompany chemotherapy and radiation.
While it may seem like monoclonal antibodies are a perfectly engineered medication that will change cancer treatment forever, they still do come with serious side-effects that need to be considered. Some of the side-effects that patients in this study experienced included fatigue, increased liver enzymes (signs of a stressed or damaged liver), rash, diarrhea, headache, and more. It is also worth noting that one patient in this study passed away due to an immune-related myocarditis, or inflammation of the heart wall, that researchers determined to be related to the study treatment. While rare, these side-effects do happen, and it is imperative for doctors to discuss these possibilities with each patient before any decisions are made on how to move forward with cancer treatment.
Many of the patients enrolled in this phase two clinical trial were still receiving the maintenance dose of immunotherapy when the study was published in August 2018. They will likely be followed for years to come in order to allow researchers to continue measuring their rate of melanoma progression, side-effect profiles, and overall survival. While the two medications - nivolumab and ipilimumab - are currently FDA approved, the exact dosages will likely be tested in a phase three clinical trial in order to further determine their efficacy and safety. This would involve large-scale testing, with randomized, blinded groups, thousands of patients, and years of follow-up. The future of cancer therapy is rapidly evolving, and with time, drugs like nivolumab and ipilimumab will undoubtedly improve the quality of life and prognosis for countless patients with cancer, autoimmune disorders, and other diseases across the world.
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