Promising Immunotherapy Combination for Melanoma Patients with Asymptomatic Brain Metastases
A combination of two immunotherapy drugs shows promise in treating patients with skin cancer that has spread to the brain, according to a study published this week the New England Journal of Medicine. Results of a clinical trial in 94 patients from 28 centers across the United States, including Roswell Park Comprehensive Cancer Center, suggest that a combination of nivolumab (brand name Opdivo) and ipilimumab (brand name Yervoy) is both effective and safe for melanoma patients with brain metastases, a group that has historically had a poor prognosis.
Melanoma, one of the deadliest forms of skin cancer, can be aggressive and spread to many organs if not detected and treated early. Among patients with advanced melanoma, one of the most frequent and difficult-to-treat sites of metastasis is the brain. A big challenge that must be overcome when treating brain tumors is the blood-brain barrier, a “filter” that acts to protect the brain from potentially harmful substances, including potentially lifesaving chemotherapy drugs.
Until recently, treatment options for patients with brain tumors were limited to surgery, radiation and chemotherapy. Although newer targeted agents (such as BRAF/MEK inhibitors and immunotherapy with checkpoint inhibitors) appear to be both more effective and better tolerated than conventional therapy, melanoma patients with brain metastases are usually left out of the clinical trials that test these new therapies because of concerns about whether the drugs will effectively cross the blood-brain barrier or interfere with other treatments.
In the study (CheckMate 204), whose leadership included Roswell Park clinicians Marc Ernstoff, MD, Chair of Medicine, and Igor Puzanov, MD, MSCI, FACP, Chief of Melanoma and Director of the Early Phase Clinical Trials Program, patients with melanoma that had metastasized to the brain but was not yet causing neurologic symptoms or requiring high-dose steroid treatment received a combination of nivolumab and ipilimumab every 3 weeks (up to four doses), followed by treatment with nivolumab alone (for up to 2 years). More than half of patients (57.4%) responded well to the combination, which is higher than that reported for ipilimumab therapy alone (24%), and 64% of patients showed no evidence of disease progression after 6 months of treatment. After 9 months, 83% of patients were still alive, which is remarkable given that for most melanoma patients with brain metastases, the disease usually progresses rapidly (in 2 or 3 months) and overall survival is only about 6 months.
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“Nivolumab combined with ipilimumab produced a clinically meaningful response in the brain similar to that seen in other sites of the body, and it was generally well tolerated,” says Dr. Ernstoff. “This immunotherapy approach will begin to change the treatment paradigm for patients with asymptomatic melanoma brain metastases.”
Drs. Ernstoff and Puzanov, who were part of a team that developed the concept and the protocol for this approach and are coauthors of the New England Journal of Medicine paper, are leading Roswell Park’s efforts to finding new treatment options for melanoma patients with brain metastases.
Nivolumab and ipilimumab are in a class of drugs known as immune checkpoint inhibitors. Checkpoints are molecules on immune cells that can be turned on or off to start or stop an immune response. Both drugs target T cells, an essential type of white blood cell that acts as a first responder, recognizing and attacking cancer cells. Nivolumab blocks a protein on the surface of T cells called PD-1, and ipilimumab blocks the protein CTLA-4. By inhibiting these checkpoints, each drug boosts the body’s natural immune response against cancer.
“This is a novel approach showing the previously unknown power of this immunotherapy combination,” says Dr. Puzanov. “Our next step is to develop a similarly powerful combination for patients whose brain metastases have become more advanced and are causing symptoms.”
Nivolumab and ipilimumab is the first combination of immunotherapy drugs approved for patients with metastatic melanoma, and the FDA recently approved this particular combination for certain types of metastatic colorectal cancer. Saby George, MD, FACP, Associate Professor of Oncology at Roswell Park, was part of the team conducting a pivotal trial showing that this same drug combination significantly improves survival among patients with never-treated kidney cancer.
The results of the CheckMate study offer yet another example of how immunotherapies have the potential to revolutionize cancer treatment and offer new hope for patients with advanced metastatic disease.