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For Your Patients-Neuro-Oncology
Combination Immunotherapy Has Persistent Effect on Shrinking Metastatic Melanoma in the Brain

ARTICLE IN BRIEF

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DR. HUSSEIN TAWBI: “What ended up happening in the brain was that the response rate was just as fast, just as deep, and just as durable as the response rate that happened outside the brain.”

Two combined immunotherapy drugs — nivolumab and ipilimumab — seemed to work as well on brain metastases as it did on systemic disease, prompting some neuro-oncologists to suggest that clinicians consider the combined regimen as a first-line therapy for melanoma patients with brain metastases.

More than half of 94 patients who received a combination of two immunotherapy drugs for metastatic melanoma to the brain showed radiologic evidence of a complete or total response for at least nine months, and shrinkage of brain tumors persisted for more than 14 months of follow-up, according to a study published August 23 in TheNewEnglandJournalofMedicine.

The open-label, multicenter, phase 2 trial — conducted at University of Texas MD Anderson Cancer Center and 27 other medical centers — tested the combined safety and efficacy of two checkpoint inhibitors, nivolumab and ipilimumab, in melanoma patients who were neurologically asymptomatic and not previously treated for their brain metastases. Prior studies of the combined drugs for metastatic melanoma had excluded patients with untreated brain metastases.

The study found that the combination immunotherapy seemed to work as well on tumors inside the brain as it did on systemic disease, prompting an accompanying editorial to suggest that clinicians should consider using the approach right from the start with melanoma patients with brain metastases.

“Although this was a relatively small, nonrandomized study, in our view, the data reported are relevant to clinical practice, given the high response rate, rapid time to response, and manageable side-effect profile,” said the editorial by Samra Turajlic, MD, PhD, and James Larkin, FRCP, PhD, of the Royal Marsden NHS Foundation Trust in London. “Therefore, outside the context of clinical trials, we would suggest that this regimen be considered as first-line therapy for all patients with brain metastases who meet the inclusion criteria for their study.”

The editorialists cautioned, however, that key questions remain to be answered, including the role and timing of radiotherapy, particularly stereotactic radiosurgery, as it relates to immunotherapy.

Independent experts interviewed by NeurologyToday said it was important to note that the study's narrow eligibility criteria mean that many patients with metastatic melanoma to the brain should not be considered candidates for the combination immunotherapy until more research is done to evaluate its efficacy in a broader population. The study also includes only a median of 14 months of follow-up.

Still, the experts said the study results were welcome news for a disease for which even a few extra months of survival is considered a good result.

The study, called CheckMate 204, was funded by the National Cancer Institute and Bristol-Myers Squibb, was involved in the study design and analysis. Bristol-Myers Squibb developed and markets nivolumab and ipilimumab.

STUDY DETAILS

To qualify for the CheckMate 204 study, patients with metastatic melanoma had to have at least one tumor 0.5 to 3 cm in diameter that had not been previously irradiated. They had to be free of neurologic symptoms and not have been treated with glucocorticoid therapy within 10 days before the initiation of the study regimen. A later amendment to the study allowed 20 symptomatic patients with brain metastases to enroll.

The patients were treated with nivolumab at a dose of 1 mg per kilogram of body weight every three weeks plus ipilimumab at a dose of 3 mg per kilogram intravenously every three weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every two weeks. Treatment continued for 24 months or until disease progression, unacceptable toxic effects, or withdrawal of consent.

The primary endpoint was the rate of intracranial clinical benefit, whether stable disease for at least six months, complete response or partial response. Secondary outcomes included the rate of extracranial (systemic) response. Patients were followed up at set points with MRI scans.

Among patients with a median follow-up of 14 months, the rate of intracranial clinical response was 57 percent. The rate of complete response was 26 percent, the partial response rate was 30 percent, and the stable disease rate for at least six months was 2 percent. The rate of extracranial clinical benefit was 56 percent, almost identical to the intracranial response.

Treatment-related grade 3 or 4 adverse events were reported in 55 percent of patients, including central nervous system events, such as headache, in 7 percent of patients. One patient died from immune-related myocarditis.

The researchers said they were concerned that brain edema could be a problem since the immunotherapy activates a T-cell response, which can cause inflammation, but the incidence of brain edema in the study turned out to be just 2 percent.

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DR. JOACHIM M. BAERHRING said that while treating metastatic melanoma to the brain has traditionally been extremely frustrating, “over the last 10 years it seems like we are chipping away and we are having some success in some subgroups of patients. The latest study is another step in that direction.”

“The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases,” who took the same combination, the researchers reported.

The researchers suggested that a change in how to treat melanoma patients with brain metastases may be warranted.

“Although current practice is to start with surgery, stereotactic radiotherapy, or both followed by immunotherapy or targeted agents, our results support the initiation of immunotherapy to achieve prompt control of both extracranial and brain metastases,” they wrote. “This approach could also lead to a decrease in or avoidance of complications of whole-brain radiation therapy and stereotactic radiotherapy (for example, cognitive decline and radiation necrosis, respectively.)”

Among the study's limitations were that it was not a randomized, controlled trial and its eligibility criteria means it not known whether the results apply to a broader group of patients. Many melanoma patients with brain metastases are on glucocorticoid therapy, an exclusion factor for the study.

Lead Investigator Hussein Tawbi, MD, PhD, associate professor of melanoma medical oncology at MD Anderson, said it was noteworthy that the combination immunotherapy had the same response rate within the brain as it did systemically.

“What ended up happening in the brain was that the response rate was just as fast, just as deep and just as durable as the response rate that happened outside the brain,” he said.

He said that more needs to be learned about the immune action unleashed by the drugs, Ipilimumab is designed to block the CTLA-4 checkpoint on T cells, while nivolumab works to suppress activation of the PD1 checkpoint.` “It is very possible that it is the T cells that get into the brain that get the job done and not the drugs themselves,” he said.

Dr. Tawbi said he and other oncologists have been using the approach as a first-line therapy for melanoma with brain metastases, following a preliminary report on the study that was presented last year at the American Society for Clinical Oncology meeting. He said the order and timing of therapy — whether to start with immunotherapy first or radiation first, and then add the other modality — will likely vary depending on the patient's degree of metastases.

Dr. Twabi said longer-term results on the trial will be announced in the net two years. His team also hopes the results will open up the possibility of testing the approach in other types of solid tumors that travel to the brain.

EXPERT COMMENTARY

Tracy T. Batchelor, MD, MPH, Giovanni Arenise-Harvard professor of neurology at Harvard Medical School, called the study “very impactful,” adding that the “impressive thing about it was the high rate of objective radiographic response in the brain and the durability of those responses.”

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THE ONSET AND DURABILITY of intracranial objective responses to the combination of nivolumab and ipilimumab, according to modified Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. Open circles indicate the first evidence of objective response (complete or partial response), and arrows indicate an ongoing response; 47 of 52 responses (90%) were ongoing at the time of the analysis. The dashed line indicates 1 year after treatment initiation. The median time to response was 2.3 months (range, 1.1 to 10.8). The median duration of intracranial response has not been reached.

“These are very impressive results and very hopeful results. This certainly could change the standard of care for the specific types of patients who would have been eligible for this trial,” said Dr. Batchelor, executive director of the Stephen E. and Catherine Papas Center for Neuro-Oncology at Massachusetts General Hospital.

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DR. TRACY BATCHELOR: “These are very impressive results and very hopeful results. This certainly could change the standard of care for the specific types of patients who would have been eligible for this trial.”

Mary R. Welch, MD,MS, assistant professor of neurology at Columbia University, recommends using the combination of nivolumab and ipilimumab in select melanoma patients with brain metastases if they are asymptomatic and have not been previously exposed to immunotherapy. ‘“We will try immunotherapy and then image at six to eight weeks. We follow them very closely,” Dr. Welch said, adding that if the response is not looking favorable on MRI, they will consider another therapeutic approach.

She said that it is important for clinicians to be open minded and and cautions against a “one size-fits-all” approach because patients differ in how they present — the location of brain metastases, response to treatment. and whether or not they experience side effects. Twenty percent of study participants could not complete all four doses of the protocol because of grade 3 or 4 adverse events, she noted.

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DR. MARY R. WELCH: “We know this combination can work well, but toxicity is a real concern. One of the unanswered questions is how can we adjust dosing to achieve the same benefits with fewer side effects?”

“We know this combination can work well, but toxicity is a real concern. One of the unanswered questions is how can we adjust dosing to achieve the same benefits with fewer side effects?” Dr. Welch said.

Joachim M. Baehring, MD, FAAN, professor of neurology and neurosurgery at Yale University, said that while treating metastatic melanoma to the brain has traditionally been extremely frustrating, “over the last 10 years it seems like we are chipping away and we are having some success in some subgroups of patients. The latest study is another step in that direction.”

Dr. Baehring said he was struck by a few points: “The immunotherapy regimen did not cause brain edema in most patients (only 2 percent) and the response in the brain mirrors the response in the rest of the body, which means the immune system response can get to it.” He was also impressed by the durability of the results.

Dr. Baehring, who does consulting work for Bristol-Meyers Squibb, has begun using the nivolumab-ipilimumab combo in select melanoma patients with brain metastases and expects the pool of candidates to expand as more research is done.

“The reality is these are all FDA-approved drugs and they are not contraindicated for brain metastases,” he said.

DISCLOSURES

Dr. Tawbi received research funding to his institution and consulting fees for Bristol-Myers Squibb, Merck, Genentech, and Novartis.

LINK UP FOR MORE INFORMATION:

•. Tawbi HA, Forsyth PA, Algazi A. Combined nivolumab and ipilimumab in melanoma metastatic to the brain https://www.nejm.org/doi/full/10.1056/NEJMoa1805453. N Engl J Med 2018: 379(8):722–730.
•. Turajlic S, Larkin J. Immunotherapy for melanoma metastatic to the brain https://www.nejm.org/doi/full/10.1056/NEJMe1807752. N Engl J Med 20018; 379(8): 789–790.