New York (Reuters Health) - Among people with melanoma whose tumors have spread to the brain, the combination of nivolumab and ipilimumab produces a complete response in 26% of asymptomatic patients, according to an open-label, phase 2 U.S. study of 94 volunteers with stage 4 disease.

The partial response rate was 30%, and 2% had stable disease for at least six months, according to the new results from the CheckMate 204 study funded by Bristol-Myers Squibb and reported online August 22 in The New England Journal of Medicine. The median follow-up was 14 months.

Therapy with nivolumab plus ipilimumab yielded an intracranial clinical benefit for 57% of patients, said the research team, led by Dr. Hussein Tawbi, associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center.

The overall one-year survival rate for patients was 82%; historically it's less than 20% because it can be so difficult to manage tumors in the brain. In fact, most melanoma studies exclude patients with untreated brain metastases.

"We were very pleased that we managed to induce responses in the brain that were as deep and durable as responses outside the brain," Dr. Tawbi told Reuters Health in a telephone interview.

"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," wrote Dr. Samra Turajlic of London's Royal Marsden NHS Foundation Trust and James Larkin of London's Francis Crick Institute in a Journal editorial.

"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 this study," they wrote.

"This approach could also lead to a decrease in or avoidance of complications of whole-brain radiation therapy and stereotactic radiotherapy" such as cognitive decline and radiation necrosis, the Tawbi team wrote.

Patients with tumors larger than 3 cm, tumors that had been irradiated, patients with symptomatic central nervous system disease, leptomeningeal disease, low performance status or who had been taking glucocorticoids within the past 14 days were excluded from the immunotherapy trial.

As many as 75% of adults with melanoma end up with tumors in the brain. Existing treatments - surgery, radiotherapy and chemotherapy that can cross the blood-brain barrier - do little to improve overall survival or lower the odds of developing new brain tumors. Only about 5% survive for 5 years and most die within 5 months.

In March, The Lancet Oncology published a study of the drugs in patients with asymptomatic melanoma brain metastases and found a response rate of 46% in 35 patients versus 20% in 25 volunteers treated with nivolumab monotherapy. Complete response rates were 17% and 12% respectively.

Dr. Tawbi said the two studies "are complementary and confirm and validate each other."

In the CheckMate study, nivolumab was given at a dose of 1 mg/kg every three weeks along with ipilimumab at a dose of 3 mg/kg IV every 3 weeks for four doses. That was followed by nivolumab treatment at a dose of 3 mg/kg every two weeks. Treatment lasted 24 months unless there was disease progression or dangerous side effects.

By the cutoff date, 18% of the volunteers had intracranial progression, 4% had extracranial progression and 13% had both.

"Intracranial responses were observed across the range of target lesions, including in patients with three or more intracranial target lesions," the researchers reported.

Among the 52 patents who responded, 47 were still showing some benefit at the time of analysis. Median time to response was 2.3 months.

The combination treatment seemed to work better in patients with tumor PD-L1 expressions and among those with above-normal lactate dehydrogenase levels.

However, grade 3 or 4 side effects appeared in 55% of patients and that caused 20% to discontinue treatment. One death, caused by inflammation of the heart, was attributed to the treatment.

Initially, there has been concern that the immunotherapy might cause inflammation and swelling in the brain, but swelling only surfaced in 5% of patients.

"We were 40 patients into this when we realized we were not seeing swelling and we were not seeing neurologic deaths," said Dr. Tawbi. "We were seeing the same toxicity profile as patients who did not have brain metastases."

In the Lancet Oncology study, serious adverse effects were experienced by 46% of patients.

The CheckMate researchers are also looking at the treatment in symptomatic patients.

The drug may not be as effective in those patients, said Dr. Tawbi, "because we usually use steroids to control the symptoms and that could counteract the immune therapy."—Gene Emery

SOURCE: https://bit.ly/2N8yyxe

N Engl J Med 2018.

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