September 20, 2018, by NCI Staff

A clinician making a treatment plan for a patient with a brain tumor.

Credit: National Cancer Institute

Results from a clinical trial show that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) halted the growth of or shrank metastatic brain tumors in more than half of participants with melanoma that had spread to the brain.

Nivolumab and ipilimumab are immune checkpoint inhibitors, drugs that unleash an immune response against cancer cells. Individually and in combination, both drugs have led to long-lasting responses in some patients with metastatic melanoma.

It hasn’t been clear whether checkpoint inhibitors are effective against brain metastases in people with melanoma because these patients have typically been excluded from clinical trials on the grounds that their health may not be stable enough to participate in a study, explained Elad Sharon, M.D., M.P.H., of NCI’s Cancer Therapy Evaluation Program.

But “that view is changing,” said the trial’s lead investigator Hussein Tawbi, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center. He and his colleagues designed this phase 2 clinical trial specifically for patients with brain metastases.

“It is remarkable that the treatment proved not only to be just as safe as in patients [with metastatic melanoma] who don’t have brain metastases, but also that it was just as effective,” Dr. Tawbi said. The trial results were reported August 23 in the New England Journal of Medicine.

“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,” Samra Turajlic, M.B.B.S., Ph.D., and James Larkin, Ph.D., of the Royal Marsden NHS Foundation Trust in London, wrote in an editorial.

Metastatic Melanoma in the Brain

Brain metastases can cause neurological problems such as seizures, dizziness, and vision and hearing problems. Although current therapies used to treat brain metastases (like surgery and radiation) may help to alleviate these symptoms, they can also compromise brain function. According to a 2010 study, only 5% of people with melanoma that has spread to the brain will live more than 5 years after a diagnosis of brain metastases.

With the availability of new immunotherapies over the past few years, though, the survival rate may be changing, Dr. Sharon said.

A handful of small studies provided initial evidence that, on their own or in combination, ipilimumab and nivolumab may shrink melanoma brain metastases. The new phase 2 trial—sponsored by Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab—was launched to provide stronger evidence.

More than 100 people with at least one metastatic melanoma tumor in the brain were enrolled in the trial. People with certain conditions or medical histories were excluded, such as those with cancer in part of the brain called the leptomeninges, with neurological symptoms from brain metastases, or who had been treated with steroids to alleviate swelling in the brain.

All study participants first received nivolumab plus ipilimumab as induction therapy, followed by nivolumab alone as maintenance therapy. Treatment was given for a maximum of 24 months or until the patient’s cancer progressed, the treatment caused unacceptable side effects, or the patient withdrew consent.

Immunotherapy Combination Shows Clinical Benefit

Brain metastases shrank in half of the 94 participants with sufficient follow-up, including 24 participants whose brain metastases were completely eliminated and 28 whose brain metastases shrunk partially. Two other participants had brain metastases that remained stable—meaning, they did not shrink or grow—for at least 6 months.

“These tumor response rates are similar to response rates for people with metastatic melanoma who don’t have brain metastases,” Dr. Sharon noted. “It appears that patients are benefitting [from the treatment] regardless of the site of metastasis.”

The responses were rapid, the investigators noted, with some tumor reductions detectable just 6 weeks after the start of treatment. And the responses were durable: 90% of patients whose brain metastases responded to the treatment had an ongoing response 14 months later.

The number of brain metastases a patient had at the time of enrollment did not affect whether the person benefited from the treatment. However, brain metastases were more likely to shrink or remain stable in patients whose tumors had high expression of PD-L1, a biomarker of immunotherapy response, than in patients whose tumors had low PD-L1 expression.

Overall, the response rate for tumors outside of the brain (56%) was similar to the response rate for brain metastases.

Tumor progression occurred inside or outside of the brain, or both, for 35% of participants. Some patients (18%) had progression in brain metastases but not in tumors outside of the brain. After 9 months, the rate of progression-free survival was 60% and the rate of overall survival was 83%.  

No New Safety Concerns

Brain metastases can hinder brain function by destroying healthy brain cells and by causing swelling in the brain. Because immunotherapies can cause inflammation, there were concerns that these treatments might trigger brain swelling and more neurological issues, Dr. Tawbi explained.

However, only seven participants (7%) had a serious neurological side effect, such as swelling or bleeding in the brain. In total, 55% of participants had a serious (grade 3 or 4) adverse event related to the treatment, most commonly an immune response in the liver (indicated by an increase in liver enzymes). One participant died from inflammation of the heart muscles (myocarditis), which was related to the treatment.

“The safety profile in this population was consistent with that reported in studies involving patients without brain metastases,” noted Drs. Turajlic and Larkin.

“It appears there’s no increased safety risk in patients” with melanoma brain metastases, said Dr. Sharon. “I think that was the most interesting finding.”

Improving Access to Clinical Trials for Patients with Brain Metastases

Addressing some of the bigger questions this new study raises will require allowing more people with brain metastases to enroll in clinical trials, Dr. Sharon said.

For example, although the immunotherapy combination seems to be a promising potential treatment for people with metastatic melanoma tumors in the brain, it can’t be assumed that it will also benefit higher-risk patients who were excluded from the study, Drs. Turajlic and Larkin wrote.

“Being realistic about the patient population, we know that some patients present with neurological symptoms and require treatment with steroids,” Dr. Tawbi explained.

Although people with metastatic melanoma who had neurological symptoms or had been treated with steroids were initially excluded from the trial, the investigators later enrolled 20 such patients. The team plans to analyze data from these participants soon.

In addition, nivolumab and ipilimumab are used to treat several kinds of cancer—including colon, liver, lung, and kidney cancer—but their efficacy on brain metastases of these cancers has not been carefully evaluated. Drs. Turajlic and Larkin stated that future clinical trials for checkpoint inhibitors should include such patients.

Another remaining question, said Dr. Sharon, is how immunotherapy might change the role and timing of radiation for treating brain metastases. Should patients be treated first with immunotherapy and then radiation only if the cancer comes back? Dr. Tawbi and his colleagues are hoping to address this question in a soon-to-be-launched clinical trial.

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