Immunotherapy Combo May ‘Potentially Cure’ Melanoma With Brain Metastases

The combination of Opdivo and Yervoy may provide a survival benefit for asymptomatic patients with melanoma who have brain metastases, although more efforts are needed to include this patient population in trials.

Asymptomatic patients with melanoma brain metastases treated with Opdivo (nivolumab) plus Yervoy (ipilimumab) continued to have responses to the treatment at a survival benefit at three years, study results demonstrated.

Findings from the CheckMate-204 study, which were published in Lancet Oncology, also established that symptomatic patients with melanoma brain metastases remain a difficult population to treat, although some patients did achieve long-term responses to the Opdivo-Yervoy combination.

“This study adds further evidence that this is an effective approach that improves survival,” said Dr. Hussein A. Tawbi, a professor of melanoma medical oncology, deputy chair for the department of melanoma medical oncology and co-director of the brain metastases clinic at The University of Texas MD Anderson Cancer Center in Houston, in an interview with CURE®. “It’ll help (medical oncologists) tell their patients that this is not just about inducing a response. This is a way to help you get cured, and then it’s important for radiation oncologists, neurosurgeons and the other medical providers that are involved in this to be aware of the fact that sometimes immunotherapy can be a really good option for those patients.”

Tawbi added that radiation or surgery are no longer the only options to help cure patients. Although they are important approaches, most of the time they’re used for palliative care rather than curative purposes.

“Being able to say that we have a treatment for melanoma patients that we could potentially cure them, even if they have brain metastases, is a huge development,” Tawbi said.

Assessing Treatment in Asymptomatic Versus Symptomatic Patients

In the phase 2 study, researchers analyzed data from 119 patients with melanoma brain metastases, of whom 101 were asymptomatic and 18 were symptomatic. Patients presenting with symptoms could be treated with low-dose dexamethasone. Both groups were treated with Opdivo plus Yervoy every three weeks for four doses, followed by Opdivo every two weeks for up to two years until toxicity or disease progression.

Several areas of interest in this study included intracranial clinical benefit rate (defined as complete responses, partial responses or stable disease lasting at least six months), intracranial progression-free survival (time when a patient lives with the disease without worsening) and overall survival (time when a patient with cancer is still alive). Asymptomatic patients were followed up for a median of 34.3 months compared with 7.5 months for those presenting with symptoms.

An intracranial clinical benefit was seen in 57.4% of patients who were asymptomatic and 16.7% in those with symptoms. In addition, a measurable response to the treatment occurred in 53.5% of asymptomatic patients and 16.7% of symptomatic patients. Intracranial complete response to the treatment was observed in 33% of patients without symptoms and 17% of those with symptoms.

Intracranial progression-free survival at 36 months occurred in 54.1% of patients without symptoms and 18.9% in those with symptoms. Overall survival was also higher in asymptomatic patients compared with symptomatic patients (71.9% versus 36.6%).

The most common severe or life-threatening side effects that occurred in 15% of asymptomatic patients treated with Opdivo plus Yervoy were increased alanine aminotransferase and aspartate aminotransferase, both of which indicate possible liver conditions. No serious treatment-related side effects occurred in more than one patient with symptoms, and no life-threatening side effects occurred.

The most common treatment-related side effects were diarrhea, colitis, increased alanine aminotransferase and inflammation of the pituitary gland. One treatment-related death occurred in an asymptomatic patient related to myocarditis.

Despite these findings, especially in asymptomatic patients, more research is needed in this area, Tawbi said.

“It’s really great to have a 55% response, but I am very greedy; I want 100% of my patents to respond, and I want 100% of them to survive,” he said. “I’m worried about the other 45% that did not respond. … I want to create and come up with newer approaches for them, novel treatments that can help us improve the response rate.”

A focus is also needed in symptomatic patients who require steroids, which is something consistently seen in the cancer clinic, Tawbi said.

“I know that immunotherapy is not going to be as effective for them,” he said. “We need to figure out ways to help those patients either with surgery, radiation, with targeted therapies or with new approaches that may help us improve the outcome in those patients.”

Excluding Patients With Brain Metastases in Studies

Although Tawbi and his team are aware of the unmet needs in this area, he noted that unfortunately many studies exclude patients with brain metastases for several reasons: they’re typically sicker with a worse prognosis and most drugs are design not to get into a patient’s brain because of potential neurological toxicity and other side effects.

“Because of all of that, that population would be taken out instead of putting them on the study, and they’re going to deteriorate really quickly, and these drugs are not going to work for the brain, so let’s just treat them with radiation or with surgery,” Tawbi said. “Well that became untenable because first, we started seeing that some of these drugs work in the brain even if they officially don’t penetrate (the brain). … (Opdivo and Yervoy) are relatively large molecules, and they typically wouldn’t get into the brain, but the immune system does get into the brain. If you activate the immune system, you can definitely get an immune response, and that’s what we saw in the study.”

Tawbi and his colleagues are cognizant of the improvements needed to research patients with melanoma brain metastases.

“We need to do better,” he said. “There’s so many drugs that are out there that are being developed, improvements are happening across the board in melanoma and other cancers, and this population remains on the sidelines. I think that is just not acceptable. It’s estimated that up to 30% of patients with metastatic solid tumors will end up having brain metastases, and we’re just completely ignoring that population.”

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