Expert Says Melanoma Clinical Trials Should Include More Patients With Brain Mets

Harriet Kluger, MD

Historically, patients with melanoma who develop brain metastases have been excluded from clinical trials, according to Harriet Kluger, MD.

As of late, an increasing number of patients in this subgroup are being included now on studies, particularly those who have received prior treatment. Yet this is still not enough, says Kluger, as brain metastases is no longer the dismal prognosis that it once was.

OncLive^®: Please provide an overview of your talk.

Kluger highlighted the systemic treatment of patients with melanoma with brain metastases in her talk at the 2017 OncLive^® State of the Science Summit^TM on Melanoma. In an interview during the meeting, Kluger, professor of medicine, associate cancer center director for Education and Training, Yale Cancer Center, discussed the lack of clinical trial inclusion as well as promising regimens coming down the pike.Kluger: The topic is systemic therapy for brain metastases in melanoma. By systemic therapy, we mean therapy that goes in via mouth or intravenously, as opposed to local therapies in the form of radiation, surgery, or stereotactic radiosurgery. Until recently, systemic therapy was not actually one of the modalities that we would first think of to treat brain metastases. The reason is that stereotactic radiosurgery is actually very effective and can control approximately 90% of the metastases long term.

That said, it is not a modality that can be offered to people who have multiple metastases, and it certainly does not present regional recurrences and metastases at other sites. Approximately 5 or 6 years ago, patients with brain metastases were excluded from clinical trials almost uniformly; sometimes they were allowed on studies if the brain metastases had been treated and were stable for many weeks without any new ones occurring. That is a standard that is not required of any other organ.

So, the question we asked around 2011 is whether this was necessary. It turns out that there are organs with a worst prognosis than the brain. For example, the prognosis of patients with liver metastases or pleural effusion involvement is worse than that of patients with brain metastases. Therefore, why should we exclude them? First, there were concerns about the effects in the brain and, second, because it wasn't known whether these drugs could penetrate the blood-brain barrier.

Can you comment on the recent findings seen with combination therapies for these patients?

A number of trials have since been conducted, primarily in patients with melanoma. However, we are starting to see this in other diseases, as well. It appears that, for the most part, the responses in the brain are actually similar to those seen in extra cerebral sites. This is a change in paradigm and, going forward, systemic therapy should be an integral part of therapy for patients whose disease has spread to the brain.There was a study for patients with brain metastases with ipilimumab (Yervoy) and nivolumab (Opdivo), and the response rate was more than 55%. There are certain toxicities that are unique to this regimen, and it is not good for everyone. There were a few episodes of seizures and cerebral edema, which is something that we have to contend with; however, it is certainly a good regimen for patients with brain metastases.

Are there any agents in early-phase studies that are looking at this patient population?

What are some big questions or challenges that we have left for patients with melanoma who have brain metastases?

Can treatments be combined with stereotactic radiotherapy?

What else would you like to emphasize?

Dabrafenib (Tafinlar) and trametinib (Mekinist) combined are associated with a slightly higher response rate most of the time, although it seems to be a little bit lower in patients with brain metastases. That being said, it is an excellent regimen for patients whose disease needs immediate control because it works very quickly. It is almost a sure thing that they are going to respond if they have a V600E mutation in BRAF. The problem with the dabrafenib/trametinib regimen is that the median duration of response is quite short—about 6 or 7 months. Therefore, immune therapies might be a better choice for these patients.Yes, there are a number of open trials. [For example], there are studies that involve combinations with PI3-kinase inhibitors. At Yale Cancer Center, we have a study where we are combining a VEGF inhibitor—so bevacizumab (Avastin) with pembrolizumab (Keytruda). There are studies with IDO inhibitors and PD-1 inhibitors, which is going through the process of obtaining FDA approval to initiate the trial, then they will open at various institutions.We have a number of challenges. What do we do about cerebral edema? What do we do about radionecrosis? If a patient gets radiation therapy to the brain and then gets immunotherapy, we see an increased incidence of radionecrosis. These patients are living much longer now, so this is becoming an increasingly common problem that we need to contend with. Depending on the location of the tumor in the brain, it may be critical to get immediate control. For example, for tumors in the brain stem, we would treat with stereotactic radiosurgery right away rather than wait to see if systemic therapy will work. One of the biggest problems that we are seeing now is patients who have leptomeningeal disease. We seem to be seeing more of it and we haven't made any progress there.Actually, there is a study looking at the combination of stereotactic radiosurgery with ipilimumab and another one with PD-1-based therapies. Certainly, we have done it at our institution and we have seen very nice responses with the combination. However, I do caution that we do see an increased instance of radionecrosis there, as well.For patients with brain metastases, the prognosis is no longer so dire; it is much better. We don't know what the median survival for patients with brain metastases is. We really need to expand our clinical trials portfolio because we are still not including patients with untreated brain metastases.

We tend to not include them in our clinical trials because of the potential for toxicities and management of problems if they do have tumor growth. However, it is time to include these patients in studies of novel therapies and not wait until these agents and regimens are fully approved before studying them in patients with brain metastases.