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.
Are there any agents in early-phase studies that are looking at this patient population?
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.
What are some big questions or challenges that we have left for patients with melanoma who have brain metastases?
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.
Can treatments be combined with stereotactic radiotherapy?
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.
What else would you like to emphasize?
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.