Surgical and Systemic Techniques Evolving for Melanoma Patients With Brain Mets

Douglas Kondziolka, MD

Approximately 30% of patients with melanoma will develop brain metastases; however, with the advancements of precise radiosurgery as well as combination systemic therapies, survival outcomes are improving.

For example, results from the phase II Anti-PD1 Brain Collaboration trial that were presented at the 2017 ASCO Annual Meeting demonstrated that the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) led to a 42% intracranial response (ICR) rate in asymptomatic patients with melanoma brain metastases who had not received prior local therapy to the brain.¹ The 6-month intracranial progression-free survival rate was 46% with the anti—PD-1/CTLA-4 combination.

Exciting findings from the phase II COMBI-MB trial were also presented at the meeting, showing that the BRAF/MEK inhibitor combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) led to an ICR rate of 58% in patients with melanoma that had metastasized to the brain.²

“[With] what was often one of the worst cancers to spread to the nervous system, patient outcomes are [now] improving and we are very excited about that,” said Douglas Kondziolka, MD.

OncLive: Please discuss the highlights of your presentation on brain metastases.

Kondziolka, a professor of neurosurgery at NYU Langone Medical Center in New York, shared insight on some of the technical advancements in treating brain metastases in patients with melanoma during an interview at the 2017 OncLive^® State of the Science Summit on Melanoma and Immuno-Oncology.Kondziolka: Brain metastases are a very common cancer and, unfortunately, [are something] that means a lot for the patient and their family. A patient with cancer, whether it be melanoma or any type of cancer, is battling it and, hopefully, successfully. If they get the news that the cancer is now in the brain or spinal cord, that’s a scary thing. It means it could potentially affect function, who they are, what they are about, their ability to walk, memory, speech, and vision. It means a lot and, often, they are aware of the fact that if the cancer is in the brain, sometimes that affects survival.

Typically, in the last 50 years since we began treating metastatic tumors [in the brain], the treatments have been surgery for large tumors. Sometimes, it is whole-brain radiation, which is a scary thought because the normal brain is being radiated—not just the tumor.

What is the prevalence of patients with melanoma who have brain metastases?

More recently, we have what is called radiosurgery, which is precise focal radiation, and that has been the thing to do for small brain metastases. What is interesting in melanoma and other cancers is this new era of drug therapy approaches. These can either help through the immune system or the cancer cells themselves to limit the spread through the brain and work together with focused radiation to provide better outcomes. For patients with advanced melanoma, about 30% of them will eventually have a site in the brain. That is common—more common than in lung cancer or certain types of breast cancer. Because of that, there has been a deeper awareness from melanoma oncologists to think about the brain as a potential site.

We saw results of combination systemic therapy for various patient populations at the 2017 ASCO Annual Meeting. Can you comment on these data?

Even if a patient doesn’t have a neurologic problem, melanoma is the first cancer where staging brain scans were obtained—a good-quality MRI to see if something was there. If the tumor was there, hopefully it would be small and could be taken care of effectively. Melanoma tumors often went to the nervous system, so melanoma oncologists were among the first to be thinking about that possibility.Patients with BRAF-mutant melanoma, who are usually on a targeted therapy, can develop brain metastases despite being on that [treatment]. Sometimes tumors grow nevertheless, and we will then treat them with focused radiation or, if it’s large, tumor removal. In the patients on immunotherapy, if the tumor develops in the brain, focused radiation or radiosurgery can be very effective.

One of the differences between those 2 types of treatment is what happens to the brain tumor. The goal of the radiation therapy is to damage and injure the tumor. Of course, with any injury in the body, it is mediated through inflammation. If the immune system is energized through immunotherapy, one might expect a more prominent inflammatory response as the tumor is dying. If this is in the brain, that can lead to swelling there. If it’s in a functional location, that can lead to an arm weakness or some speech trouble; sometimes, corticosteroid therapy is needed.

Has stereotactic radiosurgery become a standard approach for brain metastases?

Fortunately, it’s just time and it settles down on its own. That is one of the things that people like myself and people who take care of brain tumors are aware of. With the immunotherapies, as they are working, sometimes the effect can be more robust and we have to be aware of that. Stereotactic radiosurgery is very precise, 3-dimensional, powerful focused radiation into the body. It started in the brain for a couple of technical reasons. The brain doesn’t move, so we can lock things onto the head—unlike the lungs, which go up and down with each breath or the bowels, which move around.

Also, [we appreciate] the ability to be very focused in the brain because we don’t want to take extra tissue. The patient may pay a price for that; that may be a common approach. Radiosurgery became a popular approach 25 years ago. It really started in the late 1980s, but more and more academic centers and community centers embraced the technology and added it to the list of things to do for brain tumors.

What are the most important things from your talk that community oncologists should apply to clinical practice?

There has been a lot of literature; more than 5000 articles have been published on radiosurgery in the brain. The commonest indication for brain radiosurgery is brain metastases, because they are the most common tumor type. Depending on the tumor size, response rates range from 80% to 95%; the smallest do better and the bigger ones do a little worse. The big ones need [relatively] less radiation in order to keep the surrounding brain safe, so we like to treat small brain metastases. One thing I tell oncologists is, “Don’t wait too long, because if the tumor gets bigger, then it can cause functional problems and the patients can pay a price.” The main thing about advanced melanoma care is to be aware of the potential of brain tumors. Get a brain scan early, work with neurosurgeons or radiation oncologists, and figure out a strategy to treat the patient who develops one. We really want to keep them in normal, functional neurologic condition, and they need frequent imaging, even after they have been treated. You don’t wait 6 months to get another scan; patients with melanoma need to be imaged frequently, every 2 to 3 months, because new tumors may be down the road and we need to jump on them and manage them early. As we do that, we see more and more patients live longer, because any tumors in the body are being controlled better.

References

1. Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): the Anti-PD1 Brain Collaboration (ABC). J Clin Oncol. 2017;35 (suppl; abstr 9508).
2. Davies MA, Robert C, Long GV et al. COMBI-MB: a phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600-mutant (mut) melanoma brain metastases (MBM). J Clin Oncol. 2017;35(suppl; abstr 9506).