Brain may become ‘just another organ’ in treatment of metastatic melanoma
NEW YORK — A new paradigm is evolving for the treatment of brain metastases from melanoma that involves a greater role of systemic therapy, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.
“This is a very important problem, and we all know what an issue the brain is in melanoma,” Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of oncology and hematology at St. Luke’s Cancer Center, and a HemOnc Today Editorial Board member, said during his presentation. “Melanoma is a very dominant cause of brain metastases; in fact, it’s been estimated that probably all patients who die of metastatic melanoma present with brain metastases at autopsy.
Sanjiv S. Agarwala
“The issue is that we’re becoming more successful in melanoma treatment,” Agarwala added. “When you beat melanoma systemically in other organs, if the brain is something you cannot fix, then that’s where you are going to lose a lot of patients.”
Although local-regional treatment is still a mainstay in the treatment of brain metastases, systemic treatment with chemotherapy, immunotherapy and BRAF-targeted agents are increasing playing a greater role.
Historically, chemotherapy agents temozolomide or fotemustine were all clinicians had in the treatment of brain metastases, Agarwala said.
Response rates in the brain with temozolomide — which can cross the blood–brain barrier — are about 7% in patients who have not received prior chemotherapy.
Data on use of immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb) indicated patients achieved comparable response rates in (with steroids, 15.7%; without steroids, 4.8%) and outside the brain (with steroids, 13.7%; without steroids, 4.8%).
“We always thought that the brain was an immunologically privileged organ, meaning that immunotherapy would not work there,” Agarwala said. “This is the first example of an immunotherapy working in the brain, which was a major breakthrough.”
Single-agent pembrolizumab (Keytruda, Merck) has also yielded partial responses and stable disease in patients with asymptomatic brain metastases.
“We never saw the disappearance of brain lesions before — this was something we could not even think about, and these are patients who had not received radiation therapy,” Agarwala said.
The ongoing CheckMate 204 study is evaluating the combination of ipilimumab and nivolumab (Opdivo, Bristol-Myers Squibb) in 110 patients. Further, researchers of the ongoing ABC trial in Australia seek to evaluate the addition of ipilimumab to nivolumab in previously untreated and asymptomatic patients.
“Many of us have seen some incredible results anecdotally with combination immunotherapy in the brain, which is quite astounding,” Agarwala said.
Other systemic treatment options include BRAF-targeted therapies vemurafenib (Zelboraf; Genentech, Daiichi Sankyo) and dabrafenib (Tafinlar, Novartis) for BRAF-positive patients.
In the BREAK-MB trial, dabrafenib yielded 31% to 39% response rates in the brain, and 81% to 89% disease control rates in the brain.
Single-agent vemurafenib data have shown brain response rates ranging from 21% to 29% and brain disease control rates ranging from 73% to 76%.
Additional dabrafenib data from phase 1 and phase 2 studies have shown that intracranial and extracranial responses appear to correlate in most cases.
“What this is telling us overall is that maybe the brain is becoming just another organ,” Agarwala said. “Response you are getting outside of the brain you may be able to reproduce inside the brain. So, don’t just give up on your metastatic melanoma patient who gets brain metastases. That always used to lead to the hospice discussion, because we used to not have a lot of options.”
However, research has moved beyond sing-agent options to assessing combinations, such as dabrafenib plus trametinib (Mekinist, Novartis).
Whether it is safe to use radiation concurrently with immunotherapy or targeted therapies remains an important clinical question, Agarwala said. Data suggest the concurrent use of radiation with immunotherapy is safe; however, serious cutaneous toxicity can occur with concurrent BRAF inhibitors and radiation therapy.
“There is a new paradigm evolving for brain metastases, an area for which we had always given up hope,” Agarwala said. “Systemic therapy is assuming is an increasingly important role — that doesn’t mean local-regional therapy is gone, but it is becoming less and less important.”– by Alexandra Todak
Agarwala SS. Managing brain metastases in 2016. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 18-19, 2016; New York.
Disclosure: Agarwala reports no relevant financial disclosures.