CHICAGO — Patients who are undergoing stereotactic radiosurgery (SRS) for melanoma brain metastases and are carriers of the BRAF mutation and concurrently treated with BRAF inhibitors show significant increases in overall survival compared with those lacking the mutation, but the benefits appear to be linked to BRAF inhibitor treatment at or after the first SRS procedure rather than beforehand, new research shows.
"Our current study demonstrates that combined treatment of BRAF inhibitors and SRS results in improved overall survival from the time of SRS, particularly in patients with controlled disease and fewer metastases," said coauthor Amparo Myrelle Wolf, MD, PhD, from the Department of Neurosurgery, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York.
"To our knowledge, this study is the largest clinical study to date aimed at determining the impact of BRAF mutational status and treatment with BRAF inhibitors on survival outcomes in patients having undergone SRS for melanoma brain metastases," the authors conclude.
The findings were presented here at the American Association of Neurological Surgeons (AANS) 84th Annual Meeting, and also published this month in the Journal of Neuro-Oncology.
Brain metastases are common in the course of metastatic melanoma, occurring in as many as 25% to 50% of patients, and prognosis in such cases is poor. Overall survival ranges from only 3 to 6 months after diagnosis of the brain metastases. Approximately 20% to 50% of deaths among patients with melanoma are in fact linked to intracranial disease, Dr Wolf explained.
SRS treatment increases overall survival to 5 to 11 months, and for patients who carry the BRAF V600E mutation — representing approximately 50% of patients with melanoma — treatment with BRAF inhibitors has separately been shown in randomized controlled trials to further improve progression-free and overall survival. However, those studies excluded patients with brain metastasis.
For the new study, Dr Wolf and her team sought to evaluate the potential effects of BRAF inhibitor treatment on overall survival among patients with metastatic melanoma also being treated with SRS for brain metastases.
The analysis included prospective data on 80 patients with metastatic melanoma disease, involving 410 tumors, who were treated with SRS between 2012 and 2015.
Patients testing positive for a BRAF mutation (n = 35) were typically placed on BRAF inhibitor therapy, including dabrafenib, vemurafenib, or dabrafenib/trametinib combination therapy, whereas those who were not positive were treated most commonly with ipilimumab, nivolumab, or pembrolizumab.
Although the median overall survival from the first SRS procedure was 6.7 months, patients with the BRAF mutation treated with BRAF inhibitors had a median survival of 11.2 months, compared with only 4.5 months among those without the mutation.
Actuarial survival rates for patients carrying the BRAF mutation and treated with a BRAF inhibitor and SRS were 54% at 6 months and 41% at 12 months after SRS, whereas those without the BRAF mutation had significantly lower overall survival rates of 28% at 6 months and 19% at 12 months.
Importantly, the researchers found that timing of the BRAF inhibitor treatment mattered. "What we saw was that patients who started the BRAF inhibitor at or after SRS did better than those who were already on an inhibitor before the SRS," Dr Wolf said, with significantly improved overall survival (P = .05).
"Patients who were already on a BRAF inhibitor prior to the SRS in fact did no better than people who had never been treated with a BRAF inhibitor."
A multivariate analysis showed the strongest predictors of overall survival among the patients were the number of brain metastases (hazard ratio [HR], 1.12; P < .001), systemic disease status (HR, 0.30; P = .04), and Karnofsky performance score (KPS; HR, 96; P = .04).
Patients with BRAF mutations were more likely to be younger and have a higher KPS score. The two groups did not differ otherwise in such factors as prior surgery, whole-brain radiotherapy, recursive partitioning analysis class, or extent of disease.
"What we have shown is for the first time, median survival of melanoma has passed 1 year," Dr Wolf said.
"Patients are living longer as a result of more effective systemic therapy; thus, surveillance and management of intracranial disease is of increasing importance."
Randy Jensen, MD, PhD, a professor of neurosurgery, radiation oncology, and oncological sciences with the University of Utah's Huntsman Cancer Institute, Salt Lake City, commented that the research offers important insights on the role of BRAF mutation in treatment of melanoma brain metastasis.
"It's an interesting study," he told Medscape Medical News. "The take-home message is that you can do radiosurgery during BRAF therapy and the BRAF-mutated patients do best."
Dr Wolf and Dr Jensen have disclosed no relevant financial relationships.
American Association of Neurological Surgeons (AANS) 84th Annual Meeting. Abstract 728. Presented May 3, 2016.
J Neuro-Oncol. Published May 2016. Abstract
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