NEW YORK — Brain metastases are responsible for the majority of mortality and morbidity among patients with melanoma, and a multidisciplinary approach is necessary to effectively manage this complication, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
“This subject has not been well studied. This is the question that people didn’t want to address, but now people are taking on this task,” Geoffrey T. Gibney, MD, a medical oncologist in the department of cutaneous oncology at Moffitt Cancer Center, said during a presentation.
Geoffrey T. Gibney
Previous studies suggest an estimated 9,718 Americans will die of melanoma in 2014, and 49% to 75% of them will have melanoma brain metastases (MBMs). Nearly half (44%) of patients with advanced melanoma will develop MBMs, and 20% to 54% of all melanoma deaths are attributed to symptomatic MBMs.
Davies and colleagues at The University of Texas MD Anderson Cancer Center evaluated survival for 330 patients with brain metastases treated between 1986 and 2004. The results, published in 2011 in Cancer, showed median OS for patients with MBMs increased from 4.14 months in the 1986-1995 time period to 5.92 months in the 1996-2004 time period. The number of metastases also influenced survival, with median OS of 5.92 months for patients with one to three metastases, 3.52 months for patients with more than three metastases, and 1.22 months for patients with leptomeningeal disease.
Patients with one to four lesions typically undergo surgery or stereotactic radiosurgery, whereas patients with five or more lesions generally undergo whole brain radiotherapy. Historical survival outcomes range from 1.2 to 2.1 months for best supportive care, 3.4 to 4 months for whole brain radiotherapy, 6.5 to 9.8 months for surgery, and 7.5 to 10.4 months for stereotactic radiosurgery.
Two prospective trials evaluated ipilimumab in patients with active MBMs.
A single-arm phase 2 study by Di Giacomo and colleagues evaluated ipilimumab 10 mg/kg plus fotemustine in 80 patients, 20 of whom had asymptomatic MBMs. Patients who demonstrated clinical response received maintenance ipilimumab.
Results, published in 2012 in Lancet Oncology, showed a higher rate of complete response (38% vs. 0%) among treatment-naive patients but a higher combined rate of partial response/stable disease (43% vs. 23%) among patients with previously treated MBMs. Grade 3 or grade 4 treatment-related adverse events occurred in 47 patients (55%). They included increases in alanine aminotransferase or aspartate aminotransferase levels (24%), thrombocytopenia (24%) and neutropenia (19%). Among patients with MBMs, median OS was 13.4 months.
“This looks exciting, but the enthusiasm has to be dampened because of the toxicities seen in that study,” Gibney said.
An open-label, phase 2 study by Margolin and colleagues evaluated ipilimumab (Yervoy, Bristol-Myers Squibb) 10 mg/kg administered in four doses. Cohort A included 51 patients with treatment-naive MBMs and cohort B included 21 patients with previously treated MBMs. Results, published in 2012 in The Lancet, showed a higher complete response rate among patients with previously treated MBMs (5% vs. 0%) but higher rates of partial response (16% vs. 0%) and stable disease (8% vs. 0%) among those with untreated MBMs. Median OS was higher among those with previously untreated MBMs (7 months vs. 3.7 months).
“You could say the median overall survival numbers are not that impressive, because it is below what we see for stereotactic radio surgery and surgery,” Gibney said. “But I’d like to point out that the historical controls suggest about 5% long-term survival and, in cohort A, you’re seeing a number that looks greater than 20%. So while ipilimumab may not be shrinking the tumors very quickly or aggressively, there are patients with brain metastases who are treated with ipilimumab who live a long time.”
Two other multicenter trials evaluated BRAF inhibitors for treatment of BRAF V600-mutant MBMs.
The BREAK-MB study included 172 patients with BRAF V600E or V600K-mutant melanoma and active brain metastases who received dabrafenib (Tafinlar, GlaxoSmithKline) 150 mg twice daily. Of these patients, 41% had one MBM, 46% had two to four MBMs, and 13% had more than four MBMs. Researchers reported median OS of 7.7 months among the 89 patients who had treatment-naïve MBMs, and 7.3 months among patients who had undergone prior therapy for MBMs.
The M025743 study included 146 patients with BRAF V600E-mutant melanoma with active brain metastases. Of them, 14% had one MBM, 49% had two to four MBMs, and 33% had more than four MBMs. Researchers reported a median OS of 6.5 months among the 90 patients with treatment-naive MBMs and 6.4 months among patients who had undergone prior therapy for MBMs.
“The objective regression by RECIST criteria occurs in between 20% and 40% of patients depending on which cohort you’re looking at, so you see very good responses,” Gibney said. “Unfortunately, they don’t last very long. The median progression-free survival is generally under 4 months.”
Prospective trials designed to evaluate combinations of BRAF inhibitors with surgery and radiation therapy are underway. Some centers also are trying to combine BRAF inhibitors with radiation.
“This is a promising approach but has to be done with caution,” Gibney said. “There have been case reports of radionecrosis related to the combination of therapies, so I think right now it’s best done in clinical trials.”
Future studies also should investigate ways to prevention of MBMs, Gibney said.
“We’ve all been focusing on treating brain metastases after they show up,” he said. “That may be the wrong way to look at it. We really should expand research into preventing melanoma brain metastases in patients who have high-risk features or advanced melanoma.”
For more information:
Gibney GT. Multidisciplinary approach to brain metastases in melanoma. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 11-12, 2014; New York.
Disclosure: Gibney reports consultant roles with Genentech/Roche.