New therapeutic options for management of melanoma brain metastases

In a recent article published in MELANOMA RESEARCH and a subsequent commentary in British medical journal THE LANCET, researchers at Moffitt Cancer Center discussed new therapeutic options for the management of melanoma brain metastases. Patients with advanced melanoma are at high risk for developing brain metastases. Once brain metastases are present, these patients tend to have poor outcomes.

According to the researchers, systemic chemotherapy has demonstrated limited success in treating melanoma brain metastases. The current standard treatment approaches, including surgery and radiotherapy, have modestly improved the clinical outcomes. However, with a median survival of approximately eight months, melanoma patients are eagerly awaiting the development of new targeted therapies.

"Overall, the response rates to chemotherapy regimens are very low in patients with metastatic melanoma. It's not surprising that using chemotherapy to treat melanoma brain metastases is an ineffective strategy," said paper co-author Geoffrey T. Gibney, M.D., who specializes in medical oncology.

According to study co-author Peter A. Forsyth, M.D., a neuro-oncologist, most drugs do not penetrate into the brain microenvironment because of the blood-brain barrier, which contributes to the lack of responses seen with standard chemotherapy.

"For the first time, there are molecular and immunological treatments that show real promise for these patients. We know we have to do better, but now there is real hope for patients with melanoma in the brain," explained Forsyth.

A new emphasis on treating patients with brain metastases is being seen in the clinical development of drugs recently approved by the Food and Drug Administration for management of unresectable metastatic melanoma.

For example, Ipilimumab, an immunotherapy, was approved by the FDA in March 2011 for the treatment of metastatic melanoma. Although initial studies excluded patients with active brain metastases, newer studies indicate that Ipilimumab is able to generate effective immune responses against brain metastases, as well as melanoma metastases, in extracranial sites. Further results from ongoing studies are awaited to define its precise role in these patients.

"The most exciting recent drug development for melanoma brain metastases is BRAF-targeted therapy," explained Gibney. "Activating BRAF mutations occur in about half of melanoma tumors and represent a drugable target for treating melanoma patients."

The BRAF inhibitor Vemurafenib was approved by the FDA in August 2011 for unresectable metastatic melanoma after clinical trials showed very high response rates and improved survival. But again, initial studies excluded patients with active brain metastases, Gibney said.

The researchers note that early data from new clinical trials using Vemurafenib or another similar BRAF inhibitor, Dabrafenib, to treat brain metastases in patients with BRAF mutant melanoma have shown impressive responses.

Gibney and Vernon K. Sondak, M.D., a senior member at Moffitt and chair of the Cutaneous Oncology Program, reflected on Dabrafenib's activity against brain metastases in their recent commentary published in THE LANCET:

"This finding is impressive for two reasons: no previous systemic treatment has shown this degree of clinical activity against melanoma brain metastases, and Dabrafenib was not predicted to cross the blood-brain barrier in substantial quantities," they wrote.

The effect on brain metastases of drugs such as Dabrafenib, Vemurafenib and Ipilimumab - which do not normally cross the blood-brain barrier - is likely reflective of a breakdown in the integrity of the blood-brain barrier as tumors grow, explained Sondak.

Moffitt researchers are now focusing much attention to melanoma brain metastases. According to Sondak, the management of melanoma brain metastases at Moffitt occurs within the setting of a multidisciplinary team comprised of medical oncologists, neuro-oncologists/neuro-surgeons and radiation oncologists.

"We are expanding our basic science research in melanoma brain metastases and have clinical trials available to melanoma patients with active and resected brain metastases," Sondak said.

Gibney and Forsyth added, "Each patient requires an individualized therapeutic approach, which we provide in our multidisciplinary Neuro Melanoma Clinic."