BRAF Mutation Has Prognostic Significance for Brain Melanoma Patients

Manmeet Ahluwalia, MD

Cleveland Clinic researchers are planning future clinical trials based on the results of their retrospective study that shows stereotactic radiosurgery (SRS) is more beneficial in BRAF-positive patients with metastatic brain melanoma than in BRAF-negative patients.

The study, investigating the impact of BRAF mutation in patients with brain metastasis from melanoma, analyzed the response of both BRAF-positive and BRAF-negative patients to a variety of treatment modalities. Overall survival (OS) from the diagnosis of brain metastases was the primary endpoint.

Melanoma patients with brain metastasis have poor prognoses. BRAF mutation occurs in approximately 50 percent of these patients; however its impact on outcomes in brain metastases is unknown.

The researchers identified 76 patients with metastatic brain melanoma and whose BRAF status was available, according to Manmeet Ahluwalia, MD, Director of Cleveland Clinic’s Brain Metastasis Research Program. Of these patients, 35 had the BRAF mutation and 28 of those had V600 mutations: 21 subjects had V600E, four had V600K and the remainder had a less common mutation.

Stereotactic radiosurgery, with or without other modalities, was the initial treatment for 33 patients and 28 received whole-brain radiation therapy (WBRT), also with or without other modalities. Eighteen patients received the BRAF inhibitor vemurafenib (VEM) after brain metastasis.

BRAF mutation influences response to treatment

Median survival for the entire cohort of patients was 6.2 months; it was 8.8 months for BRAF-positive patients and 5.4 months for BRAF negative patients. BRAF-positive patients treated with SRS, with or without other modalities, had improved OS compared with patients without the mutation. BRAF-positive and BRAF-negative patients had median OS of 18.6 months and 5.5 months, respectively. Dr. Ahluwalia says prospective trials are planned to validate the finding that SRS is more beneficial in BRAF-positive patients with metastatic brain melanoma than in BRAF-negative patients.

“Some BRAF-positive subjects received VEM in combination with surgery and different forms of radiation in hopes it would control disease, not only intracranially, but also extracranially,” Dr. Ahluwalia says.

BRAF-positive patients treated with SRS and VEM had a median OS of 44.6 months compared with a median OS of 17.2 months for BRAF-positive patients who did not receive VEM in combination with SRS. “These findings suggest that patients with BRAF mutations tend to do better than those who do not have BRAF mutations, especially when given a combination of some form of radiation along with a BRAF inhibitor, such as VEM, but further research is necessary,” he says.

The abstract detailing this study was featured at the 2015 ASCO Annual Meeting May 29-June 2.

New clinical trial involves immunotherapy-based approach

Researchers find that many patients develop resistance to BRAF inhibitors such as VEM after four to six months of clinical use. Dr. Ahluwalia says the MEK pathway is commonly involved in the development of this resistance.

“We’re finding out that administering the BRAF and MEK inhibitors in combination offers more value than either of these inhibitors alone,” Dr. Ahluwalia says.

Researchers continue to gain a better mechanistic understanding of resistance pathways, which allows them to develop and conduct additional trials testing this combination and to address other mechanisms of resistance.

Although this retrospective study focused on the impact of these approaches on BRAF-positive patients with metastatic brain melanoma, the findings highlight the need for future studies focusing on BRAF-negative patients.

“We feel that we may need to use an immunotherapy-based approach for BRAF-negative brain metastases patients, either alone or in combination with stereotactic radiosurgery,” Dr. Ahluwalia says. “We are actually planning such studies at Cleveland Clinic, with one beginning in the near future. This trial will involve the anti PD1 monoclonal anti body, nivolumab and focused radiation treatment using Gamma Knife radiosurgery,” he says.

He adds that although this study will focus particularly on BRAF-negative patients, it will be interesting to see how BRAF-positive patients respond to these treatments.

Dr. Ahluwalia is an Associate Professor in the Department of Medicine, Clinic Lerner College of Medicine of Case Western Reserve University (CCLCM) where he subspecializes in treatment of patients with brain tumors and brain metastases. He is the Director, Brain Metastasis Research Program and the Associate Director, Clinical Trials, Operations in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center of the Neurological Institute of Cleveland Clinic. He is the Section Head of Neuro-Oncology Outcomes and is a staff in the Taussig Cancer Institute, Cleveland Clinic and has joint appointment in the Developmental Therapeutics Program, Case Comprehensive Cancer Center.