Introduction: Dabrafenib is a small molecule inhibitor of BRAF, mutated in about 50% of metastatic melanoma. The role of BRAF inhibitors in patients with melanoma brain metastases is unclear. In 2012, the BREAK-MB multicenter, phase-2 trial demonstrated median progression-free (ie. intracranial disease) survival (PFS) and overall survival (OS) of 4.0 months and 8.3 months, respectively, in patients treated with dabrafenib for BRAF V600E-mutated melanoma brain metastases. We sought to validate these findings in a patient-cohort treated at a single-institution.

Methods: Single-institution, retrospective analysis (June 2012 - August 2014) of patients harboring metastatic melanoma brain metastases treated with dabrafenib.

Results: Of 39 patients with BRAFV600E-mutated brain metastases, 12 were treated with dabrafenib. All underwent surgery and/or stereotactic radiation therapy prior to beginning dabrafenib except two who were on dabrafenib for systemic therapy prior to brain metastases development. All patients had brain metastases progression except two: one demonstrated significant radiographic response, but died from progressive leptomeningeal disease 2.2 months after dabrafenib initiation; the other continues to exhibit a stable single lesion 19.8 months since beginning dabrafenib. In the remaining 10 patients, median PFS was 5.2 months (range: 1.0-16.0 months) (Figure 1). Of the 6 expired patients, median OS was 3.5 months (range: 1.8-23.5 months), skewed by four patients with OS between 1.8-3.9 months. Notably, the four patients had =5 lesions at time of dabrafenib initiation (Figure 2).

Conclusions: Although a limited sample size, PFS data was consistent with the BREAK-MB trial, suggesting dabrafenib may prolong PFS in melanoma brain metastases. Further clinical evaluation of dabrafenib for melanoma brain metastases is warranted. Although the presence of brain metastases is often an exclusion criteria for clinical trials, our data supports including patients with melanoma brain metastases in such clinical studies. In patients with =5 lesions, initiation of dabrafenib may be inappropriate, as dabrafenib had little impact on outcome.

Patient Care: Our results support the role of optimal surgical resection and/or radiosurgery of metastatic brain lesions in patients with BRAF-mutated melanoma, prior to undergoing treatment with dabrafenib therapy. Furthermore, dabrafenib may prolong intracranial disease-free survival in these patients, although further phase 3 studies are required to answer this question.

Learning Objectives: 1. To recognize that dabrafenib may effectively treat intracranial disease in patients with metastatic BRAF-mutated melanoma to the brain after optimal surgical and/or radiotherapy. 2. To understand that patients with 5 or more brain lesions after surgical and/or radiotherapeutic intervention may not be ideal candidates for dabrafenib initiation. 3. To recognize that future phase 3 trials of dabrafenib in patients with BRAF-mutated melanoma brain metastases are warranted and should not exclude patients with a previous history of local disease treatment.

References: 1. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011;29:1239-46. 2. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. The lancet oncology 2012;13:1087-95.