BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Targeted therapies may play a key role in the multidisciplinary management of patients with brain metastases. Although BRAF inhibitors do not appear to cross an intact blood brain barrier in pre-clinical studies, multiple trials have demonstrated their efficacy in brain metastases . Evidence of activity is limited to vemurafenib and dabrafenib; no clinical trials evaluating MEK inhibitors in brain metastases have been performed.
Dabrafenib has been studied most extensively in this setting. The phase I trial of dabrafenib led by Falchook and colleagues initially suggested activity. Ten patients with untreated brain metastases were included, and eight experienced a decrease in size of their intracranial disease . A phase II trial (BREAK-MB) was then conducted exclusively for patients with BRAF V600E (n = 139) or V600K (n = 33) mutant melanoma with brain metastases . Two cohorts were evaluated; cohort A with untreated brain metastases (n = 89) and cohort B with previously treated but progressing brain metastases (n = 83). Clinical activity was similar in both cohorts for patients with BRAFV600E mutant melanoma; the objective intracranial response rate was 39% and 31% with a durable intracranial disease control rate of 81 and 89% respectively. Response rates appeared to be lower in the BRAFV600K mutant group in both cohort A (intracranial responses in 1 of 15 patients) and cohort B (4 of 18). Median PFS for both groups was similar at approximately 4 months and median OS was nearly 8 months.
In a single center subset of patients from the BREAK-MB trial, intracranial tumor regression correlated well with extracranial responses although exceptions did occur . At the time of disease progression, several patterns of tumor growth were noted. These included systemic progression with intracranial disease control, isolated intracranial progression, or commonly, multiple foci of intracranial progression. The median time to intracranial progression in this subset was 16–20 weeks. Dabrafenib has also been reported to have intracranial activity for patients with BRAFV600R melanoma .
Vemurafenib also appears to have activity in patients with brain metastases. A pilot study was performed in heavily pre-treated patients . Of 19 evaluable patients, seven had intracranial tumor shrinkage with three meeting criteria for partial response; median PFS was 3.9 months. Functional outcomes were also improved, with 25% of patients reporting a reduction in pain, 83% of patients with improvement in performance status, and 67% of patients with decreased corticosteroid requirements.
No clinical trials have been performed to evaluate the role of BRAF inhibitors in conjunction with local therapies. For patients with significant neurologic deficits on presentation, radiation therapy or surgery should be considered prior to initiating a BRAF inhibitor. However, for patients with asymptomatic brain metastases or when symptoms are controlled with steroids, BRAF inhibitors can be considered prior to or instead of local therapies, particularly when rapidly progressing extracranial disease is present . Mixed responses may be observed in some patients, necessitating local treatment to enlarging lesions. Additionally, a recent case report demonstrated the feasibility and potentially durable benefit of neoadjuvant vemurafenib followed by resection . This approach can be considered particularly for patients with borderline resectable melanoma or a metastasis that is too large for stereotactic radiosurgery. Also, the combination of vemurafenib and radiation has been described to cause skin toxicity; we therefore hold BRAF inhibitors for 2–3 days around radiation . The complexity of management in some cases highlights the need for multidisciplinary input into treatment decisions.
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