BRAFV600E-mutated central nervous system tumors benefit from treatment with dabrafenib plus trametinib: Results from the Drug Rediscovery Protocol: Results from the Drug Rediscovery Protocol

INTRODUCTION: Dual MAPK pathway inhibition with dabrafenib and trametinib has demonstrated significant activity across several BRAF V600E-mutated tumor types. The aim of this study was to evaluate the efficacy and safety of dabrafenib plus trametinib in patients with BRAF V600E-mutated progressive or recurrent tumors of the central nervous system (CNS).

METHODS: Adult patients with BRAF V600E-mutated CNS-tumors, including pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and glioblastoma, progressive on their last treatment line, were treated in the Drug Rediscovery Protocol (2023-509152-33-00) with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, until disease progression or intolerable toxicity. The primary endpoints were clinical benefit (CB: confirmed complete or partial response [PR] or stable disease [SD] ≥ 16 weeks) and safety.

RESULTS: Between January 2019 and May 2024, 30 patients started treatment, of whom 25 were evaluable for response after completing at least one full treatment cycle. CB was observed in 19 patients, including 11 with confirmed PR and eight with SD for ≥ 16 weeks, resulting in a CB-rate of 76% (95% CI, 54.9%-90.6%) and an objective response rate of 44% (95% CI, 24.4%-65.1%). After a median follow-up of 40.2 months, the median duration of response was 27.8 months (95% CI, 23.6 months-not reached). The median progression-free and overall survival were 18.1 months (95% CI, 8.4 months-not reached) and 32.3 months (95% CI, 22.0 months-not reached), respectively. No unexpected toxicities were observed.

CONCLUSIONS: Dabrafenib plus trametinib is highly effective in patients with recurrent or progressive BRAF V600E-mutated CNS-tumors, representing a valuable therapeutic option for these vulnerable patients.