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Ref Type Journal Article
PMID (41830662)
Authors Haj Mohammad SF, Spiekman IAC, Verkerk K, Verbeek FAJ, Timmer H, van Maren MA, Zeverijn LJ, Geurts BS, Daletzakis A, Roepman P, Jansen AML, de Leng WWJ, Maas SLN, de Vos FYFL, Verheul HMW, Voest EE, Gelderblom H
Title BRAFV600E-mutated central nervous system tumors benefit from treatment with dabrafenib plus trametinib: Results from the Drug Rediscovery Protocol.
Journal Vol Issue Date Pages Journal Short Title
European journal of cancer (Oxford, England : 1990) 238 2026 May 02 116674 Eur J Cancer
URL
Abstract Text Dual MAPK pathway inhibition with dabrafenib and trametinib has demonstrated significant activity across several BRAFV600E-mutated tumor types. The aim of this study was to evaluate the efficacy and safety of dabrafenib plus trametinib in patients with BRAFV600E-mutated progressive or recurrent tumors of the central nervous system (CNS).Adult patients with BRAFV600E-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.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.Dabrafenib plus trametinib is highly effective in patients with recurrent or progressive BRAFV600E-mutated CNS-tumors, representing a valuable therapeutic option for these vulnerable patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E low grade glioma sensitive Dabrafenib + Trametinib Phase II Actionable In a Phase II trial (DRUP), combined treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) in patients with central nervous system tumors harboring BRAF V600E was well tolerated and resulted in a clinical benefit rate of 76% (19/25), an objective response rate (ORR) of 44% (11/25, all partial responses), median progression-free survival (mPFS) of 18.1 mo overall, and an ORR of 43%, mPFS not reached, and overall survival of 64.8 mo in low-grade glioma patients (n=7) (PMID: 41830662; NCT02925234). 41830662
BRAF V600E high grade glioma sensitive Dabrafenib + Trametinib Phase II Actionable In a Phase II trial (DRUP), combined treatment with Tafinlar (dabrafenib) and Mekinist (trametinib) in patients with central nervous system tumors harboring BRAF V600E was well tolerated and resulted in a clinical benefit rate of 76% (19/25), an objective response rate (ORR) of 44% (11/25, all partial responses), and median progression-free survival (mPFS) of 18.1 mo overall, an ORR of 44%, mPFS of 11.1 mo, and overall survival of 22.0 mo in high-grade glioma patients (n=18) (PMID: 41830662; NCT02925234). 41830662