Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial

Wen, Patrick Y.; Stein, Alexander; Bent, Martin van den; Grève, Jacques De; Wick, Antje; Vos, Filip Yves Francine Léon De; Bubnoff, Nikolas von; Linde, Myra E. van; Lai, Albert; Prager, Gerald W.; Campone, Mario; Fasolo, Angelica; López-Martín, José A.; Kim, Tae Min; Mason, Warren P.; Hofheinz, Ralf–Dieter; Blay, Jean‐Yves; Cho, Daniel C; Gazzah, Anas; Pouessel, Damien; Yachnin, Jeffrey; Boran, Aislyn; Burgess, Paul; Ilankumaran, Palanichamy; Gasal, Eduard; Subbiah, Vivek

doi:10.1016/s1470-2045(21)00578-7

Cited by 178 publications

(106 citation statements)

References 41 publications

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“…Twelve of 18 responders had a DOR > 6 months. Dabrafenib plus trametinib was well tolerated, and the safety profile was consistent with that observed in other tumor types in which the combination has been explored, such as melanoma, biliary tract cancer, and glioma [30][31][32][33][34][35].…”

Section: Introductionsupporting

confidence: 70%

“…number of rare BRAF V600E-mutant indications, including in other ROAR cohorts (biliary tract cancer, low-grade glioma, high-grade glioma) and in another tumor-agnostic study of BRAF V600E-mutant solid tumors, lymphomas, and multiple myeloma [33][34][35]. Thus, the updated results for the ROAR ATC cohort reported here add further evidence of the broad potential of dabrafenib plus trametinib in the treatment of BRAF V600E-mutant cancers.…”

Section: Fundingsupporting

confidence: 59%

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Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

et al. 2022

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Introductionsupporting

confidence: 70%

Section: Fundingsupporting

confidence: 59%

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

et al. 2022

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“…To prevent tumor progression, concurrent inhibition of both BRAF and MEK has demonstrated efficacy in pre-clinical models. A recent phase II trial for high- and low-grade gliomas has illustrated a clinical response with combination dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor ( 86 , 87 ). In this trial, common neurological complications included fatigue, and headache, consistent with prior side effects seen with monotherapy.…”

Section: Novel Therapiesmentioning

confidence: 99%

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

2022

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Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.

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“…GBM with BRAF V600E mutations has been described as epithelioid GBM [ 55 ], especially with a co-occurring mutation in the TERT promoter and homozygous deletion of CDKN2A/2B [ 56 ]. While rare (<2% of GBM) [ 57 ] and difficult to distinguish from pleomorphic xanthoastrocytoma [ 58 ], recognizing the molecular, clinical, and radiological features of this subtype is important [ 58 ] due to the observed efficacy of combination BRAF/MEK inhibition in gliomas with BRAF V600E mutation [ 59 ]. Figure 2 provides a proposed sequential approach to molecular testing in gliomas, although many centers now opt for targeted next-generation sequencing panels, which allows for the testing of all relevant molecular markers of GBM in one custom assay.…”

Section: Pathology Molecular and Genomic Signatures And Recent Update...mentioning

confidence: 99%

“…While previous strategies have included monotherapy with RAF inhibitors such as vemurafenib [ 213 ], with a modest response seen in high-grade gliomas, the ongoing ROAR trial (NCT02034110), a phase II open-label multicenter study now closed to accrual, investigated the role of dual BRAF/MEK with dabrafenib and trametinib in gliomas (WHO grade 1–4) harboring a BRAF V600E mutation. There was clinically meaningful activity seen in both low- and high-grade glioma patients (31 of which were GBM patients) with the latter showing a 33% objective response rate [ 59 ].…”

Section: Current Approach To Newly Diagnosed Gbmmentioning

confidence: 99%

Updates in IDH-Wildtype Glioblastoma

et al. 2022

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Glioblastoma is the most aggressive primary brain tumor with a poor prognosis. The 2021 WHO CNS5 classification has further stressed the importance of molecular signatures in diagnosis although therapeutic breakthroughs are still lacking. In this review article, updates on the current and novel therapies in IDH-wildtype GBM will be discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-022-01251-6.

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Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial

Cited by 178 publications

References 41 publications

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

Updates in IDH-Wildtype Glioblastoma

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