Trametinib for progressive pediatric low-grade gliomas

Kondyli, Maria; Larouche, Valérie; Saint‐Martin, Christine; Ellezam, Benjamin; Pouliot, Lauranne; Sinnett, Daniel; Legault, Geneviève; Crevier, Louis; Weil, Arthur; Farmer, Jean‐Pierre; Jabado, Nada; Perreault, Sébastien

doi:10.1007/s11060-018-2971-9

Cited by 88 publications

(77 citation statements)

References 32 publications

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“…Given these positive results, efforts to evaluate the use of selumetinib upfront in newly diagnosed patients both as a single agent or in combinations are under way. The trial of trametinib involving 6 patients resulted in 2 partial and 3 minor responses, while 1 patient had progressive disease [115].…”

Section: Mek Inhibitorsmentioning

confidence: 99%

Pediatric low-grade glioma in the era of molecular diagnostics

Ryall

Tabori

Hawkins

2020

acta neuropathol commun

255

251

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Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behaviorin particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

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Section: Mek Inhibitorsmentioning

confidence: 99%

Pediatric low-grade glioma in the era of molecular diagnostics

Ryall

Tabori

Hawkins

2020

acta neuropathol commun

255

251

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“…79 Additionally, BRAF V600E mutations have been found in both high-grade and low-grade gliomas. 80 Given the differences in tumor location, extrapolations from adult melanoma patients to children with brain tumors should be performed carefully.…”

Section: Serine/threonine-protein Kinase B-raf and Mitogen-activated mentioning

confidence: 99%

“…Partial responses were seen with a good quality of life; only minor toxicities were observed. 80 A population analysis on data from adults with melanoma showed an increasing proportion of responders with increasing exposure to trametinib. This increase showed a plateau at a C min of 10 ng/ mL.…”

Section: Trametinibmentioning

confidence: 99%

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

Janssen

Dorlo

Steeghs

et al. 2020

Clin Pharma and Therapeutics

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In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure–efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.

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“…The effectiveness, and the effects, of these therapies continue to be defined. [1][2][3][4] We report here a child with an unresectable low-grade glioma who progressed through, or after, four sequential chemotherapy regimens but then had a remarkable response to his fifth regimen, Tissue from his initial diagnostic surgery was then re-sent for molecular testing. Testing revealed a NACC2-NTRK fusion.…”

Section: Larotrectinib Imaging Response In Low-grade Gliomamentioning

confidence: 99%

“…The treatment of low‐grade gliomas is rapidly changing due to the availability of recently introduced and remarkable targeted therapies. The effectiveness, and the effects, of these therapies continue to be defined . We report here a child with an unresectable low‐grade glioma who progressed through, or after, four sequential chemotherapy regimens but then had a remarkable response to his fifth regimen, targeted therapy with larotrectinib, accompanied by loss of contrast enhancement on magnetic resonance imaging (MRI).…”

mentioning

confidence: 99%