Larotrectinib imaging response in low‐grade glioma

Walter, Andrew W.; Kandula, Vinay; Shah, Nidhi

doi:10.1002/pbc.28002

Cited by 7 publications

(8 citation statements)

References 4 publications

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Section: Discussionmentioning

confidence: 73%

“…With the recent FDA approval of larotrectinib, a selective pan-TRK inhibitor, and entrectinib, a selective pan-TRK, ROS1, and ALK inhibitor [ 42 ], there has been much interest in characterizing and diagnosing tumors with NTRK fusions. Both therapies have demonstrated significant treatment responses in NTRK -fused tumors [ 4 , 13 , 15 – 17 , 23 , 30 ], including CNS metastases [ 13 , 16 , 17 , 23 ] and primary CNS tumors [ 1 , 9 , 16 , 50 , 57 ], and are generally well tolerated [ 4 , 13 , 15 – 17 , 23 , 30 ]. Our study addresses gaps in the knowledge of the clinical and molecular features of NTRK -fused gliomas.…”

Section: Discussionmentioning

confidence: 99%

“…The diverse histology of NTRK -fused gliomas overlaps with entities such as DIGG, GG, PXA, PA (including anaplastic), DA grades 2 and 3, and GBM in our study. In keeping with the wide spectrum of NTRK -fused CNS tumor histology, NTRK rearrangements have been previously reported in GBM [ 9 , 18 , 19 , 21 , 28 , 34 , 38 , 39 , 41 , 43 , 44 , 52 , 53 , 56 ], gliosarcoma [ 21 ], AA [ 9 , 18 , 21 , 52 ], diffuse midline glioma / DIPG [ 9 , 52 ], HGG [ 9 , 22 , 34 , 57 ], glioneuronal tumor (including high grade) [ 1 , 16 , 29 ], pilocytic astrocytoma (PA) (including anaplastic) [ 9 , 18 , 21 , 25 , 35 ], low grade astrocytroma with features of PA [ 26 ], PXA [ 55 ], GG [ 1 , 9 , 36 , 37 ], DIGG [ 6 , 9 ], LGG [ 18 , 34 , 44 , 50 , 53 ], glioma, not otherwise specified [ 9 , 18 ], neuroepithelial neoplasm [ 43 ], CNS fibroblastic tumor [ 47 ], primitive neuroectodermal tumor (PNET) [ 12 ], CNS embryonal tumor [ 14 ], and tumors with oligodendroglial or oligoastrocytic-like histology [ 12 , 21 , 29 , 37 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

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Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low-to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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“…All patients showed a radiographic response, including one complete response (2019, ASCO Annual Meeting Abstract #: 10009). To date, only a few reports describing primary NTRK-fused CNS tumors treated with either larotrectinib or entrectinib are available in the literature [8,[30][31][32]. An adult patient with a BCAN:NTRK1 fused glioneuronal tumor developed disease progression after eleven months of entrectinib [30].…”

Section: Discussionmentioning

confidence: 99%

“…An adult patient with a BCAN:NTRK1 fused glioneuronal tumor developed disease progression after eleven months of entrectinib [30]. Two reports describe patients suffering from a low-grade glioma (LGG), one with a NACC2:NTRK fusion showing more than 50% reduction in tumor volume and an ETV6:NTRK3-fused tumor with complete remission upon treatment with larotrectinib [8,31]. Moreover, in two ETV6:NTRK3 fusion-positive pHGG, larotrectinib was administered.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Mayr

Guntner

Madlener

et al. 2020

JPM

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Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

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Targeted Therapies in Paediatric Brain Tumours

Bennett,

Kilday

2024

Pediatric Neuro-Oncology

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Larotrectinib imaging response in low‐grade glioma

Cited by 7 publications

References 4 publications

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Targeted Therapies in Paediatric Brain Tumours

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