FDA Approval Summary: Entrectinib for the Treatment of <i>NTRK</i> gene Fusion Solid Tumors

Marcus, Leigh; Donoghue, Martha; Aungst, Stephanie; Myers, Claire E.; Helms, Whitney S.; Shen, Guoxiang; Zhao, Hong; Stephens, Olen; Keegan, Patricia; Pazdur, Richard

doi:10.1158/1078-0432.ccr-20-2771

Cited by 83 publications

(61 citation statements)

References 12 publications

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“…Over-expression of TrkB, a member of the same protein family, has been associated with EMT [ 10 ]. Identifying tumors with NTRK1 fusion has become important therapeutically since the FDA-approval of entrectinib as a molecularly targeted treatment for this fusion [ 48 ]. As this is a rare occurrence in GB (approximately 1% of cases), performing a randomized trial in this setting to is likely to be challenging [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling

et al. 2021

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Background Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. Methods Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. Results Potentially meaningful associations (p<0.1, Fisher’s exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11. Conclusions GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.

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Section: Discussionmentioning

confidence: 99%

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling

et al. 2021

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“…The mice developed high-grade gliomas which responded to the Ntrk1 inhibitor entrectinib. In general, patients whose cancers carry NTRK1 fusion genes have responded satisfactorily to treatment with tyrosine kinase inhibitors (85,(91)(92)(93)(94)(95).…”

Section: Table I Fusion Genes Generated By Interstitial Deletions In Cancermentioning

confidence: 99%

Interstitial Deletions Generating Fusion Genes

Panagopoulos

Heim

2021

Cancer Genomics Proteomics

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“…More recently, larotrectinib [ 38 ] and entrectinib [ 39 ] also obtained marketing authorization for tumors with NTRK fusion in a tissue-agnostic way. The TRK (tropomyosin receptor kinase) family of transmembrane receptors is composed of three members (TrkA, TrkB, TrkC), encoded, respectively, by three NTRK (neurotrophic receptor tyrosine kinases) genes (NTRK1, NTRK2, and NTRK3).…”

Section: Impact Of the Molecular Segmentation Of Cancermentioning

confidence: 99%

Drug Development in Tissue-Agnostic Indications

Rusquec

Tourneau

2021

Cancers

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A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.

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FDA Approval Summary: Entrectinib for the Treatment of NTRK gene Fusion Solid Tumors

Cited by 83 publications

References 12 publications

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling

Interstitial Deletions Generating Fusion Genes

Drug Development in Tissue-Agnostic Indications

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