Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

Chu, Paula; Batson, Sarah; Hodgson, Matt; Mitchell, C.R.; Steenrod, Anna

doi:10.2217/fon-2019-0534

Cited by 10 publications

(8 citation statements)

References 69 publications

(148 reference statements)

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“…the entrectinib cohort currently has a higher proportion of patients with CNS metastases than the larotrectinib cohort [20,46,49]), the types and relative proportions of the NTRK+ solid tumours represented and the number and type of prior lines of therapy. Further expansion of the integrated analyses in addition to the emergence of real-world data from routine clinical practice will increase the evidence base for, and hence the robustness of, indirect comparisons of the relative efficacy of these two agents [7]; hence, both developments are awaited with interest. On-target resistant mutations have been identified in patients who have progressed on entrectinib (Sect.…”

Section: Place Of Entrectinib In the Management Of Ntrk+ Solid Tumours And Ros1+ Nsclcmentioning

confidence: 99%

“…In this regard, gene rearrangements (fusions) involving the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2 and NTRK3 [encoding the tropomyosin receptor kinase (TRK) receptors TRKA, TRKB and TRKC, respectively], the c-ros oncogene 1 receptor tyrosine kinase (ROS1) gene [encoding proto-oncogene tyrosine-protein kinase ROS (ROS1)] and the anaplastic lymphoma kinase gene (ALK; encoding the ALK receptor tyrosine kinase) are variously implicated, albeit often infrequently, in a broad range of (> 40) solid tumour types [5]. NTRK fusions, which are thought to be present in up to 1% of all solid tumours, are found in a wide variety of adult and paediatric tumour types; they are extremely common (incidence > 90%) in rare cancer types, such as infantile fibrosarcoma and mammary analogue secretory carcinoma (MASC), but rare (incidence predominantly < 1%) in more common cancer types, such as lung, breast and colorectal cancers, and melanomas [2,6,7]. NTRK, ROS1 and ALK fusions are present in 0.1-1%, 1-2% and 4-6% of cases of non-small-cell lung cancer (NSCLC), respectively [8].…”

Section: Introductionmentioning

confidence: 99%

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Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

Frampton

2021

Drugs

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Entrectinib (Rozlytrek ® ) is an orally active, CNS-penetrant, small-molecule, selective inhibitor of the tropomyosin receptor tyrosine kinases TRKA/B/C [encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1/2/3 , respectively], the proto-oncogene tyrosine-protein kinase ROS1 ( ROS1 ) and the anaplastic lymphoma kinase gene ( ALK ). It is approved for the treatment of adults and paediatric patients aged ≥ 12 years with NTRK fusion-positive ( NTRK+ ) solid tumours and adults with ROS1 fusion-positive ( ROS1+ ) non-small-cell lung cancer (NSCLC). In trials in adults, entrectinib induced clinically meaningful and durable systemic responses in tyrosine kinase inhibitor (TKI)-naïve patients with locally-advanced or metastatic NTRK + solid tumours or ROS1 + NSCLC, irrespective of the presence or absence of CNS metastases at baseline. Moreover, entrectinib demonstrated substantial intracranial efficacy in patients with baseline CNS metastases. Entrectinb efficacy in paediatric patients was established on the basis of extrapolation of clinical trial data from adults with NTRK+ solid tumours and children and adolescents aged < 21 years with recurrent or refractory NTRK+ CNS/solid tumours. Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for advanced NTRK + solid tumours and ROS1 + NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases.

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Section: Place Of Entrectinib In the Management Of Ntrk+ Solid Tumours And Ros1+ Nsclcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

Frampton

2021

Drugs

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“…Because of low cost and advances in NGS technology, the NGS gene panel is clinically adopted to be used to identify actionable mutations for targeted therapy. Besides HER2-targeted therapy significantly improving the survival of HER2-positive breast cancer patients, other targeted therapies are also a powerful therapeutic strategy for breast cancer, such as poly (ADP-ribose) polymerase inhibitors (olaparib and talazoparib) for BRCA1/2 mutation carriers [ 46 ], PI3K-alpha inhibitors (alpelisib) and estrogen receptor antagonist (fulvestrant) for PIK3CA activating mutations [ 47 ], tumor-agnostic tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for NTRK fusions [ 48 ], immune checkpoint inhibitors (pembrolizumab) for high tumor mutation burden [ 49 ], etc. Given progressive biostatic analysis pipelines, the NGS assay is utilized to simultaneously detect both copy number variants and somatic mutations, which could provide more comprehensive genetic profiling for cancer patients using a single assay in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

HER2 amplification by next-generation sequencing to identify HER2-positive invasive breast cancer with negative HER2 immunohistochemistry

et al. 2022

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Background Human epidermal growth factor receptor 2 (HER2) positive breast carcinomas due to HER2 amplification are associated with aggressive behavior and a poor prognosis. Anti-HER2-targeted therapies are widely used to treat HER2-positive breast carcinomas with excellent outcomes. Accurate identification of HER2 amplification status in breast carcinomas is of important diagnostic and treatment value. Currently, HER2 amplification status is routinely determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) testing. This study will review our past HER2 data to determine and characterize discordant results between HER2 IHC and FISH. It will also determine a potential impact of HER2 amplification status by next-generation sequencing (NGS) on these patients. Methods We reviewed a total of 4884 breast carcinomas with coexisting HER2 IHC and HER2 FISH performed at our institution from 2010 to 2022. 57 cases also had a Next-Generation-Sequencing-based (NGS) gene panel performed. Given the advances in biostatic analysis pipelines, NGS methods were utilized to provide results on HER2 amplification status along with somatic mutations. Results While the majority (ranging from 98.5% with IHC score of 0 and 93.1% with IHC score of 1 +) of 4884 breast carcinomas had concordant results from HER2 IHC and HER2 FISH testing, a small percentage of patients (ranging from 1.5% in those with IHC score of 0, to 6.9% with IHC score of 1 +) had discordant results, with negative HER2 IHC and positive HER2 FISH results. These patients could be reported as HER2-negative breast carcinomas if only HER2 IHC testing has been performed according to a current cost-effective HER2 test strategy. 57 patients had HER2 amplification status determined by NGS, and all patients had concordant results between HER2 NGS and FISH tests. A HER2-amplified breast carcinoma by NGS had a negative IHC and a positive HER2 FISH result. This case was classified as a HER2-positive breast carcinoma, had anti-HER2-targeted therapy, and achieved a complete clinical response. Conclusions A small percentage of HER2-positive breast carcinomas are unidentified because of a negative HER2 IHC based on our current cost-effective HER2 test strategy. It is not feasible and affordable in routine clinical practice to perform HER2 FISH for the cases with negative HER2 IHC (IHC score 0 and 1 +). Therefore, NGS assays capable of simultaneously detecting both somatic mutations and HER2 amplification could provide a more comprehensive genetic profiling for breast carcinomas in a clinical setting. Identification of HER2 amplification by NGS in HER2-positive breast carcinomas with negative HER2 IHC results is important since these cases are concealed by our current cost-effective HER2 test strategy with IHC first (for all cases) and FISH reflex (only for cases with IHC score of 2 +), and would offer the opportunity for potentially beneficial anti-HER2-targeted therapies for these patients.

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“…[45][46][47] Several other next-generation TRK inhibitors are under early investigation in patients with NTRK gene fusions; these include multikinase inhibitors (cabozantinib, merestinib, and sitravatinib) and the ROS1/TRK tyrosine kinase inhibitor taletrectinib (DS-6051b). 48,49…”

Section: Overview Of Entrectinibmentioning

confidence: 99%

Diagnosis and management of TRK fusion cancer

2022

Am J Manag Care

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Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

Cited by 10 publications

References 69 publications

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

HER2 amplification by next-generation sequencing to identify HER2-positive invasive breast cancer with negative HER2 immunohistochemistry

Diagnosis and management of TRK fusion cancer

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