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Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for “pan-cancer” harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field. This review mainly summarizes the acquired resistance mechanisms of the first- and second-generation TRK inhibitors and firstly update the emerging selective type II TRK inhibitors to overcome the xDFG mutations mediated resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Triple‐negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type‐agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan‐TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real‐time polymerase chain reaction (RT‐PCR), and RNA‐based next‐generation sequencing (NGS). Of 83 cases, 16 showed pan‐TRK positivity although no cases had NTRK‐fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT‐PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan‐TRK IHC. Our data demonstrate that IHC has a high false‐positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.

Triple‐negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type‐agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan‐TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real‐time polymerase chain reaction (RT‐PCR), and RNA‐based next‐generation sequencing (NGS). Of 83 cases, 16 showed pan‐TRK positivity although no cases had NTRK‐fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT‐PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan‐TRK IHC. Our data demonstrate that IHC has a high false‐positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from neurotrophic tyrosine kinase receptor (NTRK) or receptor tyrosine kinase (RET) inhibitors. Methods: Patients were identified in the Calgary prospective thyroid ca ncer database (N = 482). Patients were ‘pre-screened’ with clinically available MassARRAY® BRAF test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were ‘screened’ for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3). Results: A total of 86 patients were included in 1 of 2 separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of 4 patients with NTRK fusions and 4 patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and 2 with medullary thyroid carcinoma. During pre-screening, 1 patient with an NTRK fusion, 1 patient with a RET fusion, and 30 patients with BRAF mutations were identified. The remaining 9 patients received OCAv3 screening, resulting in detection of 1 patient with an NTRK fusion and 1 with a RET fusion (4/11, 36% of analyzed patients). Conclusions: Our findings indicate a higher rate of NTRK fusions and RET fusions in patients with thyroid cancer with RAI-resistant distant metastases and ATA high or intermediate risk of recurrence. This highlights the importance of early screening to enable intervention with a NTRK or RET inhibitor.

Background: TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear., Methods: This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression., Results: Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively., Conclusion: Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression., (© The Author(s) 2024. Published by Oxford University Press.)

BackgroundNTRK (neurotrophic tyrosine receptor kinase)-rearranged spindle cell neoplasms are a new group of tumors included in the new 5th edition of the World Health Organization (WHO) classification of soft Tissue and Bone Sarcomas. These tumors are characterized by NTRK gene fusions and show a wide spectrum of histologies and clinical behavior. Several targeted therapies have recently been approved for tumors harboring NTRK fusions, including STS.Case PresentationA 26-year-old male with advanced, pretreated NTRK rearranged spindle cell neoplasm and liver, lung and bone metastases was treated with larotrectinib on a continuous 28-day schedule, at a dose of 100 mg twice daily. An 18FDG-PET/CT scan performed after 7 days of treatment showed tumor shrinkage in both visceral and bone lesions. There was no drug-related toxicity. Subsequent evaluations confirmed continued tumor regression in disease sites. The patient is well and continues treatment.ConclusionThe clinical and radiological response of our patient with an uncommon TPM4 (exon 7)-NTRK1 (exon 12) gene fusion tumor treated with a first-generation TRK inhibitor could contribute to a better understanding of the biology of this new STS entity and help to improve patient management.

Background: NTRK (neurotrophic tyrosine receptor kinase)-rearranged spindle cell neoplasms are a new group of tumors included in the new 5th edition of the World Health Organization (WHO) classification of soft Tissue and Bone Sarcomas. These tumors are characterized by NTRK gene fusions and show a wide spectrum of histologies and clinical behavior. Several targeted therapies have recently been approved for tumors harboring NTRK fusions, including STS. Case Presentation: A 26-year-old male with advanced, pretreated NTRK rearranged spindle cell neoplasm and liver, lung and bone metastases was treated with larotrectinib on a continuous 28-day schedule, at a dose of 100 mg twice daily. An 18FDG-PET/CT scan performed after 7 days of treatment showed tumor shrinkage in both visceral and bone lesions. There was no drug-related toxicity. Subsequent evaluations confirmed continued tumor regression in disease sites. The patient is well and continues treatment. Conclusion: The clinical and radiological response of our patient with an uncommon TPM4 (exon 7)-NTRK1 (exon 12) gene fusion tumor treated with a first-generation TRK inhibitor could contribute to a better understanding of the biology of this new STS entity and help to improve patient management. [ABSTRACT FROM AUTHOR]

Due to the efficacy of tropomyosin receptor kinase (TRK) inhibitor therapy and the recent Food and Drug Administration approval of larotrectinib, it is now clinically important to accurately and efficiently identify patients with neurotrophic TRK (NTRK) fusion-driven cancer. These oncogenic fusions occur when the kinase domain of NTRK1 , NTRK2 or NTRK3 fuse with any of a number of N-terminal partners. NTRK fusions are characteristic of a few rare types of cancer, such as secretory carcinoma of the breast or salivary gland and infantile fibrosarcoma, but they are also infrequently seen in some common cancers, such as melanoma, glioma and carcinomas of the thyroid, lung and colon. There are multiple methods for identifying NTRK fusions, including pan-TRK immunohistochemistry, fluorescence in situ hybridisation and sequencing methods, and the advantages and drawbacks of each are reviewed here. While testing algorithms will obviously depend on availability of various testing modalities and economic considerations for each individual laboratory, we propose triaging specimens based on histology and other molecular findings to most efficiently identify tumours harbouring these treatable oncogenic fusions. [ABSTRACT FROM AUTHOR]

Background: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making., Materials and Methods: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development., Results: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006)., Conclusions: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from neurotrophic tyrosine kinase receptor (NTRK) or receptor tyrosine kinase (RET) inhibitors., Methods: Patients were identified in the Calgary prospective thyroid cancer database (N= 482). Patients were 'pre-screened' with clinically available MassARRAY® BRAF test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were 'screened' for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3)., Results: A total of 86 patients were included in 1 of 2 separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of 4 patients with NTRKfusions and 4 patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and 2 with medullary thyroid carcinoma. During pre-screening, 1 patient with an NTRK fusion, 1 patient with a RET fusion, and 30 patients with BRAF mutations were identified. The remaining 9 patients received OCAv3 screening, resulting in detection of 1 patient with an NTRKfusion and 1 with a RET fusion (4/11, 36% of analyzed patients)., Conclusions: Our findings indicate a higher rate of NTRK fusions and RETfusions in patients with thyroid cancer with RAI-resistant distant metastases and ATA high or intermediate risk of recurrence. This highlights the importance of early screening to enable intervention with a NTRK or RET inhibitor.

Simple Summary: The use of novel therapeutic drugs in lung cancer has changed the paradigm of the diagnosis and treatment of lung cancer. Due to the development of advanced diagnostic procedures (e.g., next generation sequencing (NGS)) around half of non-small-cell lung cancer (NSCLC) patients can be identified with genetic aberrations. The presence of activating mutations of EGFR, ALK and ROS-1 have already been well explored. New targets that can be successfully targeted include NTRK, MET, RET and HER 2 genes. Some particles have already received FDA approval, whereas many more are in the late stages of clinical trials. Considering rapid changes in thoracic oncology, an up-to-date summary is needed. In this review, we present the current landscape of approved therapeutic drugs, as well as important ongoing clinical trials. Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1–2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies. [ABSTRACT FROM AUTHOR]