TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and entrectinib, were granted landmark, tumour-agnostic regulatory ...approvals for the treatment of these cancers in 2018 and 2019, respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-generation agents such as selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.
•NTRK fusions are bona fide oncogenic lung cancer drivers.•NTRK fusions share a similar clinical profile with many other fusions.•Larotrectinib and entrectinib achieve high response rates and durable ...disease control.•Next-generation inhibitors have demonstrated clinical proof of principle responses.•Side effects of TRK inhibition include weight gain, dizziness, and paresthesias.
Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.
The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases are encoded by NTRK genes and have a role in the development and normal functioning of the nervous system. Since the ...discovery of an oncogenic NTRK gene fusion in colorectal cancer in 1986, over 80 different fusion partner genes have been identified in a wide array of adult and paediatric tumours, providing actionable targets for targeted therapy. This review describes the normal function and physiology of TRK receptors and the biology behind NTRK gene fusions and how they act as oncogenic drivers in cancer. Finally, an overview of the incidence and prevalence of NTRK gene fusions in various types of cancers is discussed.
Trk gene fusions are an important driver in the development of cancers, including secretory breast cancer and infantile congenital sarcoma. Since the first-generation of small molecule Trk inhibitors ...(Larotrectinib and Entrectinib) came to market, research on small molecule TRK inhibitors, especially second-generation inhibitors that break through the resistance problem, has developed rapidly. Therefore, this article focuses on the research progress of first-generation drugs and second-generation drugs that break through drug resistance.
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The phenomenon of Trk protein fusion and its relation to tumors are described, followed by an explanation of the composition and signaling pathways of Trk kinases. The representative Trk inhibitors and the development of novel Trk inhibitors are classified according to whether they overcome drug resistance problems.
This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.
NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a ...focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.
Aims
Infantile fibrosarcoma is characterised by intersecting fascicles of spindle cells and ETV6–NTRK3 gene fusion in most cases. Given histological overlap with other spindle‐cell tumours, the ...diagnosis can be challenging and often requires molecular confirmation. A recently developed pan‐TRK antibody shows promise for identifying tumours with NTRK fusions. The purpose of this study was to evaluate the potential diagnostic utility of pan‐TRK immunohistochemistry for infantile fibrosarcoma.
Methods and results
We evaluated whole‐tissue sections from 210 cases, including 15 infantile fibrosarcomas; five each lipofibromatosis‐like neural tumour and lipofibromatosis; 10 each primitive myxoid mesenchymal tumour of infancy (PMMTI) and low‐grade myofibroblastic sarcoma; 15 each fibrous hamartoma of infancy (FHI), myofibroma/myofibromatosis and desmoid‐type fibromatosis; and 20 each low‐grade fibromyxoid sarcoma, synovial sarcoma, spindle‐cell rhabdomyosarcoma, malignant peripheral nerve sheath tumour, fibrosarcomatous dermatofibrosarcoma protuberans (F‐DFSP) and nodular fasciitis. Immunohistochemistry was performed using a rabbit monoclonal pan‐TRK antibody. Immunoreactivity for pan‐TRK was observed in all 15 (100%) infantile fibrosarcomas, including diffuse immunoreactivity (>50% of cells) in 14 (93%) cases. Pan‐TRK was positive in all five (100%) lipofibromatosis‐like neural tumours. Of the 190 histological mimics, diffuse pan‐TRK immunoreactivity was noted in 16 (8%) cases, including five PMMTI, five FHI (highlighting predominantly the primitive myxoid spindle‐cell components), three F‐DFSP, one low‐grade myofibroblastic sarcoma, one myofibroma and one spindle‐cell rhabdomyosarcoma.
Conclusions
Diffuse pan‐TRK immunoreactivity is a highly sensitive but not entirely specific diagnostic marker for infantile fibrosarcoma, and may be helpful in selecting patients for TRK‐targeted therapy. As expected, lipofibromatosis‐like neural tumours, which harbour NTRK1 fusions, also show diffuse pan‐TRK immunoreactivity.
NTRK gene fusion leads to the activation of downstream signaling pathways, which is a oncogenic driver in various cancers. NTRK fusion-positive cancers can be treated with the first-generation TRK ...inhibitors, larotrectinib and entrectinib. Unfortunately, the patients eventually face the dilemma of no drugs available as the emergence of certain resistance mutations. The development of efficient and broad-spectrum second-generation TRK inhibitors is still of great significance. Here, we analyzed the binding modes of compounds 6, 10 with TRKA protein, respectively, a series of novel indazole TRK inhibitors were designed and synthesized using molecular hybridization strategy. Among them, the optimal compound B31 showed strong antiproliferative activities against Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell lines with IC50 values of 0.3, 4.7, and 9.9 nM, respectively. And the inhibitory effect against TRKAG667C (IC50 = 9.9 nM) was better than that of selitrectinib (IC50 = 113.1 nM). Further, compound B31 exhibited moderate kinase selectivity and excellent plasma stability (t1/2 > 480 min). In vivo pharmacokinetic studies in Sprague-Dawley rats showed that B31 had acceptable pharmacokinetic properties.
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•Based on molecular hybridization strategy, novel TRK inhibitors were discovered.•B31 exhibited significant inhibitory potency against multiple TRK mutants.•B31 possessed a moderate kinase selectivity.•B31 displayed good antiproliferative activities against NTRK fusion positive cells.•B31 showed excellent plasma stability and moderate pharmacokinetic properties.
Abstract
Background
Larotrectinib, a first‐in‐class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors ...harboring
NTRK
gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas.
Methods
Patients (≥18 years old) with sarcomas harboring
NTRK
gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator‐assessed per RECIST v1.1. Data cutoff was July 20, 2021.
Results
At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41–74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment‐emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs.
Conclusions
Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow‐up. These results continue to demonstrate that testing for
NTRK
gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas.
Plain Language Summary
Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the
NTRK
gene and cause cancer in a range of tumor types.
Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer.
This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins.
Over half of patients had a durable response to larotrectinib, with no unexpected side effects.
These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas.
Larotrectinib, a first‐in‐class tropomyosin receptor kinase (TRK) inhibitor, demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas. Testing for
NTRK
gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas to identify those suitable for targeted therapy.
Aims
Secretory carcinoma (SC) of the salivary gland typically harbours ETV6–NTRK3 fusion, which can be utilised clinically to assist with diagnosis. Pan‐Trk inhibitor therapy has demonstrated drastic ...responses in patients with NTRK‐translocated tumours, including SC. Pan‐Trk immunohistochemistry (IHC) is emerging as a sensitive and specific tool for detecting NTRK1, NTRK2 and NTRK3 fusions in various cancers. We aimed to establish the specificity and sensitivity of pan‐Trk IHC in diagnosing SC and detecting ETV6–NTRK3 fusion. A literature review on the utility of pan‐Trk IHC was conducted.
Methods and results
Pan‐Trk IHC was performed on 83 salivary gland neoplasms (29 SCs and 54 non‐SCs). ETV6–NTRK3 fusion status was established in 25 cases. With any staining (nuclear or cytoplasmic) as a positive threshold, the sensitivity and specificity of pan‐Trk IHC were 90% and 70% in diagnosing SC, and 100% and 0% in detecting NTRK3 fusion. When only pan‐Trk nuclear staining was considered as positive, the sensitivity and specificity were 69% and 100% in diagnosing SC, and 92% and 100% in detecting NTRK3 fusion.
Conclusions
Nuclear pan‐Trk IHC is highly specific for SC diagnosis, with a specificity approaching 100%, making it a useful and precise diagnostic tool for differentiating SC from its histological mimics. On the other hand, any pan‐Trk staining (nuclear or cytoplasmic) is highly sensitive for SC, and can serve as an attractive, cheap, fast and accessible screening tool for selecting patients to undergo confirmative molecular testing for clinical trials using TRK inhibitors.
Aims
NTRK rearranged tumours are rare but can be successfully treated using anti‐TRK‐targeted therapies, making NTRK testing important for treatment choices in patients with advanced cancers. Pan‐Trk ...immunohistochemistry (IHC) has become a valuable and affordable screening tool in many laboratories. Unfortunately, the choice of antibodies and IHC protocols to investigate biomarkers is not standardised. In this study, we compared the performance of four pan‐Trk IHC methods, using three different clones, primarily in NTRK fusion‐positive tumours.
Methods and results
We studied the performance of four pan‐Trk IHC methods using three different clones: EPR17341 (Abcam and Ventana), EP1058Y (Abcam) and A7H6R (Cell Signaling) in 22 molecularly confirmed NTRK rearranged tumours. Additionally, selected NTRK fusion‐negative tumours were further included: NTRK mutated (n = 8) and amplified (n = 15) tumours as well as NTRK fusion‐negative tumours driven by other gene fusions, such as ALK, ROS1 and BCOR (n = 20), as well as salivary gland tumours (n = 16). Inter‐rater agreement of three pathologists was additionally calculated, including H‐score. With clone EPR17341 (Abcam in‐house and ready‐to‐use Ventana protocol), all molecularly confirmed NTRK1–3 rearranged tumours were positively detected by immunohistochemistry, while the other clones missed NTRK2–3 rearranged tumours. For the fusion‐negative cohort we found the best performance (least false‐positive cases) using the clone A7H6R (Cell Signalling).
Conclusion
Given the therapeutic importance, testing for NTRK rearrangements in daily practice has become necessary and, despite IHC being a fast and affordable tool, using it in routine diagnostics is complicated and requires a high level of expertise.
A systematic comparison of 4 pan‐Trk IHC assays in a cohort of 22 molecularly confirmed NTRK rearranged and 59 NTRK fusion‐negative tumours with defined molecular profiles, potentially causing false‐positive pan‐Trk staining: a study to better understand sensitivity, specificity and inter‐rater agreement.
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