NTRK Gene Fusions Research Articles

Clinical characteristics and outcome of central nervous system tumors harboring NTRK gene fusions.

TRK fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. 119 patients were identified. The median age at time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG) (57.1%) followed by low-grade glioma (LGG) (27.7%). Pediatric patients had a better prognosis with a median overall survival of 185.5 months compared to 24.8 months in adults (p<.0001). Patients with LGG also had a better outcome when compared to HGG (p=0.0012). The objective response was 68.8% with larotrectinib compared to 38.1% for non-targeted treatment. Children with LGG glioma had a favorable outcome compared to adult and HGG. TRK inhibitors appear to improve tumor control.

CTNI-07. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS

Abstract BACKGROUND Larotrectinib is a highly selective TRK inhibitor approved for TRK fusion tumor-agnostic use. We report updated data on larotrectinib-treated patients with TRK fusion primary CNS tumors. METHODS Patients enrolled in 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]) were included. Responses were independent review committee (IRC)-assessed (RANO). Patients from SCOUT could stop larotrectinib in the absence of on-treatment progression (wait-and-see). Data cutoff: July 2023. RESULTS Fifty-five patients (38 aged &amp;lt;18 years at enrolment) were evaluated, including 16 with non-measurable disease at baseline. Tumor histologic groups included: high-grade glioma (HGG; n=32), low-grade glioma (LGG; n=15), and other (n=8). For all patients (n=55), ORR was 27% (95% CI 16-41): 3 CR, 12 PR, 24 SD (15 for &amp;gt;24 weeks), 12 PD, and 4 not evaluable. For pediatric patients (n=38), ORR was 37% (95% CI 22-54). ORR in patients with measurable disease only was 38% (95% CI 23-55) for all patients (n=39) and 52% (95% CI 32-71) for pediatric patients (n=27). The 24-week disease control rates were 55% (95% CI 41-68) and 74% (95% CI 57-87) for all patients and pediatric patients, respectively. Median time to response, DoR, PFS, and OS were 2, 12 (95% CI 6-not estimable [NE]), 12 (95% CI 7-20), and 38 months (95% CI 23-NE), respectively. Treatment duration ranged from 1 to 64+ months. At data cutoff, 1 pediatric patient with HGG and 4 with LGG entered wait-and-see; median duration of first wait-and-see period was 20 months (range 4-29). One pediatric patient with LGG resumed treatment following disease progression in wait-and-see. Treatment-related adverse events were predominantly Grade 1/2. CONCLUSION Larotrectinib demonstrated rapid, durable responses and manageable safety in patients with TRK fusion primary CNS tumors. This supports the adoption of NGS panels containing NTRK gene fusions when testing patients to identify those who might benefit from TRK inhibitor therapy.

Rare Presentation of Extraskeletal Osteosarcoma Mimicking Phyllodes Tumor

Abstract Introduction/Objective A 57-year-old female presented with a palpable mass in the left breast, measuring up to 9 cm by ultrasound. core needle biopsy identified an atypical spindle cell lesion. The differential diagnosis included a metaplastic carcinoma, borderline phyllodes tumor, malignant phyllodes tumor with potential sarcomatous transformation. Methods/Case Report Histological examination of the tumor was performed, and immunohistochemical stains were conducted to characterize the lesion. Further consultation with a specialized pathologist at the University of Michigan was sought to confirm the diagnosis. Molecular analysis was performed to assess for specific genetic alterations and expression patterns. The histological examination revealed a proliferation of atypical spindle cells forming a fascicular and storiform pattern, with numerous large, pleomorphic, multinucleated tumor cells and a high mitotic rate. Immunohistochemical stains showed strong positivity for CD10 and vimentin, with focal weak expression for desmin, and negativity for a broad panel of cytokeratins and other markers. Consultation with Dr. Abbott at the University of Michigan supported the diagnosis of extraskeletal osteosarcoma. Molecular analysis revealed PD-L1 expression and absence of NTRK gene fusions. FISH analysis showed suggestive alterations including loss of BRAF gene, loss of MYC, and suggestive gains or polysomy of PTEN gene. Results (if a Case Study enter NA) NA Conclusion The case represents a rare presentation of extraskeletal osteosarcoma in the breast, with distinctive histological and immunohistochemical features. The comprehensive workup including histology, immunohistochemistry, and molecular analysis aids in accurate diagnosis and potential therapeutic implications. Further research may elucidate the underlying mechanisms and treatment options for this uncommon malignancy.

Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.

The standard of care for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment, however, the predictive significance of most of the targets for treatment in systemic cancer are less well established in central nervous system (CNS) tumors . In 2023 the EANO Guideline Committee presented evidence based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high Tumor Mutational Burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for patients was still limited . This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of therapeutic yield of routine next generation sequencing for mutations and fusion detection. The supplement accompanying this version contains the in depth review of all targets, whereas in the main manuscript the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.

8788 Implications of NTRK gene fusion in Papillary thyroid cancer

Abstract Disclosure: W. Medina-Torres: None. L. El Musa Penna: None. J. Segarra-Villafane: None. L.R. Sepulveda-Garcia: None. Z. Maisonet -Feliciano: None. I.C. Arroyo: None. M. Ramirez: None. M. Alvarado: None. L.A. Gonzalez-Rodriguez: None. V.J. Carlo: None. Thyroid cancer (TC) is the most common endocrine cancer. Papillary thyroid carcinoma (PTC) is the predominant contributor of this occurrence, comprising approximately 80% of all thyroid carcinomas. PTC has a good prognosis with a 5-year survival rate of more than 90% after resection. Nonetheless, factors such as tumor size, multifocality, nodal and distant metastases, characterize more aggressive cases including tall cell variant, columnar cell variant, and hobnail variant Aside from staging parameters, PTC behavior is mostly determined by morphologic variant. This is the case of 31 y/o female without known past medical history who was evaluated at endocrinology clinic due to a fine needle thyroid aspiration (FNA) positive for PTC, tall cell variant. Total thyroidectomy with central compartment dissection was performed. Pathology report presented a main tumoral mass of 3 cm but permeating multinodular pattern involving the entire gland with focal extrathyroidal extension, positive margins and six level VI positive lymph nodes. As per report, the tumor presented both papillary and follicular patterns of growth and other findings including oncocytic change, foci of clear cell change, low mitotic rate, and most notably "reverse polarization”. This pattern has the pathological features suggestive of the novel NTRK gene fusion mutation. The patient was treated with radioactive iodine (RAI) and one year post treatment there was evidence of elevated Thyroglobulin level at 904 ng/mLand thyroglobulin Ab at 2.48 IU/mL. A WBS +SPECT was done resulting in small uptake at left posterior thyroid bed and pulmonary intake. A chest CT revealed multiple bilateral sub centimeter nodules. Based on this result, a second course of RAI was given. Follow up neck ultrasound and chest CT presented persistent left level VI lymph nodes, increased amount of bilateral sub-centimeter pulmonary nodules and new thoracic(T11) lesion. FNA of left neck lymph nodes were positive for metastatic PTC for which left neck dissection was performed. Evaluation for actionable somatic mutations was requested based on resistance behavior, remarkable for TRIM33-NTRK1 chromosomal rearrangement. Patient was evaluated by Oncology service who started Larotrectinib treatment since it was approved for NTRK driven malignancies. Six-month post therapy patient achieved clinical and biochemical improvement. In the thyroid, NTRK-driven malignancies are rare and aggressive but treatable, in the evolving genomic era. As reviewed in the literature, NTRK fusion-positive TC exhibits distinctive clinicopathological features that could aid in identifying potential patients. Thus, in such patients who have PTC with non-classic pathologic patterns, specific molecular profile of the main tumor may have significant prognostic value that must be integrated into stratification system in order to provide target therapy on time. Presentation: 6/3/2024

Current Landscape of NTRK Inhibition for Pediatric CNS Tumors.

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

Atypical cellular responses mediated by intracellular constitutive active TrkB (NTRK2) kinase domains and a solely intracellular NTRK2-fusion oncogene

Trk (NTRK) receptor and NTRK gene fusions are oncogenic drivers of a wide variety of tumors. Although Trk receptors are typically activated at the cell surface, signaling of constitutive active Trk and diverse intracellular NTRK fusion oncogenes is barely investigated. Here, we show that a high intracellular abundance is sufficient for neurotrophin-independent, constitutive activation of TrkB kinase domains. In HEK293 cells, constitutive active TrkB kinase and an intracellular NTRK2-fusion oncogene (SQSTM1-NTRK2) reduced actin filopodia dynamics, phosphorylated FAK, and altered the cell morphology. Atypical cellular responses could be mimicked with the intracellular kinase domain, which did not activate the Trk-associated MAPK/ERK pathway. In glioblastoma-like U87MG cells, expression of TrkB or SQSTM1-NTRK2 reduced cell motility and caused drastic changes in the transcriptome. Clinically approved Trk inhibitors or mutating Y705 in the kinase domain, blocked the cellular effects and transcriptome changes. Atypical signaling was also seen for TrkA and TrkC. Moreover, hallmarks of atypical pTrk kinase were found in biopsies of Nestin-positive glioblastoma. Therefore, we suggest Western blot-like immunoassay screening of NTRK-related (brain) tumor biopsies to identify patients with atypical panTrk or phosphoTrk signals. Such patients could be candidates for treatment with NTRK inhibitors such as Larotrectinhib or Entrectinhib.

Performances of the Idylla GeneFusion Assay: contribution to a rapid diagnosis of targetable gene fusions in tumour samples

AimsWe aimed to evaluate the performances of the Idylla GeneFusion Assay (IGFA) designed to detect, in a single, rapid and fully automated assay, ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3...

The landscape of cancer-associated transcript fusions in adult brain tumors: a longitudinal assessment in 140 patients with cerebral gliomas and brain metastases.

Oncogenic fusions of neurotrophic receptor tyrosine kinase NTRK1, NTRK2, or NTRK3 genes have been found in different types of solid tumors. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (>75%), regardless of tumor histology and presence of metastases. Due to the efficacy of TRK inhibitor therapy of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer. In this retrospective study, we provide unique data on the incidence of oncogenic NTRK gene fusions in patients with brain metastases (BM) and gliomas. 140 samples fixed and paraffin-embedded tissue (FFPE) of adult patients (59 of gliomas [17 of WHO grade II, 20 of WHO grade III and 22 glioblastomas] and 81 of brain metastasis (BM) of different primary tumors) are analyzed. Identification of NTRK gene fusions is performed using next-generation sequencing (NGS) technology using Focus RNA assay kit (Thermo Fisher Scientific). We identified an ETV6 (5)::NTRK3 (15) fusion event using targeted next-generation sequencing (NGS) in one of 59 glioma patient with oligodendroglioma-grade II, IDH-mutated and 1p19q co-deleted at incidence of 1.69%. Five additional patients harboring TMPRSS (2)::ERG (4) were identified in pancreatic carcinoma brain metastasis (BM), prostatic carcinoma BM, endometrium BM and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted. A FGFR3 (17)::TACC3 (11) fusion was identified in one carcinoma breast BM. Aberrant splicing to produce EGFR exons 2-7 skipping mRNA, and MET exon 14 skipping mRNA were identified in glioblastoma and pancreas carcinoma BM, respectively. This study provides data on the incidence of NTRK gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. FGFR3 (17)::TACC3 (11) rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and TMPRSS (2)::ERG (4) rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.

Larotrectinib efficacy for liver metastases in papillary thyroid carcinoma patient harboring SQSTM1–NTRK1 fusion

BackgroundPooled data analysis from three phase I/II larotrectinib clinical trials revealed that larotrectinib demonstrated rapid and durable disease control and a favorable safety profile for patients with neurotrophic-tropomyosin receptor kinase (NTRK) fusion positive thyroid carcinoma. Herein, we report the case of a patient with papillary thyroid carcinoma (PTC) and liver metastases who demonstrated a durable response to treatment with larotrectinib.Case presentationA 50-year-old female with PTC was referred to our hospital for postoperative observation. Computed tomography (CT) scan was performed to screen for distant metastasis, since thyroglobulin concentration increased gradually, and revealed multiple distant metastases, including multiple liver metastases. Radioactive iodine was administered at a dose of 100 mCi. However, uptake was observed only in the thyroid bed, and distant metastases had no avidity. As liver metastases progressed, lenvatinib (24 mg/day) was initiated after confirmation of liver metastases by liver biopsy 9 years and 1 month after the initial referral to our hospital. Since the multiple metastases became refractory for lenvatinib, the OncoGuide™ NCC Oncopanel System was performed, and the SQSTM1–NTRK1 gene fusion was confirmed. Larotrectinib was subsequently administered at a dose of 200 mg/day. The CT before the initiation of larotrectinib showed multiple liver metastases with a maximum diameter of 48 mm. The first CT evaluation at 1 month after the initiation of larotrectinib treatment showed that the tumor volume was reduced by 28% in the RECIST 1.1 criteria. After 3 months of larotrectinib treatment, a 38% reduction in the tumor volume was achieved as the best clinical response. The only side effect was grade 1 myalgia. At 12 months after the initiation of larotrectinib treatment, none of the lesions had progressed.ConclusionsIn conclusion, larotrectinib demonstrated effective antitumor activity against liver metastases of PTC, a relatively rare site of distant metastasis. Furthermore, the efficacy of larotrectinib was maintained, even though the patient had a history of multi-tyrosine kinase inhibitor treatment and a relatively infrequent fusion gene, SQSTM1–NTRK1.

Discovery of novel indazole derivatives as second-generation TRK inhibitors

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.

Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer.

First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

HGG-02. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS

Abstract BACKGROUND Larotrectinib is the first-in-class, highly selective TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer. We report data on larotrectinib-treated pediatric patients with TRK fusion primary CNS tumors. METHODS Patients aged &amp;lt;18 years with TRK fusion primary CNS tumors enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Responses were independent review committee (IRC)-assessed per RANO. Patients were permitted to stop larotrectinib in the absence of on-treatment progression (wait-and-see) and remain on trial. RESULTS As of July 2023, 38 patients were eligible for efficacy analyses by IRC, including 11 patients with only non-measurable disease at baseline. Median age at enrollment was 7 years (range 0–17). Tumor histologic groups included: high-grade glioma (HGG; n=18), low-grade glioma (LGG; n=12), and other (n=8). Eleven (29%) patients had received ≥2 prior systemic therapies. Overall response rate was 37% (95% CI 22–54): three complete response, 11 partial response, 17 stable disease, five progressive disease, and two not evaluable. The 24-week disease control rate was 74% (95% CI 57–87). Medians for duration of response, progression-free survival, and overall survival (OS) were 17.2 months (95% CI 5.7–not estimable [NE]), 19.8 months (95% CI 11.1–50.8), and not reached (95% CI 32.7–NE), respectively. The 48-month OS rate was 60%. At data cutoff, one patient with HGG and four with LGG entered wait-and-see; median duration of the first wait-and-see period was 20.2 months (range 4–29). One patient with LGG resumed treatment following wait-and-see. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated rapid, durable responses and a manageable safety profile in pediatric patients with TRK fusion primary CNS tumors. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pediatric patients with CNS tumors.

Long-term efficacy and safety of larotrectinib (laro) in patients (pts) with TRK fusion thyroid carcinoma (TC).

6095 Background: NTRK gene fusions are oncogenic drivers in TC. Laro is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on overall response rate (ORR) in pts with various tumor types. Here, we report long-term efficacy and safety in a subset of pts with TRK fusion TC treated with laro. Methods: Pts with TRK fusion TC enrolled in 3 laro clinical trials (NCT02576431, NCT02122913, NCT02637687) were included. Laro was administered at 100 mg twice daily to most pts; 2 pediatric pts received 100 mg/m2. Responses were assessed per independent review committee (IRC) using RECIST v1.1. Results: As of July 20, 2023, 31 pts were enrolled and eligible for efficacy assessment by IRC. Of the 4 pts with known CNS metastases at baseline, 3 received prior cranial radiotherapy (2, 12 and 15 months prior to laro initiation, respectively). Median age was 60 years (range 6-80) and median time since initial cancer diagnosis was 5 years (range 0-46). All NTRK gene fusions were identified by next-generation sequencing (NGS). 17 pts (55%) received no prior systemic therapies, 6 (19%) received 2 or more; 22 (71%) received prior radioiodine. ORR was 65% (95% CI 45-81): 3 (10%) complete responses, 17 (55%) partial responses (PR), 5 (16%) stable disease (SD) (4 for &gt;30 months), 4 (13%) progressive disease (PD), and 2 (6%) not evaluable. For pts classified as differentiated TC (DTC; n=24 [77%]), ORR was 79% (95% CI 58-93). For pts classified as anaplastic TC (ATC; n=7 [23%]), ORR was 14% (95% CI 0-58). There were 3 pts with poorly differentiated TC, 1 (3%) classified as DTC (PR) and 2 (6%) as ATC (1 SD for &gt;39 months and 1 PD). Median time to response was 1.9 months (range 1.6-16.2) for all pts. Median duration of response was 40.5 months (95% CI 19.4-not estimable [NE]) at a median follow-up of 39.8 months. Median progression-free survival was 44.0 months (95% CI 16.6-NE) at a median follow-up of 38.7 months. Median overall survival (OS) was not reached (NR; 95% CI 48.7-NE) at a median follow-up of 58.0 months; the 48-month OS rate was 72% (95% CI 56-89). Median OS was NR (95% CI 56.3-NE) in DTC and 8.8 months (95% CI 2.6-NE) in ATC. Treatment duration ranged from 1 to 76+ months. At data cutoff, 11 pts had progressed, with 7 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 3 (10%) pts. There were no treatment discontinuations due to TRAEs. Conclusions: Laro continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in pts with TRK fusion DTC. Limited single-agent activity was observed in ATC. These results support the wider adoption of NGS panels, which include NTRK gene fusions in pts with advanced TC, to identify those who may benefit from targeted treatment. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

Prevalence of neurotrophic tropomyosin receptor kinase (NTRK) fusion gene positivity in patients with solid tumors in Japan.

Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases. Intra- or inter-chromosomal gene rearrangements produce NTRK gene fusions encoding fusion proteins which are oncogenic drivers in various solid tumors. This study investigated the prevalence of NTRK fusion genes and identified fusion partners in Japanese patients with solid tumors recorded in the Center for Cancer Genomics and Advanced Therapeutics database of comprehensive genomic profiling test. In the analysis population (n = 46,621), NTRK fusion genes were detected in 91 patients (0.20%). The rate was higher in pediatric cases (<18 years; 1.69%) than in adults (0.16%). NTRK gene fusions were identified in 21 different solid tumor types involving 38 different partner genes including 22 (57.9%) previously unreported NTRK gene fusions. The highest frequency of NTRK gene fusions was head and neck cancer (1.31%) and thyroid cancer (1.31%), followed by soft tissue sarcoma (STS; 0.91%). A total of 97 NTRK fusion gene partners were analyzed involving mainly NTRK1 (49.5%) or NTRK3 (44.2%) gene fusions. The only fusion gene detected in head and neck cancer was ETV6::NTRK3 (n = 22); in STS, ETV6::NTRK3 (n = 7) and LMNA::NTRK1 (n = 5) were common. Statistically significant mutual exclusivity of NTRK fusions with alterations was confirmed in TP53, KRAS, and APC. NTRK gene fusion was detected from 11 STS cases: seven unclassified sarcoma, three sarcoma NOS, and one Ewing sarcoma. NTRK gene fusion identification in solid tumors enables accurate diagnosis and potential TRK inhibitor therapy.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

The evolving landscape of tissue-agnostic therapies in precision oncology.

Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.

Neonatal spindle-cell CD34-positive plaque-like tumour: a new entity characterised by NTRK gene fusion.

Neonatal spindle-cell CD34-positive plaque-like tumour: a new entity characterised by NTRK gene fusion.

NTRK3-Rearranged Prostatic Acinar Adenocarcinoma: Report of a Patient and Review of the Literature.

Molecular investigations have led to increased therapeutic options for prostatic adenocarcinoma. A single case report of a PRPSAP1::NTRK3 gene fusion occurring in prostate cancer was previously reported. A review of the literature revealed that NTRK gene rearrangements are exceedingly rare molecular events in prostate cancer. NTRK gene fusions can be oncogenic drivers or develop as resistance mechanisms. The tumor-agnostic approvals of TRK inhibitors by the FDA provide additional rationale for molecular investigations of aggressive prostatic adenocarcinomas. This may prove to be an additional therapeutic option for patients with aggressive prostatic carcinomas refractory to initial therapy. We report a case of an aggressive castrate-resistant prostatic adenocarcinoma with a BMP6::NTRK3 gene fusion.

Pan-TRK immunohistochemistry as a tool in the screening for NTRK gene fusions in cancer patients

Therapy with TRK inhibitors is a tumor-agnostic treatment directed against specific molecular changes rather than cancer type. NTRK fusions are rare in most prevalent cancers, accounting for less than 0.5% of cases. However, there is a group of rare cancers in which NTRK fusion is more prevalent. These include secretory carcinoma of the breast and salivary gland, childhood sarcomas, such as infantile fibrosarcoma, and cellular and mixed congenital mesoblastic nephroblastoma. The most common rearrangement pertains to NTRK3 and the most common fusion gene is ETV6 . Identifying patients with NTRK gene fusions who would likely benefit from targeted therapy with TRK inhibitors requires practical diagnostic tools and an appropriate management strategy of diagnostic trajectory. The fusions can be detected by molecular biology techniques or pan-TRK immunohistochemistry. The latter detects NTRK1/2/3 gene fusions independently of the resulting fusion gene but does not determine which of them has been rearranged or what the fusion partner is. The sensitivity and specificity of the method reach 97% and 100%, respectively. Other advantages include the relatively low cost, short duration of examination, and broad accessibility of immunohistochemistry laboratories. These characteristics make this method a useful screening tool for detecting patients with NTRK gene fusions.