Neurotrophic Tropomyosin Receptor Kinase Research Articles

BPI-28592 as a novel second generation inhibitor for NTRK fusion tumors

Aberrant activation of tropomyosin receptor kinases (TRKs) is a well-defined oncogenic driver for neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers, and acquired resistant mutations have emerged with clinical use of the first-generation TRK inhibitors. Here we present BPI-28592, a novel second-generation TRK inhibitor with efficacy against TRK fusion-positive cancers, including those with resistant mutations. Docking simulations indicated no steric hindrance between BPI-28592 and TRK mutants, suggesting its potential to overcome drug resistance. Biochemical assays showed strong inhibition and high selectivity against TRKA, TRKB, and TRKC. The inhibitor significantly reduced cell proliferation and blocked TRK signaling. In vivo studies demonstrated effective tumor suppression in xenograft models harboring TRK fusions with or without resistant mutations. Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).

New systemic treatment options for advanced cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

The mutual interplay between NTRK fusion genes and human papillomavirus infection in cervical cancer progression (Review).

Cervical cancer is a significant global health concern, with a substantial portion of cases attributed to human papillomavirus (HPV) infection. Recent advancements in molecular profiling have identified distinct subtypes of cervical cancer based on their genomic alterations. One such subgroup is neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cervical cancers, characterized by gene fusions involving the NTRK genes. Although both NTRK fusion genes and HPV infections are independently recognized as significant risk factors in cervical cancer, their interplay and mutual effects on cancer progression are not yet fully understood. The present review is the first of its kind to explore the potential interplay between NTRK fusion genes and HPV infections. It surveys in detail how their combined effect can influence the signaling pathways during cervical cancer development and progression. Moreover, the present study discussed the clinical features, histopathological examinations, treatment procedures and follow-up outcomes of NTRK-fusion gene-positive cervical cancer. The present review may help in the understanding of the management and treatment of such rare, lethal and resistant cervical cancers.

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.

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood–brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1–15 years) and six adults (aged 27–72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

TRLS-09. CONNECT1903: A PILOT AND SURGICAL STUDY OF LAROTRECTINIB FOR TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED HGG WITH NTRK FUSION (NCT04655404)

Abstract BACKGROUND Recurrent fusions in neurotrophic tropomyosin-receptor kinase genes NTRK 1-3 are found in variety of cancers, including pediatric HGG: DIPG (~4%) and non-brainstem HGG (~10%). For non-brainstem HGG seen in children <3 years of age, approximately 40% harbor NTRK alterations. NTRK fusions provide a promising target for gliomas and to that end, Larotrectinib, a globally approved, highly potent, small molecule inhibitor of TRKA/B/C, has previously been investigated and has shown tolerability and efficacy in children with recurrent solid tumors. Compassionate use in a case of infantile GBM showed proof-of-concept with blood-brain penetrance and efficacy. Further evidence of efficacy in two earlier clinical trials has also been previously demonstrated in children with recurrent TRK-fusion primary intracranial tumors (NCT02637687, NCT02576431). METHODS This international trial conducted through the CONNECT consortium, supported in part by Bayer, investigates larotrectinib monotherapy; its feasibility and tolerability in combination with standard systemic chemotherapy (Baby POG or HIT-SKK) or radiation therapy whereby treatment plan determination is response-based. Objectives include: to assess disease control rate (CR, CCR, PR and SD) after two cycles of larotrectinib monotherapy (28-day cycles); to assess feasibility and to describe toxicities of larotrectinib in combination with standard chemotherapy; to assess objective response rate (CR and PR); to assess OS and PFS as compared to historical data from Baby POG, HIT-SKK and radiotherapy. A phase 0 surgical cohort will be explored whereby patients who are planned to undergo a definitive resection will receive pre-surgery larotrectinib, and target inhibition, intratumoral and plasma pharmacokinetics will be investigated. Radiographic responses will also be quantitated. This trial is currently open to accrual at ten CONNECT sites across North America and Australia and has enrolled five patients to date. Sites in UK, Germany and Netherlands are pending activation. A total of 15 patients are anticipated to be enrolled and evaluable.

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.

Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway.

A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Prevalence of NTRK gene fusions in solid tumors in northeastern Mexico.

e15145 Background: Gene fusions (GF) are among the intricate hallmarks of cancer that lead to abnormal cell proliferation and survival. Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are frequent in rare solid tumors but less frequent in common ones. Scarce literature has evaluated the prevalence of this aberration estimated to be from 0.5 to 1% globally. For these particular type of tumors, multikinase inhibitors is an option aside from chemotherapy with good responses. Objective: To determine the prevalence of NTRK gene fusions in a Mexican population. Methods: Sociodemographic, clinical, and histopathological data were collected in a single center from databases of Pathology and Oncology Departments of Hospital Universitario Dr. José E. González in Northeastern Mexico. Patients of all ages with solid tumors were included if tested positive for Pan-TRK by immunohistochemistry (IHC). Confirmation for gene fusion was made using Next Generation Sequencing (NGS) technology in formalin-fixed paraffin-embedded tissue. Results: A total of 156 patients from 2021 to 2023 were included for analysis. 67 (42.9%) did test positive for IHC. Of these, 52.2% were male and 20.8% were pediatric. Adult and pediatric median age of 57 and 13 years, respectively. Most frequent tumors locations were central nervous system &amp; extremities. Gene fusion anomaly was confirmed in 6 patients. Among these, 83.3% were male and 16.7% pediatric population. Only NTRK1 and NTRK3 were found in gene fusions. Four translocations were prevalent TPM3:NTRK1 and ETV6:NTRK3 with 2 cases (33.3%), respectively. Followed by LMNA:NTRK1 and EML4:NTRK3 each with one patient. For location, arranged in descending order, head and neck (33.3%), extremities (33.3%), central nervous system and occult primary tumors both 16.6%. The only non-adult tumor reported was infantile fibrosarcoma. Prevalence was estimated to be 3.8% in our population. Conclusions: Understanding the molecular biology of tumor cells enables the development of targeted treatments other than chemotherapy. In our population, NTRK gene fusions were a little more prevalent (~4%) than global estimation. Unfortunately, in Mexico there's a lack of access to multikinase inhibitors. Further studies with large samples are required in Mexico and all over the world to afford access to these tumor-agnostic therapies.

Novel therapeutic strategies for rare mutations in non-small cell lung cancer

Lung cancer is still the leading cause of cancer-related mortality. Over the past two decades, the management of non-small cell lung cancer (NSCLC) has undergone a significant revolution. Since the first identification of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin receptor kinase (NTRK) and hepatocyte growth factor receptor (MET), have been found. With the development of gene sequencing technology, the development of targeted drugs for rare mutations, such as multikinase inhibitors, has provided new strategies for treating lung cancer patients with rare mutations. Patients who harbor this type of oncologic driver might acquire a greater survival benefit from the use of targeted therapy than from the use of chemotherapy and immunotherapy. To date, more new agents and regimens can achieve satisfactory results in patients with NSCLC. In this review, we focus on recent advances and highlight the new approval of molecular targeted therapy for NSCLC patients with rare oncologic drivers.

Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

Current Status of Targeted Therapy for Biliary Tract Cancer in the Era of Precision Medicine.

First-line chemotherapy has been established for advanced biliary tract cancer (BTC). However, few treatment options are available as second-line treatment. Advances in comprehensive genomic analysis revealed that nearly half of patients with BTC harbor targetable genetic alterations such as fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), BRAF, human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI)-high, neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), and poly (adenosine diphosphate-ribose) polymerase (PARP). This review summarizes currently available options in precision medicine and clinical trials for patients with advanced BTC.

Disseminated juvenile xanthogranulomas with underlying neurotrophic tyrosine receptor kinase fusion and response to larotrectinib.

Recent molecular characterizations of histiocytoses, including juvenile xanthogranuloma (JXG), have identified diverse kinase gene mutations, suggesting that various targeted therapies may be promising treatments for these lesions. We herein present a case of an infant with disseminated JXG lesions with an underlying NTRK mutation who was successfully treated with larotrectinib.

Fusion Oncogenes in Patients With Locally Advanced or Distant Metastatic Differentiated Thyroid Cancer.

Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. We aimed to investigation between fusion oncogenes and clinicopathological characteristics involving a large-scale cohort of patients with advanced DTC. We collected 278 tumor samples from patients with locally advanced (N1b or T4) or distant metastatic DTC. Targeted next-generation sequencing with a 26-gene ThyroLead panel was performed on these samples. Fusion oncogenes accounted for 29.86% of the samples (72 rearrangement during transfection (RET) fusions, 7 neurotrophic tropomyosin receptor kinase (NTRK) fusions, 4 anaplastic lymphoma kinase (ALK) fusions) and occurred more frequently in pediatric patients than in their adult counterparts (P = .003, OR 2.411, 95% CI 1.329-4.311) in our cohort. DTCs with fusion oncogenes appeared to have a more advanced American Joint Committee on Cancer (AJCC)_N and AJCC_M stage (P = .0002, OR 15.47, 95% CI 2.54-160.9, and P = .016, OR 2.35, 95% CI 1.18-4.81) than those without. DTCs with fusion oncogenes were associated with pediatric radioactive iodine (RAI) refractoriness compared with those without fusion oncogenes (P = .017, OR 4.85, 95% CI 1.29-15.19). However, in adult DTCs, those with fusion oncogenes were less likely to be associated with RAI refractoriness than those without (P = .029, OR 0.50, 95% CI 0.27-0.95), owing to a high occurrence of the TERT mutation, which was the most prominent genetic risk factor for RAI refractoriness in multivariate logistic regression analysis (P < .001, OR 7.36, 95% CI 3.14-17.27). Fusion oncogenes were more prevalent in pediatric DTCs than in their adult counterparts and were associated with pediatric RAI refractoriness, while in adult DTCs, TERT mutation was the dominant genetic contributor to RAI refractoriness rather than fusion oncogenes.

Neurotrophic tropomyosin receptor kinase (NTRK) fusion positive tumors: a historical cohort analysis

ABSTRACT Background NTRK gene fusions have been identified in various tumors; some requiring aggressive therapy and sometimes new TRK inhibitors (TRKi). We aimed to describe a national, unselected, retrospective, multicenter cohort. Research design and methods Patients were identified through the French sarcoma diagnostic laboratory at Institut Curie through samples analyzed by RT-qPCR or whole-transcriptome sequencing. Results From 2001 to 2019, 65 NTRK fusion tumors were identified within 2120 analyses (3.1%): 58 by RNA sequencing (including 20 after RT-qPCR analysis) and 7 exclusively by RT-qPCR. Of the 61 patients identified, 37 patients had infantile soft tissue or kidney fibrosarcomas (IFS), 15 other mesenchymal (Other-MT) and nine central nervous system (CNS) tumors. They encompassed 14 different tumor types with variable behaviors. Overall, 53 patients had surgery (3 mutilating), 38 chemotherapy (20 alkylating agents/anthracycline), 11 radiotherapy, two ‘observation strategy’ and 13 received TRKi. After a median follow-up of 61.0 months [range, 2.5–226.0], 10 patients died. Five-year overall survival is, respectively, 91.9% [95%CI, 83.5–100.0], 61.1% [95%CI, 34.2–100.0] and 64.8% [95%CI, 39.3–100.0] for IFS, Other-MT, and CNS groups. Conclusions NTRK-fusion positive tumors are rare but detection is improved through RNA sequencing. TRKi could be considered at diagnosis for CNS NTRK-fusion positive tumors, some IFS, and Other-MT. Trial Registration Not adapted.

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer.

We performed a retrospective analysis to determine the incidence of neurotrophic tropomyosin-receptor kinase (NTRK) fusion in non-small cell lung cancer (NSCLC). Archival NSCLC tissues between 2018-2020 were screened by immunohistochemistry (IHC) with IHC-positive cases undergoing confirmatory molecular analysis. Correlative clinicopathologic parameters were collected. Of 289 samples analyzed, 10 (3.5%) cases had NTRK expression on IHC. The median age of patients with NTRK-positivity on IHC was 74.9 (range, 44-88) years and 70% had a smoking history. The cohort included seven adenocarcinomas and one each squamous cell carcinoma, large-cell neuroendocrine and not otherwise specified histologies. PDL1 expression was ≤50% in five cases. Concurrent EGFR mutations were detected in three cases, with two cases also showing a PIK3CA E542K mutation and MET amplification, respectively. Due to insufficient tumor material, RNA-sequencing was undertaken in only one IHC-positive case, with the other nine cases analyzed by Fluorescent in-situ Hybridisation. A NTRK fusion, EML4-NTRK3 gene fusion was detected in one patient, a frequency of 0.35%. NTRK fusions in NSCLC are rare. This study highlights real world diagnostic challenges regarding NTRK testing, such as requirements of adequate tumor tissue and appropriate testing methodologies.

Efficient Identification of Patients With NTRK Fusions Using a Supervised Tumor-Agnostic Approach.

The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a "tumor-agnostic" manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm. To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions. A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward. Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.

China special issue on gastrointestinal tumors-NTRK fusion in a large real-world population and clinical utility of circulating tumor DNA genotyping to guide TRK inhibitor treatment.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers and targets of TRK inhibitors in solid tumors. Little is known about NTRK fusion in Chinese patients with pan-cancer. Our study investigated the prevalence and genomic features of NTRK1/2/3 gene fusions in 67 883 Chinese patients with pan-cancer using next-generation sequencing (NGS) data and circulating tumor DNA (ctDNA) NGS to guide TRK inhibitor treatment and resistance monitoring. The prevalence of NTRK fusion (tissue NGS) in the pan-cancer population was 0.18%, with 46 unique NTRK-fusion partner pairs, of which 33 were not previously reported. NTRK2 breakpoint occurred more frequently in intron 15 than intron 12. In colorectal cancers (CRCs), compared to NTRK-negative tumors, NTRK-positive tumors displayed higher tumor mutational burden (TMB) levels (54.6 vs 17.7 mut/Mb, P < .0001). In microsatellite instability-high (MSI-H) CRC, patients with NTRK fusion had a significantly lower TMB than NTRK-negative cases (69.3 vs 79.9 mut/Mb, P = .012). The frequency of NTRK fusion in a ctDNA NGS cohort of 20 954 patients with cancer was similar to that of the tissue NGS cohort. In eight NTRK fusion ctDNA-positive patients, larotrectinib induced objective response in 75% of patients and median progression-free survival was 16.3 months. Blood samples collected from a patient with disease progression after larotrectinib treatment revealed NTRK3 G623R as the potential resistance mechanism. Our study revealed previously unreported NTRK fusion partners, associations of NTRK fusion with MSI and TMB, and the potential utility of ctDNA to screen candidates for TRK inhibitors and monitor drug resistance.

Targeted therapy using larotrectinib and venetoclax for the relapsed/refractory T-cell acute lymphoblastic leukemia harboring a cryptic ETV6-NTRK3 fusion.

Outcomes for patients with relapsed and refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are dismal, with few available treatments. Recently, identification of cancer patients harboring neurotrophic tropomyosin receptor kinase (NTRK) gene fusions is constantly increasing, especially with the advent of NTRK inhibitors. However, the role of ETV6-NTRK3 in T-ALL has not been investigated. This case represented the first detailed report of T-ALL patient harboring a cryptic ETV6-NTRK3 fusion with an unfavorable prognosis, not only because of leukemia resistant to the standard multiagent chemotherapy but also early relapse after allo-HSCT. Acquired EP300 mutation was found at relapse, which could explain the cause of recurrence and affect the follow-up treatment. Combined targeted therapy like larotrectinib allied with pan-targeted BCL-2 inhibitor venetoclax, may be a potential maintenance treatment in R/R ETV6-NTRK3 positive leukemia after allo-HSCT. The leukemic clonal evolution might be revealed through transcriptome sequencing and overcome by drugs with universal targets. Our case demonstrated that both comprehensive profiling techniques (such as transcriptome sequencing, multiparameter flow cytometry, and digital droplet polymerase chain reaction) and a multimodality treatment strategy were critical for anticipating an early relapse and personalized therapy of R/R T-cell leukemia.

Evolution of the Targeted Therapy Landscape for Cholangiocarcinoma: Is Cholangiocarcinoma the 'NSCLC' of GI Oncology?

In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized. In 2019, a fibroblast growth factor receptor 2 (FGFR2) inhibitor, pemigatinib, was the first approved targeted therapy for patients with locally advanced or metastatic intrahepatic CCA who had FGFR2 gene fusions or rearrangement. More regulatory approvals for matched targeted therapies as second-line or subsequent treatments in advanced CCA followed, including additional drugs that target FGFR2 gene fusion/rearrangement. Recent tumor-agnostic approvals include (but are not limited to) drugs that target mutations/rearrangements in the following genes and are hence applicable to CCA: isocitrate dehydrogenase 1 (IDH1); neurotrophic tropomyosin-receptor kinase (NTRK); the V600E mutation of the BRAF gene (BRAFV600E); and high tumor mutational burden, high microsatellite instability, and gene mismatch repair-deficient (TMB-H/MSI-H/dMMR) tumors. Ongoing trials investigate HER2, RET, and non-BRAFV600E mutations in CCA and improvements in the efficacy and safety of new targeted treatments. This review aims to present the current status of molecularly matched targeted therapy for advanced CCA.