Tumours Harbouring NTRK Gene Fusions Research Articles

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas.

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. Patients (≥18years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. 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. 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. 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.

Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

Diagnostic testing approaches for the identification of patients with TRK fusion cancer prior to enrollment in clinical trials investigating larotrectinib

IntroductionNTRK gene fusions are targetable oncogenic drivers independent of tumor type. Prevalence varies from highly recurrent in certain rare tumors to <1% in common cancers. The selective TRK inhibitor larotrectinib was shown to be highly active in adult and pediatric patients with tumors harboring NTRK gene fusions. MethodsWe examined the techniques used by local sites to detect tumor NTRK gene fusions in patients enrolled in clinical trials of larotrectinib. We also report the characteristics of the detected fusions in different tumor types. ResultsThe analysis included 225 patients with 19 different tumor types. Testing methods used were next-generation sequencing (NGS) in 196 of 225 tumors (87%); this was RNA-based in 96 (43%); DNA-based in 53 (24%); DNA/RNA-based in 46 (20%) and unknown in 1 (<1%); FISH in 14 (6%) and PCR-based in 12 (5%). NanoString, Sanger sequencing and chromosome microarray were each utilized once (<1%). Fifty-four different fusion partners were identified, 39 (72%) of which were unique occurrences. ConclusionsThe most common local testing approach was RNA-based NGS. Many different NTRK gene fusions were identified with most occurring at low frequency. This supports the need for validated and appropriate testing methodologies that work agnostic of fusion partners.

Investigating the natural history and prognostic nature of NTRK gene fusions in solid tumors.

Several TRK inhibitors have demonstrated clinical efficacy in patients with solid tumors harboring NTRK gene fusions. However, the natural history and prognostic implications of NTRK fusions in solid tumors remain unknown. A cohort of 77 MD Anderson Cancer Center patients (MDACC) with NTRK gene fusions was identified and retrospectively compared to a second cohort from the Cancer Genome Atlas (TCGA) database. Due to paucity of events in early stage cancers and lack of TCGA data in rare tumors, 25 randomly selected MDACC patients were matched to 122 TCGA patients without NTRK gene fusion. Next we assessed the associations between NTRK gene fusion and overall (OS) and progression-free survivals (PFS). Among the 77 MDACC patients with NTRK gene fusions, 18 NTRK fusion partners were identified. There were insufficient OS events for analysis in the matched cohort. PFS was not significantly different (p = 0.49) between the NTRK-fusion positive MDACC patients (median PFS 786weeks, 95% CI 317-NE) and the NTRK-fusion negative TCGA patients (median PFS NE). The adjusted hazard ratio comparing TCGA patients to MDACC patients was HR = 0.72 (95% CI: 0.23-2.33), which trended towards a reduced rate of progression or death experienced by TCGA patients. This study did not identify statistically significant associations between NTRK fusion and PFS. Nonsignificant trends estimated increases in the risk of progression or death events for patients with NTRK fusions when compared to matched controls. Our findings help illuminate the influence of NTRK fusions on the natural history of a variety of solid tumors.

Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer.

Chromosomal rearrangements of NTRK1-3 resulting in gene fusions (NTRK gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically, NTRK gene fusions involve both inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of NTRK genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of NTRK gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers. Two small-molecule TRK inhibitors have recently received regulatory approval for the treatment of patients with solid tumors harboring NTRK gene fusions, including the selective TRK inhibitor larotrectinib and the TRK/ROS1/ALK multikinase inhibitor entrectinib. In this review, we consider the practicalities of detecting tumors harboring NTRK gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.

EPCT-08. ACTIVITY OF LAROTRECTINIB IN PEDIATRIC TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

BACKGROUNDTRK fusions are oncogenic drivers in a variety of tumors, many involving the CNS. Larotrectinib, a selective FDA- and EMA-approved TRK inhibitor, demonstrated a 79% objective response rate (ORR) and a 35.2-month median duration of response (DoR) in adult and pediatric patients with various non-CNS solid tumors harboring NTRK gene fusions. We report the clinical activity of larotrectinib in pediatric patients with primary TRK fusion CNS tumors.METHODSPatients aged <18 years with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO).RESULTSAs of February 2019, 14 pediatric patients with primary TRK fusion CNS tumors were identified. Gene fusions involved NTRK2 (n=10), NTRK1 (n=2), and NTRK3 (n=2). Median age was 7.0 years (range 1.3–16.7). ORR was 45% (95% CI 17–77%) among 11 evaluable patients. Two patients had complete responses (pending confirmation), three had confirmed partial responses, and six had stable disease. 24-week disease control rate was 73%. DoR ranged from 2.6+ to 5.5+ months and progression-free survival ranged from 0.03+ to 13.9+ months. Duration of treatment ranged from 0.03+ to 16.6+ months. Treatment-emergent adverse events were mainly grade 1–2.CONCLUSIONSLarotrectinib resulted in objective responses and durable disease control in pediatric patients with primary TRK fusion CNS tumors. These results support expanded testing for NTRK gene fusions in patients with CNS tumors.

First-time in-human study of VMD-928, an allosteric and irreversible TrkA selective inhibitor, in patients with solid tumors or lymphoma.

TPS3146 Background: Tropomysin receptor kinase A (TrkA) is a protein encoded by the NTRK1 gene. NTRK fusions involving the kinase domain are oncogenic for multiple tumor types and larotrectinib was recently approved for advanced solid tumors harboring NTRK gene fusions. Larotrectinib, an ATP-competitive, reversible pan-TrkA/B/C inhibitor, has shown impressive response rates in patients harboring these fusions; however, resistance can develop due to acquired ATP-site mutations. This has been previously identified in other oncogenic driver kinases such as ALK and EGFR treated with ATP-competitive kinase inhibitors. A newly approved allosteric ALK/EGFR inhibitor brigatinib was able to clinically overcome acquired resistance of many ATP-competitive ALK/EGFR inhibitors (1). Also, irreversible EGFR inhibitors such as afatinib (ATP-competitive) were active against tumors resistant to first-generation inhibitors (2), although their efficacy can be compromised by acquired ATP-site mutations (3). VMD-928 is the first oral small-molecule TrkA (NTRK1) selective inhibitor with dual allosteric and irreversible mechanisms of action. It inhibits TrkA non-competitively at an allosteric (non-ATP) site and has no resistance in vitro to acquired ATP-site mutations such as G667C. VMD-928 in vitro has little or no activity against 348 other kinases including TrkB (NTRK2) and TrkC (NTRK3). We are conducting the first time in human phase 1 trial of oral VMD-928, a novel allosteric and irreversible TrkA selective inhibitor. Methods: This is an open label, Phase 1 study investigating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral VMD-928 in adults with advanced solid tumors or lymphoma (NCT03556228). In part 1 of the study, an accelerated titration scheme will be utilized to determine the recommended phase 2 dose and evaluate PK / PD of VMD-928. In part 2, expansion cohorts including patients with thymic, pancreatic, triple-negative breast carcinoma, or solid tumors with TrkA alterations will be accrued to further evaluate safety and efficacy. Part 3 of the study will characterize the biologically active dose. The study is open and accruing patients at City of Hope. Clinical trial information: NCT03556228.

Antitumor activity of larotrectinib in tumors harboring NTRKgene fusions: a short review on the current evidence.

The development of deep-sequencing methods is now unveiling a new landscape of previously undetected gene fusion across different tumor types. Chromosomal translocation involving the NTRK gene family occur across a wide range of cancers in both children and adults. Preclinical studies have demonstrated that chimeric proteins encoded by NTRK rearrangements have oncogenic properties and drive constitutive expression and ligand-independent activation. Larotrectinib (ARRY470, LOXO101, Vitrakvi) is a highly and potent inhibitor of TRKA, TRKB, and TRKC, and has demonstrated rema rkable antitumor activity against TRK-fusion-positive cancers with a favorable side-effect profile in phase I/II clinical trials. In November 2018, the US Food and Drug Administration granted accelerated approval to larotrectinib for adult and pediatric patients with solid tumors harboring NTRK gene fusions without known acquired resistance mutation. In this review, we discuss the clinical activity and safety profile of larotrectinib, focusing on the clinical trials that led to its first global approval.

TRK Inhibition: A New Tumor-Agnostic Treatment Strategy

Oncogenic somatic chromosomal rearrangements involving the NTRK1, NTRK2 or NTRK3 genes (NTRK gene fusions) occur in up to 1% of all solid tumors, and have been reported across a wide range of tumor types. The fusion proteins encoded by such rearranged sequences have constitutively activated TRK tyrosine kinase domains, providing novel therapeutic anticancer targets. The potential clinical effectiveness of TRK inhibition in patients with tumors harboring NTRK gene fusions is being assessed in phase I and II trials of TRK inhibitors, such as larotrectinib and entrectinib. Clinical trial results have demonstrated that larotrectinib is generally well tolerated and has shown high response rates that are durable across tumor types. These data validate NTRK gene fusions as actionable genomic alterations. In this review, we present the clinical data, discuss the different approaches that might be used to routinely screen tumors to indicate the presence of NTRK gene fusions, explore the issue of acquired resistance to TRK inhibition, and reflect on the wider regulatory considerations for tumor site agnostic TRK inhibitor drug development.

Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3-13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. Loxo Oncology Inc.