Dataset Information

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

ABSTRACT: The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ?20?000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

SUBMITTER: Yan W

PROVIDER: S-EPMC7875308 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

Yan Wei W Lakkaniga Naga Rajiv NR Carlomagno Francesca F Santoro Massimo M McDonald Neil Q NQ Lv Fengping F Gunaganti Naresh N Frett Brendan B Li Hong-Yu HY

Journal of medicinal chemistry 20180919 4

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase ...[more]

PMID: 30188734

Similar Datasets

Project description:Abstract Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. Methods Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. Conclusions In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.

Project description:Abstract BACKGROUND TRK fusion proteins are oncogenic drivers of various CNS and non-CNS tumors. Larotrectinib, a highly selective FDA- and EMA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various non-CNS cancers (Hong et al. Lancet Oncol. 2020). We report data in an expanded set of TRK fusion primary CNS tumors treated with larotrectinib. METHODS Patients with primary CNS tumors harboring an NTRK gene fusion treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Disease status was investigator-assessed (RANO). Data cutoff: July 15, 2019. RESULTS Twenty-four patients with TRK fusion primary CNS tumors were identified. Eighteen patients had gliomas (13 high-grade and five low-grade). Median age was 8.0 years (range 1.3–79.0), with 20 patients < 18 years old. ORR was 29% (95% CI 13–51%); best responses were two complete responses, five partial responses (two pending confirmation), 15 stable disease, and two progressive disease. The 24-week disease control rate was 63% (95% CI 41–81%). For the five confirmed responders, median time to best response was 1.8 months and median duration of response was 4.9 months (range 1.7+ to 10.1+). Median progression-free survival was 11.0 months (range 1.1 to 19.8+) and median overall survival was not reached (range 1.9+ to 21.4+) at a median follow-up of 6.0 months. Treatment duration ranged from 1.2 to 21.4+ months; three patients continued treatment beyond progression. Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2. Grade 3–4 TEAEs occurred in 10 patients, with two deemed related to larotrectinib. The most common neurological TEAE was headache in three patients (Grade 1–2). No patients discontinued larotrectinib due to AEs. CONCLUSIONS Larotrectinib was active and well tolerated in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with primary CNS tumors.

Project description:Abstract INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumours. Larotrectinib, a highly selective TRK inhibitor, demonstrated an objective response rate (ORR) of 75% across 206 evaluable patients with various non-primary CNS cancers (Hong et al, ASCO 2021). We report long-term data on larotrectinib-treated paediatric patients with TRK fusion-positive primary CNS tumours. METHODS: Patients aged <18 years with TRK fusion-positive primary CNS tumours enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg/m2 (maximum: 100 mg) twice-daily. Response was investigator-assessed per RECIST v1.1 and RANO. RESULTS: As of July 2021, 28 patients with TRK fusion-positive primary CNS tumours were enrolled, including 14 high-grade and eight low-grade gliomas. Median age at enrolment was 7.0 years (range 1.0–17.0). Twenty-three patients (82%) received prior systemic therapy and 12 (43%) received prior radiotherapy. The ORR was 39% (95% confidence interval [CI] 22–59): three complete responses, eight partial responses, 15 stable disease and two progressive disease. The 24-week disease control rate was 82% (95% CI 63–94). Median duration of response (DoR) was not reached; median follow-up was 25.6 months. Median progression-free survival was 21.9 months (95% CI 9.2–not estimable). Median overall survival (OS) was not reached; median follow-up was 27.6 months. DoR and OS 24-month rates were 53% and 71%, respectively. Treatment duration ranged from 1.0 to 39.0+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. Grade 3–4 events occurred in three patients (increased gamma-glutamyltransferase, hyperglycaemia, hypernatraemia, hyponatraemia and neutropaenia). No patients discontinued treatment due to TRAEs. Fourteen patients progressed on treatment; four continued treatment post-progression for ≥4 weeks. CONCLUSION: Larotrectinib demonstrated high disease control rate, durable responses and a manageable safety profile. These results support testing for NTRK gene fusions in paediatric patients with primary CNS tumours.

Dataset Information

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

Publications

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets