NTRK

  • Neurotrophic tropomyosin kinase receptors (NTRK)

NTRK Biology

  • Neurotrophic tropomyosin kinase receptors (NTRK) are transmembrane kinases involved in neural cells’ development, proliferation, and survival.1-3
  • After localization to cell membranes, the protein family is activated by nerve growth factor (NGF) ligands, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4, and NT-5.1,3,4
  • The TRK family consists of 3 members, including TKRA, TKRB, and TRKC and activation of these proteins leads to downstream activation of the signal pathways RAS-RAF-MEK-ERK, phosphatidylinositol-3 (PI3) kinase, and phospholipase C gamma (PLC-γ).3,4

Etiology and Epidemiology

  • NTRK genes are proto-oncogenes that activate into oncogenic driver mutations via gene fusions that lead to chimeric TRK proteins.1,3,4
  • The prevalence of NTRK gene fusions is approximately 1% in solid tumors, but there is a lack of data regarding the prevalence in gastroesophageal cancer.1
  • NTRK gene fusions occur through chromosome rearrangements, point mutations, deletions, or gene fusions and cause spontaneous ligand-independent dimerization.3
  • These chimeric proteins have constitutive TRK protein activity or overexpression of the kinase function.4
  • Current research suggests that oncogenic mutations cause a change exclusively in the extracellular domain of chimeric proteins, suggesting a common regulatory domain.3

Testing for NTRK Gene Fusions

  • When to Test: Patients with gastric cancer should undergo testing for NTRK gene fusions and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.5
  • Available Testing Methods: Feasible testing methods include immunohistochemistry (ICH), fluorescence in situ hybridization (FISH), DNA-based next-generation sequencing, and RNA-based NGS.2,4 The ideal approach appears to be RNA-based NGS because of the higher rates of false positives and lack of evidence of functional transcription present in other methods.1,5
  • Guideline Recommendations for Testing: Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include HER2 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, NTRK fusion, RET fusion, and BRAF V600E mutation.5

NTRK-Targeted Therapy

  • Approved Agents: Currently, 2 FDA-approved options exist for treating unresectable or metastatic NTRK gene fusion–positive solid tumors.5-7 Larotrectinib and entrectinib are recommended as second- or subsequent-line treatments in NTRK+ patients. Their favorable safety profile and clinically meaningful response support regular screening for gene fusions.5-7 Approval for larotrectinib was based on the data from 3 trials, LOCO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).5,7,8 The overall response rate in 55 patients was 75% (95% CI, 61-85), 71% of responses remained ongoing at 1 year, and 55% remained progression-free at 1 year.5,7,8 Entrectinib approval was based on data from the trials STARTRK-2 (NCT02568267) and STARTRK-1 (NCT02097810), and ALKA-372-001.5,6,9 The study population comprised 54 adults with an overall response rate of 57% (95% CI, 43-71), progression-free survival 11.2 months (95% CI, 8.0-14.9), and overall survival 20.9 (95% CI, 14.9-NR).5,7,9
  • Mechanism of Action: Larotrectinib and entrectinib are tyrosine kinase inhibitors specifically targeting TRKA, TRKB, and TRKC, anaplastic lymphoma kinase (ALK), and the proto-oncogene tyrosine-protein kinase 1 (ROS1).6,7

Learn more about Entrectinib >

Learn more about Larotrectinib >

References

  1. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Annals of Medicine & Surgery. 2022;79:103893. doi:10.1016/j.amsu.2022.103893
  2. Solomon JP, Hechtman JF. Detection of NTRK fusions: merits and limitations of current diagnostic platforms. Cancer Res. 2019;79(13):3163-3168. doi:10.1158/0008-5472.CAN-19-0372
  3. Lange A, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers. 2018;10(4):105. doi:10.3390/cancers10040105
  4. Arnold A, Daum S, Von Winterfeld M, et al. Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry. Pathology - Research and Practice. 2019;215(11):152662. doi:10.1016/j.prp.2019.152662
  5. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: gastric cancer. May 29, 2024. Accessed May 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  6. ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf
  7. VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf
  8. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
  9. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2018;29(suppl 8):viii713. doi:10.1093/annonc/mdy424.017