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

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

NTRK Testing

Per the National Comprehensive Cancer Network guidelines, comprehensive genomic profiling should be considered rather than sequential testing of single biomarkers to avoid exhausting the tissue sample.5 The initial testing modality should be immunohistochemistry, in situ hybridization, or targeted polymerase chain reaction (PCR) assay.5 The treating physician can also consider a validated next-generation sequencing assay performed in a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory.5

NTRK-Targeted Therapy

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

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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.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
  7. VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.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