NTRK

  • Neurotrophic tropomyosin kinase receptors (NTRK)

NTRK Biology

  • Neurotrophic tropomyosin kinase receptors (NTRK) are a family of transmembrane proteins involved in neuronal development, proliferation, survival, and differentiation.1,2
  • The genes NTRK1, NTRK2, and NTRK3 encode the proteins TRKA, TRKB, and TRKC, respectively.1–3
  • TRK proteins are activated via neurotrophin ligands that trigger receptor dimerization and phosphorylation.3
  • After activation, TRK proteins active signal transduction pathways RAS-RAF-MEK-ERK (MAPK), phosphatidylinositol-3-kinase (PI3K), phospholipase C-γ1, and others.1–3

Etiology and Epidemiology

  • NTRK is a driver oncogene that promotes tumorigenesis via constitutive expression or increased kinase domain activity.1,3,4
  • Gene fusions involve one of the three NTRK genes fusing the c-terminal with an n-terminal fusion partner, resulting in a chimeric protein that promotes solid tumor growth.4
  • NTRK gene fusion mutations are rarely present in cancers (<1%) and have a similarly low prevalence in pancreatic cancer (0.34-0.8%).2,4,5

NTRK Testing

When to Test:

  • Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy6

Available Testing Methods:

  • Testing can be performed via immunohistochemistry (IHC) or via an FDA-approved or validated next-generation sequencing (NGS) assay; RNA assays are preferred over DNA assays for gene fusion detection.6
  • It has been suggested that if immunohistochemistry (IHC) is used to detect NTRK gene fusions, then positive samples should be confirmed with RNA-NGS.4

Testing Guideline Recommendations:

  • For patients with locally advanced or metastatic disease eligible for anticancer therapy, the NCCN Panel recommends testing for actionable somatic mutations, including fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET), mutations (BRAF, BRCA1/2, HER2, KRAS, PALB2), amplifications (HER2), MSI, dMMR, and TMB.6

NTRK Targeted Therapy

Approved Agents:

  • Larotrectinib and entrectinib are the two drugs currently approved by the FDA for treating NTRK gene fusion-positive solid tumors that are unresectable or metastatic.7–10 They are both tropomyosin receptor tyrosine kinase inhibitors with slightly different molecular target profiles.7,8
  • Larotrectinib was approved based on data from three phase I-II studies, with the primary endpoint overall response rate (ORR) and secondary endpoints duration of response (DOR), progression-free survival (PFS), and safety.6,8,9 Based on outcomes data, larotrectinib was approved in 2018, with updated data published in 2020 that showed ORR 79% (95% CI 72-85) and 16% showing a complete response.6
  • In 2019, the FDA approved entrectinib based on clinical data from phase I-II trials ALKA-372-001, STARTRK-1, and STARTRK-2.6,7,10 ORR was 57.4 (95% CI 43.2-70.8), DOR 10.4 months (95% CI 7.1-NR), and PFS 11.2 months (95% CI 8.0-14.9).7,10

Entrectinib7

  • FDA-Approved Indication:
    • The FDA has approved entrectinib for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment.
    • This indication has received accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Mechanism of Action:
    • Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib also inhibits JAK2 and TNK2.
    • Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.
  • Drug Information:
  • Patient Resources:

Larotrectinib8

  • FDA-Approved Indication:
    • The FDA has approved larotrectinib for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment.
    • This indication has received accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Mechanism of Action:
    • Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3.
    • Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.
  • Drug Information:
  • Patient Resources:

References

  1. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precision Oncology. 2018;(2):1-20. doi:10.1200/PO.18.00183
  2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Annals of Medicine & Surgery. 2022;79. doi:10.1016/j.amsu.2022.103893
  3. Lange A, Lo HW. Inhibiting TRK Proteins in Clinical Cancer Therapy. Cancers. 2018;10(4):105. doi:10.3390/cancers10040105
  4. Demols A, Rocq L, Perez-Casanova L, et al. A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas. The Oncologist. 2023;28(7):e520-e525. doi:10.1093/oncolo/oyad075
  5. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. 2023;76(3):158-165. doi:10.1136/jclinpath-2021-207781
  6. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: Pancreatic Adenocarcinoma. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  7. ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf
  8. VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf
  9. 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
  10. 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:viii713. doi:10.1093/annonc/mdy424.017