NTRK

  • Neurotrophic tropomyosin receptor kinase (NTRK)

NTRK Biology

  • NTRK genes encode for tropomyosin receptor kinases (TRKs) that attach to cell membranes and are involved in normal nervous system development.1
  • Under normal circumstances, neurotrophins activate TRK receptors, which lead to downstream ERK signaling, cellular proliferation, and growth.1
  • This receptor family has 3 known members: TRKA, TRKB, and TRKC.2
  • Their respective endogenous ligands are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3, 4, and 5.2
  • Other pathways implicated in broad NTRK signaling include mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT.3

Etiology and Epidemiology

  • NTRK gene fusions are a driver gene for tumorigenesis.4 Oncogenesis occurs via hybrid gene fusions that result in the rearrangement of NTRK sequences to attach to constitutively activated genes.1
  • The C-terminal of the NTRK gene fuses with an N-terminal target, which results in an overexpression of the kinase domain of kinase function by the chimeric protein.4,5
  • The presence of NTRK gene fusions in solid tumors is approximately 1% but is more prevalent in certain rare tumors.2 They are present in less than 1% of BTC, and the rarity of these oncogenes limits our ability to form precise incidence estimates.6

Testing for NTRK Gene Fusions

When to Test:

  • Patients with unresectable or metastatic biliary tract cancers (BTCs) who are candidates for systemic therapy should receive comprehensive molecular profiling at diagnosis.6

Available Testing Methods:

  • Given the rarity of NTRK fusions, National Comprehensive Cancer Network guidelines recommend multigene next-generation sequencing (NGS), preferably using a transcriptome-based approach.6
  • While immunohistochemistry, fluorescence in situ hybridization (FISH), and reverse transcriptase–chain polymerase reaction have been used to detect NTRK fusions, these methods are not mentioned in the guidelines for BTC.2,5

Guideline Recommendations for Testing:

  • NTRK gene fusions are found in multiple unresectable or metastatic biliary tract cancers including gallbladder malignancies, intrahepatic cholangiocarcinomas (CCAs), and extrahepatic CCAs.6
  • Testing for these gene fusions is recommended for these 3 types of biliary tract cancer (BTC).6

NTRK Targeted Therapy

Approved Agents:

  • Two drugs have been approved by the FDA for the treatment of NTRK gene fusion–positive, unresectable or metastatic solid tumors including BTC.7,8
  • Larotrectinib was approved in 2018, and entrectinib was approved in 2019.7,8
  • Entrectinib is an inhibitor of TRKA, TRKB, and TRK3; larotrectinib is a selective pan-TRK inhibitor.2
  • Both have shown specificity to patients with NTRK gene fusions with little to no activity when fusions are absent.4,7,8
  • Both TRK inhibitors have a favorable safety profile with a 57% to 75% response rate in pretreated, NTRK-positive tumors.4,6-9

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. Farha N, Dima D, Ullah F, Kamath S. Precision oncology targets in biliary tract cancer. Cancers. 2023;15(7):2105. doi:10.3390/cancers15072105
  2. Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. Ann Med Surg (Lond). 2022;79:103893. doi:10.1016/j.amsu.2022.103893
  3. 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 Precis Oncol. 2018;(2):1-20. doi:10.1200/PO.18.00183
  4. Lange A, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105. doi:10.3390/cancers10040105
  5. 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. Oncologist. 2023;28(7):e520-e525. doi:10.1093/oncolo/oyad075
  6. NCCN. Clinical Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  7. ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
  8. VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf
  9. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi:10.1016/S1470-2045(19)30856-3