NTRK

  • Neurotrophic tropomyosin receptor kinase (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 gene fusions occur in less than 1% of NSCLC cases, but act as oncogenic drivers by causing ligand-independent activation of TRK kinases and downstream signaling pathways (eg, MAPK and PI3K) that promote cancer cell proliferation and survival.4,5
  • NTRK fusions are mutually exclusive with other driver mutations in NSCLC. Data are limited [TMT1], yet NTRK fusions do not seem to be associated with high PD-L1 expression or CD8+ T-cell infiltration, suggesting a potential lack of response to immunotherapy.
  • Conversely, TRK inhibitors including larotrectinib and entrectinib demonstrate significant clinical activity, including against brain metastases, although acquired resistance typically develops via secondary NTRK mutations or activation of bypass pathways (eg, MAPK or PI3K).4,5

Testing for NTRK Gene Fusions

When to Test:

  • Given the availability of targeted TRK inhibitors, patients with metastatic NSCLC should undergo molecular testing for NTRK gene fusions at the time of diagnosis.6

Available Testing Methods:

  • Multiple techniques can be employed to test for NTRK1/2/3 gene fusions, such as next-generation sequencing (NGS), fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction assays.6
  • However, false negatives may arise due to complexities associated with baseline expression and fusion breakpoint within large intronic regions.6
  • NGS testing offers broad detection capabilities and is generally recommended.6
  • It is noteworthy that DNA-based NGS may not detect certain NTRK1/2/3, thus RNA-based NGS is preferred for comprehensive fusion assessment.6

Guideline Recommendations for Testing:

  • The National Comprehensive Cancer Network (NCCN) NSCLC Panel recommends NTRK1/2/3 gene fusion testing in patients with metastatic NSCLC based on clinical trial data showing the efficacy of larotrectinib or entrectinib for patients with NTRK gene fusion-positive disease and their associated FDA approval.6

NTRK Targeted Therapy

Approved Agents:

  • There are currently 2 FDA-approved treatment options for unresectable or metastatic solid tumors with NTRK gene fusions: larotrectinib and entrectinib.6-8

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 mediatric Malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 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. Ann Med Surg (Lond). 2022;79:103893. doi:10.1016/j.amsu.2022.103893
  3. Lange AM, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018;10(4):105. doi:10.3390/cancers10040105
  4. Olmedo ME, Cervera R, Cabezon-Gutierrez L, et al. New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2. World J Clin Oncol. 2022;13(4):276-286. doi:10.5306/wjco.v13.i4.276
  5. Liu F, Wei Y, Zhang H, Jiang J, Zhang P, Chu Q. NTRK fusion in non-small cell lung cancer: diagnosis, therapy, and TRK inhibitor resistance. Front Oncol. 2022;12:864666. doi:10.3389/fonc.2022.864666
  6. National Comprehensive Cancer Network. NCCN guidelines version 5.2024: Non-Small Cell Lung Cancer. Accessed May 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  7. Rozlytrek (entrectinib). Prescribing information. Genentech USA, Inc.; 2024. Accessed November 11, 2024. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf
  8. Vitrakvi (larotrectinib). Prescribing information. Bayer Pharmaceuticals Inc.; December 2023. Accessed November 18, 2024. https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf

Additional Reading

Farago AF, Taylor MS, Doebele RC, et al Clinicopathologic features of non-small-cell lung cancer harboring an NTRK gene fusion. JCO Precis Oncol. 2018;2018:PO.18.00037. doi: 10.1200/PO.18.00037 

Garrido P, Hladun R, de Álava E et al. Multidisciplinary consensus on optimising the detection of NTRK gene alterations in tumours. Clin Transl Oncol. 2021;23(8):1529-1541. doi: 10.1007/s12094-021-02558-0

Marchiò C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417-1427. doi: 10.1093/annonc/mdz204

Liu F, Wei Y, Zhang H, Jiang J, Zhang P, Chu Q. NTRK fusion in non-small cell lung cancer: diagnosis, therapy, and TRK inhibitor resistance. Front Oncol. 2022;12:864666. doi: 10.3389/fonc.2022.864666