NTRK

  • Neurotrophic-tropomyosin receptor tyrosine kinase (NTRK)

NTRK Biology

  • The neurotrophic-tropomyosin receptor tyrosine kinase 1 (NTRK1), NTRK2, and NTKR3 genes encode for proteins TRKA, TRKB, and TRKC, respectively.1,2
  • NTRK proteins localize to cell membranes, and their endogenous ligands are neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, and neurotrophin-5.1–3
  • NTRK gene activation activates downstream signaling pathways RAS-RAF-MEK-ERK, phospholipase C, and phosphatidylinositol 3 kinase (PI3K).1–3

Etiology and Epidemiology

  • The NTRK proteins are involved in the growth and proliferation of neural cells in particular, and gene fusions can induce tumorigenesis in neural and non-neural cell cancers.1
  • When oncogenic, NTRK gene fusions are drivers for tumorigenesis and lead to constitutively active downstream signaling of various growth pathways.1,4 
  • NTRK gene fusions are present in approximately 1% of solid tumors but are much less common in CRCs, with an estimated prevalence ranging from 0.35% to 0.7%.2,4–6
  • The rarity of NTRK gene fusions in CRC makes it challenging to elucidate clinicopathological characteristics.
  • In a 2022 study, researchers analyzed a cohort of 16 patients with NTRK+ colorectal cancer (CRC) and found that of the three genes, NTRK1 rearrangements were the most common, and TPM3 was the most common fusion partner in introns 7-11. NTRK+ CRC variants were more likely to have microsatellite instability.5

Testing for NTRK Gene Fusions

When to Test:

  • Given the availability of targeted TRK inhibitors, patients with metastatic colorectal cancer should undergo molecular testing for NTRK gene fusions at the time of diagnosis.4

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.4

Guideline Recommendations for Testing:

  • Guidelines endorse using multiple testing methodologies, depending on the accessibility of assays and available testing material.4

NTRK Targeted Therapy

Available Agents:

  • There are currently two treatment options for unresectable or metastatic solid tumors with NTRK gene fusions: larotrectinib and entrectinib.
  • Notably, NTRK inhibitors have demonstrated effectiveness only in cases with NTRK fusions, not in those with NTRK point mutations.
  • While these targeted therapies are only appropriate for a small subset of CRC patients, they do offer an additional option with an attractive safety profile and an overall response rate of 57-79%.4,7,8

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 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 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 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. Solomon JP, Hechtman JF. Detection of NTRK Fusions: Merits and Limitations of Current Diagnostic Platforms. Cancer Research. 2019;79(13):3163-3168. doi:10.1158/0008-5472.CAN-19-0372
  4. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: Colon Cancer. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  5. Wang H, Li Z, Ou Q, et al. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Medicine. 2022;11(13):2541-2549. doi:10.1002/cam4.4561
  6. Cocco E, Benhamida J, Middha S, et al. Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions. Cancer Research. 2019;79(6):1047-1053. doi:10.1158/0008-5472.CAN-18-3126
  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. FDA approves larotrectinib for solid tumors with NTRK gene fusions | FDA. Accessed March 18, 2024. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions
  10. 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
  11. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC | FDA. Accessed March 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc
  12. 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