Neurotrophic Tyrosine Receptor Kinase (NTRK) Fusion-Positive Cancers

Advances in biomarker discovery are helping scientists learn more about the drivers that cause many types of cancers to grow. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are an actionable biomarker for cancer therapy and can be found in over 25 different types of cancer, regardless of where they are located in the body.^1,2

What is NTRK?

• The NTRK gene family contains three members, NTRK1, NTRK2 and NTRK3, which produce TRKA, TRKB and TRKC proteins, respectively.¹
• The TRK proteins are receptor kinases that help regulate cell signaling and function in healthy tissues.^1,2,3
• Rearrangements in the NTRK genes can result in two genes fusing together and producing altered TRK proteins, which can lead to uncontrolled growth of cancer cells.^{1, 2}

What are NTRK fusion-positive tumors, and what is their prevalence?

• NTRK fusion-positive tumors have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.^1,2,4
• NTRK can be found in approximately 1,500 to 5,000 children, adolescents and adults with cancer annually.⁴ The prevalence of NTRK gene fusions, however, varies across these tumor types.²
• In pediatric tumors, these fusions have been identified in CNS tumors including gliomas, as well as in melanoma, soft-tissue sarcomas, inflammatory myofibroblastic tumors, congenital infantile fibrosarcoma and mesoblastic nephroma.¹

How are NTRK fusion-positive tumors identified?

• Similar to other cancer biomarkers, NTRK gene fusions are identified with biomarker tests, which can include next-generation sequencing (NGS), immunohistochemistry (IHC), DNA fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR).^5,6
• Biomarker testing for NTRK gene fusions is the only way to identify people who may be eligible for therapies that target these genomic alterations.^5,6

How are NTRK fusion-positive tumors treated?

• Recent advances in personalized medicine mean that NTRK fusion-positive tumors may be appropriate for treatment with a targeted medicine regardless of the type of cancer or where it originated. This is called a tumor-agnostic treatment approach.⁷

<sup>1. Lange AM, Lo HW. Cancers (Basel). 2018;10(4). https://www.ncbi.nlm.nih.gov/pubmed/29617282
2. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. https://www.ncbi.nlm.nih.gov/pubmed/25527197
3. Kheder ES, Hong DS. Clin Cancer Res. 2018:1156. [Epub ahead of print.] https://www.ncbi.nlm.nih.gov/pubmed/29986850
4. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023. https://www.ncbi.nlm.nih.gov/pubmed/27843590
5. Bubendorf L, Büttner R, Al-Dayel F, et al. Virchows Arch. 2016;469(5):489-503. https://www.ncbi.nlm.nih.gov/pubmed/27535289
6. Murphy DA, Ely HA, Shoemaker R, et al. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523. https://www.ncbi.nlm.nih.gov/pubmed/27028240
7. Flaherty KT, Le DT, Lemery S. Tissue-Agnostic Drug Development. Am Soc Clin Oncol Educ Book. 2017;37:222-230. doi: 10.14694/EDBK_173855. Accessed April 2019. https://www.ncbi.nlm.nih.gov/pubmed/28561648.</sup>