Frequency of NTRK* gene fusions

across various tumor types

Estimated NTRK gene fusion frequencies in various cancers are based on reports from isolated studies that used variable testing methodologies. Not all of these tumor types were treated in the clinical trial with VITRAKVI®.

Frequency in selected common cancers

  • Lung1,2a 0.2%-3.3%
  • Thyroid1,3 2.4%-12%b
  • Glioblastoma4 1.2%
  • Sarcoma1 1%
  • GI* Cancer1,5-7c 0.7%-3.6%
*GI, gastrointestinal; GIST, gastrointestinal stromal tumor; NTRK, neurotrophic receptor tyrosine kinase. aLung adenocarcinoma.1,2 bPapillary thyroid carcinoma (12% based on a Polish population).1,3 cColorectal cancer: 0.7%; gastric cancer: 1.5%; GIST*: 3.2% (based on an Italian population); intrahepatic cholangiocarcinoma: 3.6%.1,5-7

Frequency in Other Cancers

80% to 100%
  • Mammary analogue secretory carcinoma (MASC): up to 100%8
  • Secretory breast cancer: 92%9
  • Infantile fibrosarcoma: 91%-100%10,11
  • Congenital mesoblastic nephroma (cellular subtype): 83%-92%11,12
5% to 20%
  • Spitzoid neoplasms: 16%13
  • Pediatric high-grade gliomas: 10%14
1% to 5%
  • Pilocytic astrocytoma: 3.1%15
<1%
  • Brain low-grade glioma: 0.4%1
  • Head and neck squamous cell carcinoma: 0.5%1
  • Skin cutaneous melanoma: 0.3%-0.5%1,16

TEST EARLY FOR ACTIONABLE ALTERATIONS SUCH AS NTRK GENE FUSIONS

Select patients for treatment with VITRAKVI based on the presence of an NTRK gene fusion in tumor specimens. An FDA*-approved test for the detection of NTRK gene fusion is not currently available.17

  • NTRK gene fusions can be identified by sensitive and specific molecular testing18-20

    NGS* testing allows for efficient multiplex testing, with the ability to find NTRK gene fusions, as well as other genomic targets, such as ROS1,* BRAF,* EGFR,* HER2,* and KRAS18,21-24*

    • RNA testing is preferred over DNA testing because it offers more wide-ranging fusion identification25
    • NTRK1, NTRK2, and NTRK3 should be included in the NGS panel
    More Information »
  • IHC* may be used as a screening diagnostic18

    Following a positive TRK* IHC test, confirmation of NTRK gene fusions is needed prior to initiation of VITRAKVI treatment26

    • There are currently research-use-only antibodies commercially available. Pan-TRK antibodies detect TRK proteins A,B,C, which are known to be conserved across wild-type and chimeric fusion proteins. Therefore, protein expression may not be related to a gene fusion
    More Information »
  • Other tests

    DNA FISH* can be used to detect NTRK gene fusions; however, in order to detect fusions at multiple locations, such as the 3 NTRK genes, multiple FISH tests would need to be run22

    • There is utility in using FISH in diseases such as IFS,* where the predominant driver for IFS is ETV6-NTRK10,27
  • RT-PCR* is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners28

    • Turnaround time is rapid with RT-PCR testing29
Existing NGS reports may reveal an NTRK gene fusion that is now actionable.

*BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IFS, infantile fibrosarcoma; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma; NGS, next-generation sequencing; ROS1, c-ros oncogene 1; RT-PCR, reverse transcription polymerase chain reaction; TRK, tropomyosin receptor kinase.
See the Interactive PI

Indication

VITRAKVI is indicated 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, and
  • have no satisfactory alternative treatments or that have progressed following treatment.

This indication is approved under accelerated approval based on 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.

Important Safety Information

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

For important risk and use information about VITRAKVI, please see the full Prescribing Information.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For Bayer products you can report these directly to Bayer by clicking here.


References:

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  • 2. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469-1472.
  • 3. Brzeziańska E, Karbownik M, Migdalska-Sęk M, Pastuszak-Lewandoska D, Włoch J, Lewiński A. Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population. Mutat Res. 2006;599(1-2):26-35.
  • 4. Kim J, Lee Y, Cho H-J, et al. NTRK1 fusion in glioblastoma multiforme. PLoS One. 2014;9(3):e91940. doi:10.1371/journal.pone.0091940.
  • 5. Lee SJ, Li GG, Kim ST, et al. NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line. Oncotarget. 2015;6(36):39028-39035.
  • 6. Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. 2016;238(4):543-549.
  • 7. Ross JS, Wang K, Gay L, et al. Oncologist. 2014;19(3):235-242.
  • 8. Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH. Most nonparotid “acinic cell carcinomas” represent mammary analogue secretory carcinomas. Am J Surg Pathol. 2013;37(7):1053-1057.
  • 9. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367-376.
  • 10. Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PHB. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000;24(7):937-946.
  • 11. Rubin BP, Chen C-J, Morgan TW, et al. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol. 1998;153(5):1451-1458.
  • 12. Argani P, Fritsch M, Kadkol SS, Schuster A, Beckwith JB, Perlman EJ. Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors. Mod Pathol. 2000;13(1):29-36.
  • 13. Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumors and spitzoid melanomas. Nat Commun. 2014;5:3116. doi:10.1038/ncomms4116.
  • 14. Wu G, Diaz AK, Paugh BS, et al; for the St Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014;46(5):444-450.
  • 15. Jones DTW, Hutter B, Jäger N, et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45(8):927-932.
  • 16. Lezcano C, Shoushtari AN, Ariyan C, Hollmann TJ, Busam KJ. Primary and metastatic melanoma with NTRK fusions. Am J Surg Pathol. 2018. doi:10.1097/PAS.0000000000001070.
  • 17. VITRAKVI [package insert]. Stamford, CT: Loxo Oncology, Inc.; November 2018.
  • 18. Hechtman JF, Benayed R, Hyman DM, et al. Pan-trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547-1551.
  • 19. Su D, Zhang D, Chen K, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36(1):1-12.
  • 20. Lih C-J, Harrington RD, Sims DJ, et al. Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial: Molecular Analysis for Therapy Choice clinical trial. J Mol Diagn. 2017;19(2):313-327.
  • 21. Park HS, Park S-J, Kim JY, et al. Next-generation sequencing of BRCA1/2 in breast cancer patients: potential effects on clinical decision-making using rapid, high-accuracy genetic results. Ann Surg Treat Res. 2017;92(5):331-339.
  • 22. Rogers T-M, Arnau GM, Ryland GL, et al. Multiplexed transcriptome analysis to detect ALK, ROS1 and RET rearrangements in lung cancer. Sci Rep. 2017;7:42259. doi:10.1038/srep42259.
  • 23. Fox AJ, Hiemenz MC, Lieberman DB, et al. Next generation sequencing for the detection of actionable mutations in solid and liquid tumors. J Vis Exp. 2016;(115):e52758. doi:10.3791/52758.
  • 24. Boland GM, Piha-Paul SA, Subbiah V, et al. Clinical next generation sequencing to identify actionable aberrations in a phase I program. Oncotarget. 2015;6(24):20099-20110.
  • 25. Ozsolak F, Milos PM. RNA sequencing: advances, challenges and opportunities. Nat Rev Genet. 2011;12(2):87-98.
  • 26. Murphy DA, Ely HA, Shoemaker R, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523.
  • 27. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PHB. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18(2):184-187.
  • 28. Abel H, Pfeifer J, Duncavage E. Translocation detection using next-generation sequencing. In: Kulkarni S, Pfeifer J, eds. Clinical Genomics. Amsterdam, Netherlands: Elsevier/Academic Press; 2015:151-164.
  • 29. Data on file. Whippany, NJ: Bayer; 2018.
  • 30. Foundation Medicine. FoundationOne CDx technical specifications.
    https://assets.ctfassets.net/vhribv12lmne/4ZHUEfEiI8iOCk2Q6saGcU/3be7b2679375f1acc6e508e323234004/F1CDx_Technical_Specifications.pdf. Accessed May 2, 2018.
  • 31. Caris Life Sciences. Tumor profiling services.
    https://www.carismolecularintelligence.com/wp-content/uploads/2017/03/TN0276-v5_Profile-Menu-Brochure.pdf. Accessed May 3, 2018.
  • 32. Archer FusionPlex. Archer® FusionPlex® solid tumor kit. http://archerdx.com/fusionplex-assays/solid-tumor. Accessed May 3, 2018.
  • 33. Sirona Dx. Oncomine focus. http://www.sironadx.com/assay-menu/oncomine-focus-assay. Accessed May 3, 2018.
  • 34. PathGroup. Solid tumor fusion gene list.
    http://www.pathgroup.com/wp-content/uploads/2013/08/PathGroup_Solid-Tumor-Fusion-Gene-List_11.2017-FINAL.pdf. Accessed May 3, 2018.
  • 35. Neogenomics. Test catalog. https://neogenomics.com/DesktopModules/NeoGenomics/TestMenu/Assets/NeoGenomicsTestCatalog.pdf.
    Accessed May 3, 2018.
  • 36. Knight Diagnostic Laboratories. Solid tumors GeneTrails comprehensive solid tumor panel.
    https://www.ohsu.edu/custom/knight-diagnostic-labs/print-test?id=GeneTrails+Comprehensive+Solid+Tumor+Panel. Accessed May 3, 2018.
  • 37. OmniSeq. OmniSeq comprehensive. https://www.omniseq.com/comprehensive/. Accessed May 3, 2018.
  • 38. Paradigm. Requisition form. http://www.paradigmdx.com/pcdx/order-pcdx/. Accessed May 3, 2018.
  • 39. Tempus. xT gene panel. https://s3.amazonaws.com/website-tempus-com/files/TempusxTPanelGeneList.pdf. Accessed May 4, 2018.
  • 40. Illumina. TruSight Tumor 170 gene list. https://www.illumina.com/content/dam/illumina.../gene_lists/gene_list_tst_170.xlsx. Accessed May 4, 2018.
  • 41. Archer FusionPlex. Archer FusionPlex NTRK Panel.
    https://www.illumina.com/content/dam/illumina-marketing/documents/products/brochures/archer-fusionplex-ntrk-brochure.pdf. Accessed May 4, 2018.
  • 42. Thermo Fisher Scientific. Oncomine focus assay.
    https://www.thermofisher.com/us/en/home/clinical/preclinical-companion-diagnostic-development/oncomine-oncology/oncomine-focusassay.html. Accessed May 4, 2018.
  • 43. Thermo Fisher Scientific. Oncomine comprehensive assay v3.
    https://tools.thermofisher.com/content/sfs/brochures/oncomine-comprehensive-assay-v3-flyer.pdf. Accessed May 4, 2018.
  • 44. Abam. Anti-TrkA + TrkB + TrkC antibody. http://www.abcam.com/trka--trkb--trkc-antibody-epr18413-ab189903.html Accessed May 4, 2018.
  • 45. Cell Signal Technology. Trk (pan) (A7H6R) rabbit mAb.
    https://www.cellsignal.com/products/primary-antibodies/trk-pan-a7h6r-rabbit-mab/92991?_=1525467899111&Ntt=trk&tahead=true.
    Accessed May 4, 2018.
  • 46. Roche launches first IVD pan-TRK immunohistochemistry assay. Cision® PR Newswire. https//www.prnewswire.com/news-releases/roche-launches-first-ivd-pan-trK-immunohistochemistry-assay-300755647.html. Accessed November 30, 2018.

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How to implement TESTING FOR NTRK* GENE FUSION

Considerations

Next-generation sequencing can be used to identify NTRK gene fusions as well as other actionable alterations. However, it is important to know whether the NGS* assay used has the capacity to detect NTRK gene fusions.22,28

Commercial laboratories performing NGS that include NTRK1, NTRK2, and NTRK3

  • Foundation Medicine30
  • Caris Life Sciences31
  • Cancer Genetics, Incorporated32
  • Sirona Dx33
  • PathGroup34
  • NeoGenomics Laboratories35
  • Knight Diagnostic Laboratories36
  • OmniSeq37
  • Paradigm Diagnostics38
  • Tempus39

NGS kits that include NTRK1, NTRK2, and NTRK3

  • Illumina TruSight Tumor 17040
  • Archer® FusionPlex®41a
  • Thermo Fisher Oncomine Focus42a
  • Thermo Fisher Oncomine Comprehensive43a

Companies offering TRK* IHC* antibodies

  • Abcam44a,b
  • Cell Signaling Technology45a,c
  • Roche Tissue Diagnostics46
*IHC, immunohistochemistry; NGS, next-generation sequencing; NTRK, neurotrophic receptor tyrosine kinase; TRK, tropomyosin receptor kinase. aResearch use only. bAbcam: Anti-TrkA + TrkB + TrkC antibody [EPR18413]. cCell Signaling Technology: Trk (pan) (A7H6R) Rabbit mAb #92991.