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TRK Inhibitors in Non-Small Cell Lung Cancer

  • Lung Cancer (HA Wakelee and TA Leal, Section Editors)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Care should be taken to ensure that the diagnostic strategy for a recently diagnosed advanced non-small cell lung cancer includes NTRK fusion testing. RNA sequencing is the gold standard method of detection of NTRK fusion; however, pan-TRK immunohistochemistry could be used as a screening method with good sensitivity. Larotrectinib and entrectinib are approved therapies for TRK fusion-positive lung cancers as first or subsequent lines of therapy. TRK inhibition has demonstrated clinically meaningful, deep, and durable systemic and central nervous system responses. Larotrectinib and entrectinib have a manageable safety profile, including some TRK-related adverse events, such as dizziness and weight gain. At disease progression on first-generation TRK inhibitors, enrollment on a clinical trial should be encouraged, as new-generation TRK inhibitors are being tested.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer [Internet]. 2013;13(11):772–87. Available from:. https://doi.org/10.1038/nrc3612.

  2. • Schram AM, Chang MT, Jonsson P, Drilon A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol [Internet]. 2017;14(12):735–48. https://doi.org/10.1038/nrclinonc.2017.127 Agnostic fusions in solid tumours.

    Article  CAS  Google Scholar 

  3. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  Google Scholar 

  4. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377(9):829–38.

    Article  CAS  Google Scholar 

  5. Ou SHI, Tan J, Yen Y, Soo RA. ROS1 as a “druggable” receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway. Expert Rev Anticancer Ther. 2012;12(4):447–56.

    Article  CAS  Google Scholar 

  6. Subbiah V, Velcheti V, Tuch BB, Ebata K, Busaidy NL, Cabanillas ME, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29(8):1869–76.

    Article  CAS  Google Scholar 

  7. Jonna S, Feldman RA, Swensen J, Gatalica Z, Korn WM, Borghaei H, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25(16):4966–72.

    Article  Google Scholar 

  8. • Farago AF, Taylor MS, Zhu VW, Boyle TA, Arcila ME, Horick NK, et al. Clinicopathologic features of non–small-cell lung cancer harboring an NTRK gene fusion abstract. JCO Precis Oncol. 2018. https://doi.org/10.1093/annonc/mdz063/5445460.NTRK fusions in lung cancer – clinicopathological features.

  9. Drilon A, Kummar S, Moreno V, Patel J, Lassen U, Rosen L, et al. 111O Activity of larotrectinib in TRK fusion lung cancer. Ann Oncol [Internet]. 2019;30(Supplement_2):43–4. Available from:. https://doi.org/10.1093/annonc/mdz063/5445460.

  10. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, et al. Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther. 2016;15(4):628–39.

    Article  CAS  Google Scholar 

  11. •• Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol [Internet]. 2018;15(12):731–47. https://doi.org/10.1038/s41571-018-0113-0 Comprehensive review about NTRK fusions and their treatment.

  12. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25–34.

    Article  CAS  Google Scholar 

  13. Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D, et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol [Internet]. 2019;33(1):38–46. Available from: https://doi.org/10.1038/s41379-019-0324-7.

  14. • Marchiò C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417–27 ESMO guidelines on diagnostic methods for NTRK fusions.

    Article  Google Scholar 

  15. •• Hsiao SJ, Zehir A, Sireci AN, Aisner DL. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy. J Mol Diagnostics [Internet]. 2019;21(4):553–71. https://doi.org/10.1016/j.jmoldx.2019.03.008 Comprehensive review regarding clinical laboratory techniques for identifying tumor harboring NTRK fusion.

    Article  CAS  Google Scholar 

  16. Hechtman JF, Benayed R, Hyman DM, Drilon A, Zehir A, Frosina D, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547–51.

    Article  Google Scholar 

  17. Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol [Internet]. 2019;32(1):147–53. Available from:. https://doi.org/10.1038/s41379-018-0118-3.

  18. Wong D, Yip S, Sorensen PH. Methods for identifying patients with tropomyosin receptor kinase (TRK) fusion cancer. Pathol Oncol Res. 2019. https://doi.org/10.1007/s12253-019-00685-2.

  19. Kirchner M, Neumann O, Volckmar A, Stögbauer F, Allgäuer M, Kazdal D, et al. RNA-based detection of gene fusions in formalin-fixed and paraffin-embedded solid cancer samples. Cancers (Basel) [Internet]. 2019;11(9):1309 Available from: https://www.mdpi.com/2072-6694/11/9/1309.

    Article  CAS  Google Scholar 

  20. Benayed R, Offin M, Mullaney K, Sukhadia P, Rios K, Desmeules P, et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019;25(15):4712–22.

    Article  Google Scholar 

  21. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247–53.

    Article  CAS  Google Scholar 

  22. Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30(35):4352–9.

    Article  CAS  Google Scholar 

  23. Bergethon K, Shaw AT, Ou SHI, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863–70.

    Article  CAS  Google Scholar 

  24. Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469–72.

    Article  CAS  Google Scholar 

  25. Xia H, Xue X, Ding H, Ou Q, Wu X, Nakasaga M, et al. Evidence of NTRK1 fusions as resistance mechanism to EGFR TKI in EGFR+ NSCLC. Results from a large-scale survey of NTRK1 fusions in Chinese lung cancer patients. Clin Lung Cancer [Internet]. 2019;(19):30262–1. Available from: https://doi.org/10.1016/j.cllc.2019.09.004.

  26. Schrock AB, Zhu VW, Hsieh WS, Madison R, Creelan B, Silberberg J, et al. Receptor tyrosine kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors. J Thorac Oncol [internet]. 2018;13(9):1312–23. Available from:. https://doi.org/10.1016/j.jtho.2018.05.027.

  27. •• Drilon A, Laetsch TW, Kummar S, Dubois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731–9 Seminal paper showing the efficacy of larotrectinib in TRK fusion-positive cancers.

    Article  CAS  Google Scholar 

  28. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 2015;5(10):1049–57.

    Article  CAS  Google Scholar 

  29. Hyman D, Tan DSW, van Tilburg C, Albert C, Geoerger B, Farago A, et al. 365O Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Ann Oncol [Internet]. 2019;30 Suppl 9:ix123. Available from: https://doi.org/10.1093/annonc/mdz431.002/5638369.

  30. Anderson D, Ciomei M, Banfi P, Cribioli S, Ardini E, Galvani A, et al. 310 Inhibition of Trk-driven tumors by the pan-Trk inhibitor RXDX-101. Eur J Cancer. 2014;50:101.

    Article  Google Scholar 

  31. Demetri GD, Paz-Ares L, Farago AF, Liu SV, Chawla SP, Tosi D, et al. LBA4 Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: pooled analysis of STARTRK-2, STARTRK-1, and ALKA-372-001. Ann Oncol [Internet]. 2018;29 Suppl 9:ix173–ix178. Available from: https://doi.org/10.1093/annonc/mdy483.

  32. Drilon A, Siena S, Ou SHI, Patel M, Ahn MJ, Lee J, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400–9.

    Article  CAS  Google Scholar 

  33. Paz-Ares L, Doebele RC, Farago AF, Liu SV, Chawla SP, Tosi D, et al. 113O Entrectinib in NTRK fusion-positive non-small cell lung cancer (NSCLC): integrated analysis of patients (pts) enrolled in STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2019;30:ii48–ii49.

  34. Facchinetti F, Proto C, Minari R, Garassino M, Tiseo M. Mechanisms of resistance to target therapies in non-small cell lung cancer. In: Mandalà M, Romano E, editors. Mechanisms of drug resistance in cancer therapy [internet]. Cham: springer international publishing; 2017. p. 63–89. Available from: https://doi.org/10.1007/164_2017_16, 2018.

  35. Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(8):viii23–30.

    Article  CAS  Google Scholar 

  36. • Cocco E, Schram AM, Kulick A, Misale S, Won HH, Yaeger R, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med. 2019;25(9):1422–7 Off-target mechanisms of resistance to TRK inhibition.

    Article  CAS  Google Scholar 

  37. Hyman D, Kummar S, Farago A, Geoerger B, Mau-Sorensen M, Taylor M, et al. Abstract CT127: Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Cancer Res [Internet]. 2019l;79(13 Supplement):CT127 LP-CT127 Available from: http://cancerres.aacrjournals.org/content/79/13_Supplement/CT127.abstract.

    Google Scholar 

  38. Drilon A, Ou SHI, Cho BC, Kim DW, Lee J, Lin JJ, et al. Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ROS1/TRK/ALK solvent-front mutations. Cancer Discov. 2018;8(10):1227–1236. https://doi.org/10.1158/2159-8290.

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Authors and Affiliations

  1. Oncology Center, Hospital Sírio-Libanes, Rua Dona Adma Jafet 91, São Paulo, SP, 01308-060, Brazil

    Guilherme Harada MD, Aline Bobato Lara Gongora MD, Cesar Martins da Costa MD, MSc & Fernando Costa Santini MD

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Guilherme Harada declares that he has no conflict of interest. Aline Bobato Lara Gongora declares that she has no conflict of interest. Cesar Martins da Costa declares that he has no conflict of interest. Fernando Costa Santini has received reimbursement for travel and accommodations from and has received compensation for participation on advisory boards from AstraZeneca, Roche, Lilly, Bayer, and MSD.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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Harada, G., Gongora, A.B.L., da Costa, C.M. et al. TRK Inhibitors in Non-Small Cell Lung Cancer. Curr. Treat. Options in Oncol. 21, 39 (2020). https://doi.org/10.1007/s11864-020-00741-z

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