NTRK Somatic Fusions and Tumor Agnostic Treatment in Pediatric Cancers

Yıl 2022, Cilt: 12 Sayı: 6, 1019 - 1024, 30.11.2022

Sonay İncesoy Özdemir , Ayça Yağmur Şimşek , Emel Ünal

https://doi.org/10.16899/jcm.1113357

Öz

Neurotrophic tyrosine receptor kinase (NTRK) gene rearrangements have been recently identified and developed as one of the biomarkers that have been utilized as new targets for cancer therapy. NTRK gene fusions have taken their place in individualized targeted therapy by being used as a predictive (diagnostic) biomarker as well as a treatment target. Selective inhibitors of NTRK fusion proteins have potent efficacy in the treatment of NTRK fusion-positive solid tumors. Detection of these fussions have become important since the finding of new drugs for which U.S. Food and Drug Administration (FDA) granted approval are used on the treatment of patients who has NTRK fussions positive cansers. Clinical trials have shown that first generation tyrosine receptor kinase (TRK) inhibitors, larotrectinib (Vitrakvi, Bayer HealthCare Pharmaceutical Inc, New Jersey, U.S.) and entrectinib (Rozlytrek, Genentech Inc, California, U.S.), have potent efficacy in the treatment of NTRK fusion positive cancers. In the future, with the increase in the number of comprehensive studies on these drugs further information will become available and beneficial.

Anahtar Kelimeler

NTRK fussion, tumor agnostic treatment, precision medicine, larotrectinib, entrectinib

Çocukluk Çağı Kanserlerinde NTRK Somatik Füzyonları ve Tümör Agnostik Tedavi

Öz

Nörotrofik tirozin reseptör kinaz (NTRK) geni yeniden düzenlemeleri yakın zamanda kanser tedavisi için yeni hedefler olarak ortaya konulan biyobelirteçlerden (biyomarker) bir tanesi olarak tanımlanmış ve geliştirilmiştir. NTRK gen füzyonları öngörücü (prediktif-tanısal) bir biyobelirteç olarak kullanılmasının yanı sıra tedavi hedefi olarak da kullanılarak bireyselleştirilmiş hedef tedavide yerini almıştır. NTRK füzyon proteinlerinin selektif inhibitörleri, NTRK füzyon pozitif solid tümörlerin tedavisinde güçlü etkinliğe sahiptir (tümör-agnostik tedavi). Tümörlerinde NTRK füzyonları saptanan hastaların tedavisinde etkili olan FDA (Amerika Birleşik Devletleri Gıda ve İlaç Yönetimi) onaylı yeni tedavilerle birlikte, bu füzyonların test edilmesi önemli hale gelmiştir. Yapılan klinik çalışmalar birinci nesil tirozin reseptör kinaz (TRK) inhibitörleri olan larotrectinib ve entrectinibin NTRK füzyonu pozitif kanserlerin tedavisinde yüksek oranda başarılı olduğu görülmüştür. İlerleyen zamanlarda bu ilaçlar üzerine geniş kapsamlı araştırmaların sayısının artması bu ilaçlar hakkında daha fazla bilgiyi mevcut kılacak ve faydalı olacaktır.

Anahtar Kelimeler

NTRK füzyonu, tümör agnostik tedavi, hassas tıp, larotrectinib, entrectinib

Kaynakça

• Salto-Tellez M, James JA, Hamilton PW. Molecular pathology—The value of an integrative approach. Mol Oncol. 2014. 8:1163–1168.
• Collins, F.S, Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 2015, 372: 793–795.
• Kheder ES, Hong DS. Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. Clin. Cancer Res. 2018.24:5807–5814.
• Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev.Clin. Oncol. 2018. 15: 731–747.
• Amatu A, Sartore-Bianchi A, Bencardino K, et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019 Nov 1;30: viii5-viii15.
• Chao MV. Neurotrophin receptors: A window into neuronal diferentiation. Neuron 1992. 9:583–593.
• Chao MV. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat. Rev. Neurosci. 2003. 4: 299–309.
• Weiss LM, Funari VA. NTRK fusions and Trk proteins: what are they and how to test for them. Hum Pathol. 2021. 112:59-69.
• Zito Marino F, Pagliuca F, Ronchi A, et al. NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine. Int J Mol Sci. 2020 May 25;21(10):3718.
• Zhao X, Kotch C, Fox E, et al. NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome. JCO Precis Oncol. 2021. 14;1:PO.20.00250
• Frederique Penault-Llorca, Erin R Rudzinski, Antonia R Sepulveda. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol. 2019.72(7):460-467.
• Yoshino T, Pentheroudakis G, Mishima S, et al. JSCO-ESMO-ASCO-JSMO-TOS: international expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann Oncol. 2020.31(7):861-872.
• A. Drilon, TRK inhibitors in TRK fusion-positive cancers. Annals of Oncology 30 (Supplement 8): viii23–viii30, 2019
• Ahmad Awada,Thierry Berghmans,Paul M. Clement, et al. Belgian expert consensus for tumor-agnostic treatment of NTRK gene fusion-driven solid tumors with larotrectinib. Critical Reviews in Oncology/Hematology Volume 169, January 2022, 103564
• Nathan D. Seligson,Todd C. Knepper,Susanne Ragg, et al. Developing Drugs for Tissue-Agnostic Indications: A Paradigm Shift in Leveraging Cancer Biology for Precision Medicine. Clinical Pharmacology & Therapeutics. 2020 June 14 109(2):334-342
• R. McDermott, C.M. van Tilburg, A.F. Farago, et al. 1955P Survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Ann. Oncol., 31 (2020), p. S1101
• U.S. Food and Drug Administration. FDA Approves Companion Diagnostic to identify NTRK fusions in solid tumors for Vitrakvi. Accessesd March 16, 2022, https://www.fda.gov
• Alexander Drilon, M.D., Theodore W. Laetsch, M.D., Shivaani Kummar, M.D., et al. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. N Engl J Med 2018; 378:731-739
• ClinicalTrials.gov. Study to Learn More about the Safety and Effectiveness of the Drug Vitrakvi During Routine Use in Patients With Trk Fusion Cancer Which Is Locally Advanced or Spread From the Place Where It Started to Other Places in the Body (ON-TRK) [NCT04142437]. Accessed: March 15 2022 https://clinicaltrials.gov/ct2/show/NCT04142437?cond=NTRK&cntry=BE&draw=2&rank=4
• J Delgado, E Pean, D Melchiorri. The European Medicines Agency review of entrectinib for the treatment of adult or paediatric patients with solid tumours who have a neurotrophic tyrosine receptor kinase gene fusions and adult patients with non-small-cell lung cancer harbouring ROS1 rearrangements. ESMO Open 2021 Apr;6(2):100087
• Liu D., Offin M., Harnicar S., et al. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors . 20 July 2018 Volume 2018:14 Pages 1247—1252
• Christian Rolfo, Rossana Ruiz, Elisa Giovannetti, et al. Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500.
• U.S. Food and Drug Administration. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Accessed: March 16 2022, https://www.fda.gov
• Alexander Drilon, Salvatore Siena, Sai-Hong Ignatius Ou, 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): 400–409.