Entrectinib

Entrectinib
Names
Trade namesRozlytrek
Other namesRXDX-101, NMS-E628
IUPAC name
  • N-[5-(3,5-Difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesNon-small cell lung cancer, solid tumors[2]
Side effectsTiredness, constipation, change in taste, swelling due to fluid retention, dizziness, diarrhea, nausea, numbness, difficulty breathing, increased weight, cough, fever, thinking problems, vision problems[2]
Pregnancy
category
  • AU: D[3]
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    Typical dose600 mg OD[2]
    External links
    AHFS/Drugs.comMonograph
    US NLMEntrectinib
    MedlinePlusa619049
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC31H34F2N6O2
    Molar mass560.650 g·mol−1
    3D model (JSmol)
    SMILES
    • CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6
    InChI
    • InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
    • Key:HAYYBYPASCDWEQ-UHFFFAOYSA-N

    Entrectinib, sold under the brand name Rozlytrek, is a medication used to treat non-small cell lung cancer (NSCLC) which are ROS1-positive or solid tumors that are NTRK fusion-positive.[2] It is taken by mouth.[2]

    Common side effects include tiredness, constipation, change in taste, swelling due to fluid retention, dizziness, diarrhea, nausea, numbness, difficulty breathing, increased weight, cough, fever, thinking problems, and vision problems.[2] Other side effects include heart failure, bone fractures, liver problems, high uric acid, and QT prolongation.[2] Use in pregnancy may harm the baby.[2] It is a tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1), and anaplastic lymphoma kinase (ALK).[1]

    Entrectinib was approved for medical use in the United States in 2019, and Australia and Europe in 2020.[2][3][5] In the United Kingdom a month of treatment costs the NHS about £5,200 as of 2021.[6] This amount in the United States costs about 16,800 USD.[7]

    Medical uses

    Entrectinib, in USA, is indicated to treat people whose cancers are ROS1-positive (have a specific genetic feature (biomarker)).[2] It is to be used in those with solid tumors that:[8]

    • are caused by certain abnormal neurotrophic tyrosine receptor kinase (NTRK) genes, and
    • have spread or if surgery to remove their cancer is likely to cause severe complications, and
    • there is no acceptable treatment, or the cancer grew or spread on other treatment

    Entrectinib is not approved for use in those less than twelve years of age.[2][5][8]

    In the European Union, entrectinib as monotherapy is indicated for the treatment of adults and adolescents twelve years of age and older with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,[5]

    • who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and[5]
    • who have not received a prior NTRK inhibitor[5]
    • who have no satisfactory treatment options.[5]

    It is also indicated for the treatment of adults with ROS1 positive, advanced non small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.[5]

    Dosage

    It is generally used at a dose of 600 mg per day.[2]

    Side effects

    The common side effects of entrectinib include fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, weight gain, cough, vomiting, fever, arthralgia and vision disorders.[9]

    The most serious side effects of entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation and vision disorders.[9]

    Mechanism of action

    The process of tumorigenesis frequently involves protein kinase activation events, which can result from either mutations, or chromosomal rearrangements.[10][11] Gene rearrangements, leading to the expression of constitutively activated fusion tyrosine kinase receptors, have been increasingly identified as a common feature of malignancies over the last three decades, and success has been demonstrated using these rearrangements as targets for drug development.[11][12]

    The expression of such gene fusions in a tumor can create a phenomenon termed 'oncogene addiction' in which the tumor becomes dependent on signaling by the aberrant kinase pathway, thus rendering its survival and continued proliferation exquisitely sensitive to targeted inhibition with small molecule tyrosine kinase inhibitor drugs.[11] Expression of the proteins encoded by these tyrosine kinase fusion genes can, in most cases, be shown to function independently as oncogenic drivers, capable of activating critical downstream pathways involved in the malignant phenotype, resulting in transformation of cells in vitro.[11] Some of the most important kinases that have been shown to undergo rearrangement in human cancers include the anaplastic lymphoma kinase (ALK), ROS1 kinase, and the neurotrophic receptor tyrosine kinases (NTRKs).[11][12][13][14]

    Entrectinib is a selective tyrosine kinase inhibitor with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the NTRK1, 2, and 3 genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases.[15] The drug is orally administered, once daily, and is being studied in patients whose tumors have been shown to have fusions in NTRK1/2/3, ALK, or ROS1.[16] As a ROS1 inhibitor, entrectinib has demonstrated in cellular anti-proliferative studies to have a 36-fold greater potency against ROS1 as compared with another commercially available ROS1 inhibitor, crizotinib.[17]

    Target TrkA TrkB TrkC ROS1 ALK
    IC50 (nM) 1.7 0.1 0.1 0.2 1.6[18]

    Entrectinib has also demonstrated in-vitro efficacy against potential Trk inhibitor resistance mutations such as NTRK1 F589L, NTRK1 V573M, NTRK1 G667S.[17]

    History

    In the U.S., entrectinib has orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC).[19] It has an EU orphan designation for neuroblastoma.[20] FDA approved entrectinib for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours.[21] It is first FDA-approved treatment designed to target both ROS1 and NTRK that also shows response in cancer that has spread to the brain.[22] In June 2019, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved the agent for the treatment of adult and pediatric patients with NTRK fusion–positive, advanced recurrent solid tumors.[23]

    The U.S. Food and Drug Administration (FDA) approved entrectinib based on the evidence from four clinical trials of 355 patients with various types of solid tumors: Trial 1 (EudraCT 2012-000148-88), Trial 2 (NCT02097810), Trial 3 (NCT02568267),[24] and Trial 4 (NCT02650401).[25] The trials were conducted in the United States, Europe and Asia/Pacific region.[25][8]

    The FDA granted entrectinib accelerated approval, priority review, breakthrough therapy, and orphan drug designation.[9] The approval of Rozlytrek was granted to Genentech, Inc.[9]

    Society and culture

    It was approved for medical use in the United States in August 2019,[26] and in Australia in May 2020.[3]

    Economics

    Investigations of entrectinib were conducted by Ignyta Pharmaceuticals.[27] On 21 December 2017, Roche announced plans to buy Ignyta for $1.7 billion.[28]

    Names

    Entrectinib is the International nonproprietary name (INN).[29]

    Research

    Entrectinib is currently being tested in a global phase II basket clinical trial called STARTRK-2.[24] Interim results from two ongoing phase 1 trials have been reported at the 2016 AACR American Association for Cancer Research Conference in April 2016:[17] among the patients treated with entrectinib, four patients had tumors harboring NTRK fusions, including patients with non-small cell lung cancer (NSCLC), mCRC, salivary gland cancer, and astrocytoma.

    The preliminary results seen with entrectinib in the phase I studies of patients with NTRK/ROS1/ALK fusions have led to the initiation of an open-label, multicenter, global, phase II basket study[24] to examine the use of entrectinib in patients having tumors with these gene rearrangements. The study will enroll any patient with a solid tumor having evidence of an NTRK/ROS1/ALK fusion, assuming the patient meets all other entry criteria. Examples of such tumor types include NSCLC, mCRC, salivary gland cancer, sarcoma, melanoma, thyroid cancer, glioblastoma, astrocytoma, cholangiocarcinoma, lymphoma and others.

    References

    1. 1 2 "Entrectinib Monograph for Professionals". Drugs.com. Archived from the original on 13 October 2020. Retrieved 15 December 2021.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Rozlytrek- entrectinib capsule". DailyMed. 8 June 2020. Archived from the original on 27 February 2021. Retrieved 16 August 2020.
    3. 1 2 3 4 "Rozlytrek Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 25 May 2020. Archived from the original on 8 October 2020. Retrieved 16 August 2020.
    4. ↑ "Rozlytrek 100 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 9 October 2020. Retrieved 11 September 2020.
    5. 1 2 3 4 5 6 7 8 "Rozlytrek EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 28 October 2020. Retrieved 11 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    6. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1024. ISBN 978-0857114105.
    7. ↑ "Entrectinib Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 15 December 2021.
    8. 1 2 3 "Drug Trials Snapshots: Rozlytrek (solid tumors)". U.S. Food and Drug Administration (FDA). 13 September 2019. Archived from the original on 11 August 2020. Retrieved 23 November 2019.Public Domain This article incorporates text from this source, which is in the public domain.
    9. 1 2 3 4 "FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor". U.S. Food and Drug Administration (FDA) (Press release). 15 August 2019. Archived from the original on 14 September 2019. Retrieved 23 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
    10. ↑ Puig de la Bellacasa R, Karachaliou N, Estrada-Tejedor R, Teixidó J, Costa C, Borrell JI (April 2013). "ALK and ROS1 as a joint target for the treatment of lung cancer: a review". Translational Lung Cancer Research. 2 (2): 72–86. doi:10.3978/j.issn.2218-6751.2013.03.1 (inactive 31 May 2021). PMC 4369855. PMID 25806218.{{cite journal}}: CS1 maint: DOI inactive as of May 2021 (link)
    11. 1 2 3 4 5 Shaw AT, Hsu PP, Awad MM, Engelman JA (November 2013). "Tyrosine kinase gene rearrangements in epithelial malignancies". Nature Reviews Cancer. 13 (11): 772–87. doi:10.1038/nrc3612. PMC 3902129. PMID 24132104.
    12. 1 2 Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C (September 2014). "The landscape of kinase fusions in cancer". Nature Communications. 5: 4846. Bibcode:2014NatCo...5.4846S. doi:10.1038/ncomms5846. PMC 4175590. PMID 25204415.
    13. ↑ Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, et al. (20 January 2014). "Kinase fusions are frequent in Spitz tumours and spitzoid melanomas". Nature Communications. 5: 3116. Bibcode:2014NatCo...5.3116W. doi:10.1038/ncomms4116. PMC 4084638. PMID 24445538.
    14. ↑ Berge EM, Doebele RC (February 2014). "Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor". Seminars in Oncology. 41 (1): 110–25. doi:10.1053/j.seminoncol.2013.12.006. PMC 4159759. PMID 24565585.
    15. ↑ Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, et al. (March 2016). "Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model". Cancer Letters. 372 (2): 179–86. doi:10.1016/j.canlet.2016.01.018. PMC 4792275. PMID 26797418.
    16. ↑ Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, et al. (April 2016). "Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications". Molecular Cancer Therapeutics. 15 (4): 628–39. doi:10.1158/1535-7163.MCT-15-0758. PMID 26939704.
    17. 1 2 3 Drilon A (16 April 2016). "Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements - updated phase 1 results. (Abstract number CT007) Presented at 2016 Annual Meeting of the American Association of Cancer Research" (PDF). Archived from the original (PDF) on 16 August 2016. Retrieved 26 June 2016.
    18. ↑ Siena S, Drilon AE, Ou IS, Farago AF, Patel M, Bauer TM, Hong D, Liu SV, Lee J, Patel R, Schechet L (September 2015). "29LBA Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements". European Journal of Cancer. 51: S724–5. doi:10.1016/S0959-8049(16)31947-5.
    19. ↑ "Ignyta Receives Orphan Drug Designation From FDA For Entrectinib For The Treatment Of Molecularly Defined Subsets Of Non-Small Cell Lung Cancer". Archived from the original on 31 October 2018. Retrieved 6 August 2021.
    20. ↑ "Ignyta's entrectinib an Orphan Drug in Europe for neuroblastoma". Archived from the original on 31 October 2018. Retrieved 6 August 2021.
    21. ↑ "FDA approves Roche's Rozlytrek (Entrectinib) for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours". F. Hoffmann-La Roche Ltd. Archived from the original on 8 November 2020. Retrieved 6 August 2021.
    22. ↑ "FDA Approves Entrectinib for ROS1+ NSCLC and NTRK+ Solid Tumors". TargetedOnc. Archived from the original on 16 August 2019. Retrieved 6 August 2021.
    23. ↑ "Japan becomes the first country to approve Roche's personalised medicine Rozlytrek". Roche (Press release). 18 June 2019. Archived from the original on 23 November 2019. Retrieved 23 November 2019.
    24. 1 2 3 Clinical trial number NCT02568267 for "Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) (STARTRK-2)" at ClinicalTrials.gov
    25. 1 2 "Drug Trials Snapshots: Rozlytrek (non-small cell lung cancer)". U.S. Food and Drug Administration (FDA). 12 September 2019. Archived from the original on 27 September 2020. Retrieved 23 November 2019.Public Domain This article incorporates text from this source, which is in the public domain.
    26. ↑ "Drug Approval Package: Rozlytrek". U.S. Food and Drug Administration (FDA). 16 September 2019. Archived from the original on 23 November 2019. Retrieved 23 November 2019.
    27. ↑ Pacenta HL, Macy ME (2018). "Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma". Drug Design, Development and Therapy. 12: 3549–3561. doi:10.2147/DDDT.S147384. PMC 6204873. PMID 30425456.
    28. ↑ Mulier T, Kresge N (22 December 2017). "Roche to Buy U.S. Cancer-Drug Maker Ignyta for $1.7 Billion". Bloomberg. Archived from the original on 29 March 2018. Retrieved 16 February 2018.
    29. ↑ World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 114. hdl:10665/331046.
    External sites:
    Identifiers:
    • "Entrectinib". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 11 July 2021. Retrieved 6 August 2021.
    • "Entrectinib". National Cancer Institute. 16 September 2019. Archived from the original on 15 August 2021. Retrieved 6 August 2021.
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