Entrectinib

Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors.[5] It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).[5]

Entrectinib
Clinical data
Trade namesRozlytrek
Other namesRXDX-101, NMS-E628
AHFS/Drugs.comMonograph
MedlinePlusa619049
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAntineoplastic agent
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • N-[5-(3,5-Difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide
CAS Number
PubChem CID
PubChem SID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC31H34F2N6O2
Molar mass560.650 g·mol−1
3D model (JSmol)
SMILES
  • CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
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

The most common side effects include tiredness, constipation, dysgeusia (taste disturbances), edema (swelling with fluid retention), dizziness, diarrhea, nausea (feeling sick), dysesthesia (unpleasant and abnormal feeling when touched), dyspnea (difficulty breathing), anemia (low red blood cell count), increased weight, increased blood creatinine (possible sign of kidney problems), pain, cognitive disorders (problems with ability to think, learn and remember), vomiting, cough, and fever.[6][7]

It was approved for medical use in the United States in August 2019,[7][8][9] in Australia in May 2020,[1] and in the European Union in July 2020.[6]

Medical uses

In the US, entrectinib is indicated to treat patients whose cancers are ROS1-positive (have a specific genetic feature (biomarker)).[5] It is to be used in those with solid tumors that:[10]

  • 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.[5][6][10]

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,[6]

  • who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and[6]
  • who have not received a prior NTRK inhibitor[6]
  • who have no satisfactory treatment options.[6]

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.[6]

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.[7]

The most serious side effects of entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation and vision disorders.[7]

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).[11] It has an EU orphan designation for neuroblastoma.[12] FDA approved entrectinib for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours.[13] 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.[14] 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.[15]

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),[16] and Trial 4 (NCT02650401).[17] The trials were conducted in the United States, Europe and Asia/Pacific region.[17][10]

The FDA granted entrectinib accelerated approval, priority review, breakthrough therapy, and orphan drug designation.[7] The approval of Rozlytrek was granted to Genentech, Inc.[7]

Mechanism of action

The process of tumorigenesis frequently involves protein kinase activation events, which can result from either mutations, or chromosomal rearrangements.[18][19] 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.[19][20]

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.[19] 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.[19] 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).[19][20][21][22]

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.[23] 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.[24] 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.[25]

Target TrkA TrkB TrkC ROS1 ALK
IC50 (nM) 1.7 0.1 0.1 0.2 1.6[26]

Entrectinib has also demonstrated in-vitro efficacy against potential Trk inhibitor resistance mutations such as NTRK1 F589L, NTRK1 V573M, NTRK1 G667S.[25]

Clinical development

Entrectinib is currently being tested in a global phase II basket clinical trial called STARTRK-2.[16] Interim results from two ongoing phase 1 trials have been reported at the 2016 AACR American Association for Cancer Research Conference in April 2016:[25] 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[16] 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.

Society and culture

It was approved for medical use in the United States in August 2019,[9] and in Australia in May 2020.[1]

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]

References
  1. "Rozlytrek Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 25 May 2020. Retrieved 16 August 2020.
  2. "Rozlytrek Product information". Health Canada. Retrieved 29 May 2022.
  3. "Summary Basis of Decision (SBD) for Rozlytrek". Health Canada. Retrieved 29 May 2022.
  4. "Rozlytrek 100 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). Retrieved 11 September 2020.
  5. "Rozlytrek- entrectinib capsule". DailyMed. 8 June 2020. Retrieved 16 August 2020.
  6. "Rozlytrek EPAR". European Medicines Agency (EMA). 26 May 2020. Retrieved 11 September 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. "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. This article incorporates text from this source, which is in the public domain.
  8. "FDA Approves Genentech's Rozlytrek (entrectinib) for People With ROS1-Positive, Metastatic Non-Small Cell Lung Cancer and NTRK Gene Fusion-Positive Solid Tumors". Genentech (Press release). Genentech. Retrieved 16 August 2019.
  9. "Drug Approval Package: Rozlytrek". U.S. Food and Drug Administration (FDA). 16 September 2019. Retrieved 23 November 2019.
  10. "Drug Trials Snapshots: Rozlytrek (solid tumors)". U.S. Food and Drug Administration (FDA). 13 September 2019. Retrieved 23 November 2019. This article incorporates text from this source, which is in the public domain.
  11. "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 20 April 2016.
  12. Ignyta's entrectinib an Orphan Drug in Europe for neuroblastoma
  13. "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.
  14. "FDA Approves Entrectinib for ROS1+ NSCLC and NTRK+ Solid Tumors". TargetedOnc. Archived from the original on 16 August 2019. Retrieved 16 August 2019.
  15. "Japan becomes the first country to approve Roche's personalised medicine Rozlytrek". Roche (Press release). 18 June 2019. Retrieved 23 November 2019.
  16. 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
  17. "Drug Trials Snapshots: Rozlytrek (non-small cell lung cancer)". U.S. Food and Drug Administration (FDA). 12 September 2019. Retrieved 23 November 2019. This article incorporates text from this source, which is in the public domain.
  18. 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 July 2022). PMC 4369855. PMID 25806218.{{cite journal}}: CS1 maint: DOI inactive as of July 2022 (link)
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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 for Cancer Research" (PDF). Archived from the original (PDF) on 16 August 2016. Retrieved 26 June 2016.
  26. 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.
  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. 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.
  • "Entrectinib". Drug Information Portal. U.S. National Library of Medicine.
  • "Entrectinib". NCI Drug Dictionary. National Cancer Institute.
  • "Entrectinib". National Cancer Institute. 16 September 2019.
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