Entrectinib

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Entrectinib
Entrectinib.svg
Clinical data
Trade names Rozlytrek
Other namesRXDX-101, NMS-E628
AHFS/Drugs.com Monograph
MedlinePlus a619049
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • 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
PubChemSID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C31H34F2N6O2
Molar mass 560.650 g·mol−1
3D model (JSmol)
  • CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
  • 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 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]

Contents

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] [8]

It was approved for medical use in the United States in August 2019, [8] [9] [10] 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: [11]

Entrectinib is not approved for use in those less than twelve years of age. [5] [6] [11]

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]

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. [8]

The most serious side effects of entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation and vision disorders. [8]

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). [12] [ failed verification ] It has an EU orphan designation for neuroblastoma. [13] FDA approved entrectinib for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours. [14] 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. [15] 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. [16]

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), [17] and Trial 4 (NCT02650401). [18] The trials were conducted in the United States, Europe and Asia/Pacific region. [18] [11]

The FDA granted entrectinib accelerated approval, priority review, breakthrough therapy, and orphan drug designation. [8] The approval of Rozlytrek was granted to Genentech, Inc. [8]

Mechanism of action

The process of tumorigenesis frequently involves protein kinase activation events, which can result from either mutations, or chromosomal rearrangements. [19] [20] 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. [20] [21]

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. [20] 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. [20] 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). [20] [21] [22] [23]

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. [24] The drug is orally administered, once daily, and is being studied[ when? ] in patients whose tumors have been shown to have fusions in NTRK1/2/3, ALK, or ROS1. [25] 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. [26]

TargetTrkATrkBTrkCROS1ALK
IC50 (nM)1.70.10.10.21.6 [27]

Entrectinib has also demonstrated in-vitro efficacy against potential Trk inhibitor resistance mutations such as NTRK1 F589L, NTRK1 V573M, NTRK1 G667S. [26]

Clinical development

Entrectinib is currently[ when? ] being tested in a global phase II basket clinical trial called STARTRK-2. [17] Interim results from two ongoing phase 1 trials have been reported at the 2016 AACR American Association for Cancer Research Conference in April 2016: [26] 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.[ citation needed ]

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 [17] 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.[ citation needed ]

Society and culture

It was approved for medical use in the United States in August 2019, [10] and in Australia in May 2020. [1]

Economics

Investigations of entrectinib were conducted by Ignyta Pharmaceuticals. [28] On 21 December 2017, Roche announced plans to buy Ignyta for $1.7 billion. [29]

Names

Entrectinib is the International nonproprietary name (INN). [30]

Related Research Articles

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

<span class="mw-page-title-main">Anaplastic lymphoma kinase</span> Protein-coding gene in the species Homo sapiens

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.

<span class="mw-page-title-main">ROS1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in mammary secretory carcinoma, mammary analogue secretory carcinoma of salivary glands, salivary gland–type carcinoma of the thyroid, secretory carcinoma of the skin, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

<span class="mw-page-title-main">Adenocarcinoma of the lung</span> Medical condition

Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.

<span class="mw-page-title-main">Crizotinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms. It also acts as an ALK and ROS1 inhibitor.

<span class="mw-page-title-main">ALK inhibitor</span>

ALK inhibitors are anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation. They fall under the category of tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it. A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion, although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC. For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.

<span class="mw-page-title-main">ALK positive lung cancer</span> Medical condition

ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein, most frequently, the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. Less frequently, there will be novel translocation partners for the ALK gene, in place of EML4. This abnormal gene fusion leads to the production of a protein that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.

<span class="mw-page-title-main">Ceritinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Ceritinib is a prescription-only drug used for the treatment of non-small cell lung cancer (NSCLC). It was developed by Novartis and received FDA approval for use in April 2014.

<span class="mw-page-title-main">Alectinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Alectinib (INN), sold under the brand name Alecensa, is an anticancer medication that is used to treat non-small-cell lung cancer (NSCLC). It blocks the activity of anaplastic lymphoma kinase (ALK). It is taken by mouth. It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group.

Mammary analogue secretory carcinoma (MASC), also termed MASCSG, is a salivary gland neoplasm. It is a secretory carcinoma which shares the microscopic pathologic features with other types of secretory carcinomas including mammary secretory carcinoma, secretory carcinoma of the skin, and salivary gland–type carcinoma of the thyroid. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors, i.e. a (12;15)(p13;q25) fusion gene mutation. The other secretory carcinoma types carry this fusion gene.

<span class="mw-page-title-main">Lorlatinib</span> Kinase inhibitor for treatment of non-small-cell lung cancer

Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer medication used for the treatment of non-small cell lung cancer. It is an orally administered inhibitor of anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (ROS1), two enzymes that play a role in the development of cancer. It was developed by Pfizer.

<span class="mw-page-title-main">Selpercatinib</span> Chemical compound

Selpercatinib, sold under the brand name Retevmo among others, is a medication for the treatment of cancers in people whose tumors have an alteration in a specific gene. It is taken by mouth.

Pralsetinib, sold under the brand name Gavreto, is a medication approved for RET mutation-positive medullary thyroid cancer (MTC) and RET fusion-positive differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) therapy. Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.

RET inhibitors are targeted therapies that act on tumors with activating alterations in the RET proto-oncogene, such as point mutations or fusions. They fall under the category of the tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of cancer cells. Existing molecules fall in two main categories: the older multikinase inhibitors and the more recent selective inhibitors. Although RET alterations are found at low frequency in a broad range of tumors, the three main indications for RET inhibitors today are non-small cell lung cancer, medullary thyroid cancer and papillary thyroid cancer. As of 2020, up to 48 fusion partners have been catalogued in NSCLC rearrangements, with KIF5B and CCDC6 being the most prevalent. At least 10 different fusion variants have been described for KIF5B-RET, each with different breakpoints within the partner gene, but unclear clinical impact as of 2018.

Lipofibromatosis-like neural tumor (LPF-NT) is an extremely rare soft tissue tumor first described by Agaram et al in 2016. As of mid-2021, at least 39 cases of LPF-NT have been reported in the literature. LPF-NT tumors have several features that resemble lipofibromatosis (LPF) tumors, malignant peripheral nerve sheath tumors, spindle cell sarcomas, low-grade neural tumors, peripheral nerve sheath tumors, and other less clearly defined tumors; Prior to the Agaram at al report, LPF-NTs were likely diagnosed as variants or atypical forms of these tumors. The analyses of Agaram at al and subsequent studies uncovered critical differences between LPF-NT and the other tumor forms which suggest that it is a distinct tumor entity differing not only from lipofibromatosis but also the other tumor forms.

<span class="mw-page-title-main">Repotrectinib</span> Medication

Repotrectinib, sold under the brand name Augtyro, is an anti-cancer medication used for the treatment of non-small cell lung cancer. It is taken by mouth. Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC.

References

  1. 1 2 3 4 "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. 23 October 2014. Retrieved 29 May 2022.
  4. ↑ "Rozlytrek 100 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). Retrieved 11 September 2020.
  5. 1 2 3 4 5 "Rozlytrek- entrectinib capsule". DailyMed. 8 June 2020. Retrieved 16 August 2020.
  6. 1 2 3 4 5 6 7 8 9 "Rozlytrek EPAR". European Medicines Agency (EMA). 26 May 2020. Retrieved 11 September 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ↑ "Rozlytrek Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  8. 1 2 3 4 5 6 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. ↑ "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). Retrieved 16 August 2019.
  10. 1 2 "Drug Approval Package: Rozlytrek". U.S. Food and Drug Administration (FDA). 16 September 2019. Retrieved 23 November 2019.
  11. 1 2 3 "Drug Trials Snapshots: Rozlytrek (solid tumors)". U.S. Food and Drug Administration (FDA). 13 September 2019. Retrieved 23 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. ↑ "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.
  13. ↑ House DW (8 December 2015). "Ignyta's entrectinib an Orphan Drug in Europe for neuroblastoma". Seeking Alpha.
  14. ↑ "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.
  15. ↑ "FDA Approves Entrectinib for ROS1+ NSCLC and NTRK+ Solid Tumors". TargetedOnc. Archived from the original on 16 August 2019. Retrieved 16 August 2019.
  16. ↑ "Japan becomes the first country to approve Roche's personalised medicine Rozlytrek". Roche (Press release). 18 June 2019. Retrieved 23 November 2019.
  17. 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
  18. 1 2 "Drug Trials Snapshots: Rozlytrek (non-small cell lung cancer)". U.S. Food and Drug Administration (FDA). 12 September 2019. Retrieved 23 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  19. ↑ 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 January 2024). PMC   4369855 . PMID   25806218.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  20. 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): 772–787. doi:10.1038/nrc3612. PMC   3902129 . PMID   24132104.
  21. 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.
  22. ↑ 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.
  23. ↑ 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): 110–125. doi:10.1053/j.seminoncol.2013.12.006. PMC   4159759 . PMID   24565585.
  24. ↑ 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): 179–186. doi:10.1016/j.canlet.2016.01.018. PMC   4792275 . PMID   26797418.
  25. ↑ 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): 628–639. doi: 10.1158/1535-7163.MCT-15-0758 . PMID   26939704.
  26. 1 2 3 Drilon A, De Braud FG, Siena S, Ou SH, Patel M, Ahn MJ, et al. (July 2016). "Abstract CT007: Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements: Updated phase I results" (PDF). Cancer Research. 15 (76 14_Supplement): CT007. doi:10.1158/1538-7445.AM2016-CT007. Archived from the original (PDF) on 16 August 2016.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ Mulier T, Naomi K (22 December 2017). "Roche to Buy U.S. Cancer-Drug Maker Ignyta for $1.7 Billion". Bloomberg. Retrieved 16 February 2018.
  30. ↑ World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 114. hdl: 10665/331046 .
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