Larotrectinib

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Larotrectinib
Larotrectinib.svg
Clinical data
Trade names Vitrakvi
Other namesLOXO-101, ARRY-470
AHFS/Drugs.com Monograph
MedlinePlus a619006
License data
Pregnancy
category
  • AU:D
Routes of
administration
By mouth, oropharyngeal
ATC code
Legal status
Legal status
Identifiers
  • (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H22F2N6O2
Molar mass 428.444 g·mol−1
3D model (JSmol)
  • O[C@H]1CCN(C1)C(=O)Nc2cnn3ccc(nc23)N4CCC[C@@H]4c5cc(F)ccc5F
  • InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
  • Key:NYNZQNWKBKUAII-KBXCAEBGSA-N

Larotrectinib, sold under the brand name Vitrakvi, is a medication for the treatment of cancer. [1] [5] [7] It is an inhibitor of tropomyosin kinase receptors TrkA, TrkB, and TrkC. [8] [9] [10] It was discovered by Array BioPharma and licensed to Loxo Oncology in 2013.

Contents

Larotrectinib was initially awarded orphan drug status in 2015, for soft tissue sarcoma, and breakthrough therapy designation in 2016 for the treatment of metastatic solid tumors with NTRK fusion. [11] Some clinical trial results were announced in 2017. [12] On 26 November 2018, Larotrectinib was approved by the FDA. [13]

Larotrectinib was the first drug to be specifically developed and approved to treat any cancer containing certain mutations, as opposed to cancers of specific tissues (i.e., the approval is "tissue agnostic"). Several earlier drugs, including pembrolizumab, were eventually approved by the FDA for treatment of specific mutations independent of the type of cancer, but those drugs had been initially developed for specific cancer types. [14] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [15]

Larotrectinib was approved for medical use in the European Union in September 2019. [16] [6] It was approved for medical use in Australia in August 2020. [1]

Research

Phase II clinical trials evaluating the drug for efficacy and safety in treating several types of solid tumors are ongoing. [17]

Related Research Articles

<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">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.

<span class="mw-page-title-main">Olaparib</span> Chemical compound (cancer therapy drug)

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.

<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">Selumetinib</span> Chemical compound

Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

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

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Entrectinib</span> TKI inhibitor used for cancer treatment

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. 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).

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

Capmatinib, sold under the brand name Tabrecta, is an anticancer medication used for the treatment of metastatic non-small cell lung cancer whose tumors have a mutation that leads to the exon 14 skipping of the MET gene, which codes for the membrane receptor HGFR.

<span class="mw-page-title-main">Ivosidenib</span> Anti-cancer medication

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

Tissue-agnosticcancer drugs are antineoplastic drugs that treat cancers based on the mutations that they display, instead of the tissue type in which they appear. Tissue-agnostic drugs that have been approved for medical use include Pembrolizumab, Larotrectinib, Selpercatinib, Entrectinib, and Pralsetinib.

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

Sotorasib, sold under the brand names Lumakras and Lumykras, is an anti-cancer medication used to treat non-small-cell lung cancer. It targets a specific mutation, G12C, in the protein K-Ras encoded by gene KRAS which is responsible for various forms of cancer. Sotorasib is an inhibitor of the RAS GTPase family.

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

Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Avapritinib is a kinase inhibitor.

<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.

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 "Vitrakvi". Therapeutic Goods Administration (TGA). 16 September 2020. Archived from the original on 19 September 2020. Retrieved 22 September 2020.
  2. "Vitrakvi Product information". Health Canada. 25 April 2012. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  3. "Summary Basis of Decision (SBD) for Vitrakvi". Health Canada . 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  4. "Vitrakvi 25mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 7 March 2022. Archived from the original on 28 November 2022. Retrieved 28 November 2022.
  5. 1 2 "Vitrakvi- larotrectinib capsule Vitrakvi- larotrectinib solution, concentrate". DailyMed. 26 July 2019. Archived from the original on 7 April 2021. Retrieved 22 September 2020.
  6. 1 2 "Vitrakvi EPAR". European Medicines Agency (EMA). 23 July 2019. Archived from the original on 2 October 2020. Retrieved 22 September 2020.
  7. "Larotrectinib" (PDF). Statement on a Nonproprietary Name Adopted by the USAN Council. American Medical Association (AMA). 26 October 2016. Archived (PDF) from the original on 13 March 2018. Retrieved 31 January 2017.
  8. Berger S, Martens UM, Bochum S (2018). "Larotrectinib (LOXO-101)". Small Molecules in Oncology. Recent Results in Cancer Research Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer. Vol. 211. pp. 141–151. doi:10.1007/978-3-319-91442-8_10. ISBN   978-3-319-91441-1. PMID   30069765.
  9. Federman N, McDermott R (October 2019). "Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer". Expert Review of Clinical Pharmacology. 12 (10): 931–939. doi: 10.1080/17512433.2019.1661775 . PMID   31469968.
  10. Scott LJ (February 2019). "Larotrectinib: First Global Approval". Drugs. 79 (2): 201–206. doi:10.1007/s40265-018-1044-x. PMID   30635837. S2CID   57772716.
  11. "Larotrectinib". AdisInsight. Archived from the original on 12 March 2018. Retrieved 31 January 2017.
  12. "Novel Agent Shows Antitumor Activity in TRK-Fusion Cancers. June 2017". Archived from the original on 24 January 2021. Retrieved 9 June 2017.
  13. "FDA approves larotrectinib for solid tumors with NTRK gene fusions". U.S. Food and Drug Administration (FDA). 26 November 2018. Archived from the original on 24 March 2021. Retrieved 22 September 2020.
  14. Dun L (27 November 2018). "FDA approves a new cancer drug targeted to genetic mutation, not cancer type". NBC . Archived from the original on 2 December 2018. Retrieved 3 December 2018.
  15. New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Archived from the original on 17 September 2020. Retrieved 16 September 2020.
  16. Gallagher J (23 September 2019). "'Revolutionary' new class of cancer drugs approved". Archived from the original on 26 September 2019. Retrieved 30 September 2019.
  17. Clinical trial number NCT02576431 for "A Phase 2 Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects With NTRK Fusion-positive Tumors" at ClinicalTrials.gov