Mobocertinib

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.[5][7]

Mobocertinib
Clinical data
Trade namesExkivity
Other namesTAK-788, AP-32788
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAntineoplastic
ATC code
Legal status
Legal status
Identifiers
  • Propan-2-yl 2-(4-{[2-(dimethylamino)ethyl]methylamino}-2-methoxy-5-(prop-2-enamido)anilino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC32H39N7O4
Molar mass585.709 g·mol−1
3D model (JSmol)
  • CC(C)OC(=O)C1=CN=C(N=C1C2=CN(C3=CC=CC=C32)C)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC
  • InChI=1S/C32H39N7O4/c1-9-29(40)34-24-16-25(28(42-8)17-27(24)38(6)15-14-37(4)5)35-32-33-18-22(31(41)43-20(2)3)30(36-32)23-19-39(7)26-13-11-10-12-21(23)26/h9-13,16-20H,1,14-15H2,2-8H3,(H,34,40)(H,33,35,36)
  • Key:AZSRSNUQCUDCGG-UHFFFAOYSA-N

  • as salt: InChI=1S/C32H39N7O4.C4H6O4/c1-9-29(40)34-24-16-25(28(42-8)17-27(24)38(6)15-14-37(4)5)35-32-33-18-22(31(41)43-20(2)3)30(36-32)23-19-39(7)26-13-11-10-12-21(23)26;5-3(6)1-2-4(7)8/h9-13,16-20H,1,14-15H2,2-8H3,(H,34,40)(H,33,35,36);1-2H2,(H,5,6)(H,7,8)
  • Key:YXYAEUMTJQGKHS-UHFFFAOYSA-N

The most common side effects include diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.[5]

Mobocertinib is a small molecule tyrosine kinase inhibitor structurally similar to osimertinib (differs only by the presence of an additional isopropyl ester group).[8] Its molecular target is epidermal growth factor receptor (EGFR) bearing mutations in the exon 20 region.[9][10] Mobocertinib is an irreversible kinase inhibitor, forming a covalent bond with the cysteine 797 in the EGFR active site, leading to sustained inhibition of EGFR enzymatic activity. The irreversible binding leads to increased potency via higher affinity binding, more sustained EGFR kinase activity inhibition, and greater overall selectivity, as only a limited number of other kinases possess a cysteine in the equivalent position.[11]

Mobocertinib was approved for medical use in the United States in September 2021.[5][7] It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.[7]

Medical uses

Mobocertinib is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[5]

Mechanism of action

Mobocertinib acts to inhibit EGFR exon 20 insertion mutations at a lower concentration than it does on wild-type proteins.[12]

Pharmacokinetics

The volume of distribution of Mobocertinib at steady state is 3,509 L.[12] The mean oral bioavailability of Mobocertinib is 37%.[12] The median Tmax is 4 hours.[12] The average half-life of Mobocertinib and its metabolites is 18 hours.[12] Mobocertinib is metabolized by CYP3A enzymes.[12]

Warnings

Mobocertinib may increase the chance of QTC prolongation, specifically Torsades de Pointes which can be fatal.[13]

Adverse Effects

More serious side effects of Mobocertinib may include agitation, bloating of the eyes, lips, feet, blurred vision, coma, decreased urine output, headache, hostility, diarrhea, depression, dizziness, fainting, lethargy, anxiety, nausea, seizures, weight gain, fatigue as well as edema.[13] Other side effects which may be less frequent are: chills, cough, dilated neck veins, ill-feeling and trouble with breathing.[13] Other notable side effects of taking Mobocertinib are: having an acidic stomach, heartburn, acidity, hair loss/thinning, bone pain, sore throat, stuffy nose, trouble swallowing, vomiting and weakness in hands and feet.[13]

History

Mobocertinib was studied in participants with previously treated metastatic non-small cell lung cancer with EGFR exon 20 insertions.[14][15]

The FDA granted the application for mobocertinib orphan drug designation.[16]

References
  1. "Exkivity APMDS". Therapeutic Goods Administration (TGA). 1 August 2022. Archived from the original on 2 August 2022. Retrieved 2 August 2022.
  2. "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Retrieved 2 January 2023.
  3. "Exkivity- mobocertinib capsule". DailyMed. U.S. National Library of Medicine. Archived from the original on 1 October 2021. Retrieved 30 September 2021.
  4. "Exkivity 40 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 24 March 2022. Archived from the original on 25 March 2022. Retrieved 24 March 2022.
  5. "FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations". U.S. Food and Drug Administration (FDA). 16 September 2021. Archived from the original on 16 September 2021. Retrieved 16 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  6. "Takedas Exkivity mobocertinib Receives Approval from the NMPA of China Becoming the First and Only Therapy Available for Patients with EGFR Exon20 Insertion+ NSCLC" (Press release). Takeda. 11 January 2023. Retrieved 10 February 2023.
  7. "Takeda's Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC" (Press release). Takeda Pharmaceutical Company. 15 September 2021. Archived from the original on 17 September 2021. Retrieved 16 September 2021 – via Business Wire.
  8. Wang J, Lam D, Yang J, Hu L (October 2022). "Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations". Medicinal Chemistry Research. 31 (10): 1647–1662. doi:10.1007/s00044-022-02952-5. PMC 9433531. PMID 36065226.
  9. "TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations". Clinicaltrials.gov. 28 January 2021. Archived from the original on 2 August 2022. Retrieved 17 February 2021.
  10. Zhang SS, Zhu VW (2021). "Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations". Lung Cancer. 12: 61–65. doi:10.2147/LCTT.S307321. PMC 8286072. PMID 34285620.
  11. Gonzalvez F, Vincent S, Baker TE, Gould AE, Li S, Wardwell SD, et al. (July 2021). "Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer". Cancer Discovery. 11 (7): 1672–1687. doi:10.1158/2159-8290.CD-20-1683. PMID 33632773. S2CID 232056169.
  12. "Mobocertinib". go.drugbank.com. Archived from the original on 3 July 2022. Retrieved 3 July 2022.
  13. "Mobocertinib Side Effects: Common, Severe, Long Term". Drugs.com. Archived from the original on 3 July 2022. Retrieved 3 July 2022.
  14. Zhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, et al. (December 2021). "Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial". JAMA Oncology. 7 (12): e214761. doi:10.1001/jamaoncol.2021.4761. PMC 8517885. PMID 34647988.
  15. Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, et al. (July 2021). "Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial". Cancer Discovery. 11 (7): 1688–1699. doi:10.1158/2159-8290.CD-20-1598. PMC 8295177. PMID 33632775.
  16. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
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