Mobocertinib Explained

Tradename:Exkivity
Dailymedid:Mobocertinib
Pregnancy Au:D
Pregnancy Au Comment:[1]
Pregnancy Category:Contraindicated
Routes Of Administration:By mouth
Class:Antineoplastic
Atc Prefix:L01
Atc Suffix:EB10
Legal Au:S4
Legal Au Comment:[2]
Legal Uk:POM
Legal Uk Comment:[3]
Legal Us:Rx-only
Legal Us Comment:[4]
Legal Status:Rx-only[5]
Index2 Label:as salt
Cas Number:1847461-43-1
Cas Number2:2389149-74-8
Pubchem:118607832
Drugbank:DB16390
Drugbank2:DBSALT003192
Chemspiderid:84455481
Unii:39HBQ4A67L
Unii2:53QIA92ZEE
Kegg:D12001
Kegg2:D11969
Chembl:4650319
Synonyms:TAK-788, AP-32788
Iupac Name:Propan-2-yl 2-(4--2-methoxy-5-(prop-2-enamido)anilino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate
C:32
H:39
N:7
O:4
Smiles: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
Stdinchi: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)
Stdinchi2:1S/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)
Stdinchikey:AZSRSNUQCUDCGG-UHFFFAOYSA-N
Stdinchikey2:YXYAEUMTJQGKHS-UHFFFAOYSA-N

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.[6] [7]

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

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. It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.

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.

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. The mean oral bioavailability of Mobocertinib is 37%. The median Tmax is 4 hours. The average half-life of Mobocertinib and its metabolites is 18 hours. Mobocertinib is metabolized by CYP3A enzymes.

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. Other side effects which may be less frequent are: chills, cough, dilated neck veins, ill-feeling and trouble with breathing. 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.

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]

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: Exkivity APMDS . Therapeutic Goods Administration (TGA) . 1 August 2022 . 2 August 2022 . 2 August 2022 . https://web.archive.org/web/20220802063446/https://www.tga.gov.au/apm-summary/exkivity . live .
  3. Web site: Exkivity 40 mg hard capsules - Summary of Product Characteristics (SmPC) . (emc) . 24 March 2022 . 24 March 2022 . 25 March 2022 . https://web.archive.org/web/20220325080858/https://www.medicines.org.uk/emc/product/13468/smpc . live .
  4. Web site: Exkivity- mobocertinib capsule . DailyMed . U.S. National Library of Medicine . 30 September 2021 . 1 October 2021 . https://web.archive.org/web/20211001031812/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1a91500-a944-4cb8-b4a8-ae278bcf728d . live .
  5. Takedas Exkivity mobocertinib Receives Approval from the NMPA of China Becoming the First and Only Therapy Available for Patients with EGFR Exon20 Insertion+ NSCLC . Takeda . 11 January 2023 . 10 February 2023 . 10 February 2023 . https://web.archive.org/web/20230210043716/https://www.takeda.com/newsroom/newsreleases/2023/takedas-exkivity-mobocertinib-receives-approval-from-the-nmpa-of-china-becoming-the-first-and-only-therapy-available-for-patients-with-egfr-exon20-insertion-nsclc/ . live .
  6. Web site: 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 . 16 September 2021 . 16 September 2021 . https://web.archive.org/web/20210916200908/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20 . live .
  7. Takeda's Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC . . Business Wire . 15 September 2021 . 16 September 2021 . 17 September 2021 . https://web.archive.org/web/20210917053004/https://www.businesswire.com/news/home/20210915006101/en/ . live .
  8. Wang J, Lam D, Yang J, Hu L . 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 . October 2022 . 36065226 . 9433531 . 10.1007/s00044-022-02952-5 .
  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 . 17 February 2021 . 2 August 2022 . https://web.archive.org/web/20220802063450/https://clinicaltrials.gov/ct2/show/NCT04129502?term=tak-788&phase=2&draw=2&rank=1 . live .
  10. Zhang SS, Zhu VW . Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations . Lung Cancer: Targets and Therapy. 12 . 61–65 . 2021 . 34285620 . 8286072 . 10.2147/LCTT.S307321 . free .
  11. Gonzalvez F, Vincent S, Baker TE, Gould AE, Li S, Wardwell SD, Nadworny S, Ning Y, Zhang S, Huang WS, Hu Y, Li F, Greenfield MT, Zech SG, Das B, Narasimhan NI, Clackson T, Dalgarno D, Shakespeare WC, Fitzgerald M, Chouitar J, Griffin RJ, Liu S, Wong KK, Zhu X, Rivera VM . 6 . Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer . Cancer Discovery . 11 . 7 . 1672–1687 . July 2021 . 33632773 . 10.1158/2159-8290.CD-20-1683 . 232056169 . free .
  12. Web site: Mobocertinib . 3 July 2022 . go.drugbank.com . 3 July 2022 . https://web.archive.org/web/20220703004550/https://go.drugbank.com/drugs/DB16390 . live .
  13. Web site: Mobocertinib Side Effects: Common, Severe, Long Term . 3 July 2022 . Drugs.com . en . 3 July 2022 . https://web.archive.org/web/20220703005501/https://www.drugs.com/sfx/mobocertinib-side-effects.html . live .
  14. Zhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, Mekhail T, Nguyen D, Garcia Campelo MR, Felip E, Vincent S, Jin S, Griffin C, Bunn V, Lin J, Lin HM, Mehta M, Jänne PA . 6 . 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 . December 2021 . 34647988 . 8517885 . 10.1001/jamaoncol.2021.4761 .
  15. Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, Tsao AS, Patel JD, Gadgeel SM, Bazhenova L, Zhu VW, West HL, Mekhail T, Gentzler RD, Nguyen D, Vincent S, Zhang S, Lin J, Bunn V, Jin S, Li S, Jänne PA . 6 . 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 . July 2021 . 33632775 . 8295177 . 10.1158/2159-8290.CD-20-1598 .
  16. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 . U.S. Food and Drug Administration (FDA) . 13 May 2022 . PDF . 22 January 2023 . 6 December 2022 . https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download . live .

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