Cobimetinib

Cobimetinib
Names
Pronunciation/ˌkoʊbɪˈmɛtɪnɪb/ KOH-bim-ET-i-nib
Trade namesCotellic
Other namesGDC-0973, XL-518
IUPAC name
  • (S)-[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone
Clinical data
Drug classMEK inhibitor[1]
Main usesMelanoma[1]
Side effectsDiarrhea, rash, nausea, fever, sunburns, liver problems, muscle damage[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
    Routes of
    use    		By mouth (tablets)[1]
    Typical dose60 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa615057
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • CA: ℞-only
    • UK: POM (Prescription only)
    • US: ℞-only [1]
    • EU: Rx-only [2]
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailabilityreported from 28%[3] to 46%[1]
    Protein binding95%[1]
    MetabolismIntestinal and low liver clearance (mostly CYP3A4 oxidation and UGT2B7 glucuronidation)[1][3]
    Elimination half-life44 hours (mean)[1]
    ExcretionFeces (76–77%), urine (17.9–18%) (after oral and IV administration)[1][4]
    Chemical and physical data
    FormulaC21H21F3IN3O2
    Molar mass531.318 g·mol−1
    3D model (JSmol)
    SMILES
    • C1CCN[C@@H](C1)C2(CN(C2)C(=O)C3=C(C(=C(C=C3)F)F)NC4=C(C=C(C=C4)I)F)O
    InChI
    • InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1
    • Key:BSMCAPRUBJMWDF-KRWDZBQOSA-N

    Cobimetinib, sold under the brand name Cotellic among others, is a medication used to treat melanoma.[1] Specifically it is used for advanced disease with either BRAF V600E or V600K mutation.[1] It is used together with vemurafenib.[1] Use is not recommended in the United Kingdom.[5] It is taken by mouth.[1]

    Common side effects include diarrhea, rash, nausea, fever, sunburns, liver problems, or muscle damage.[2] Other side effects may include bleeding, heart damage, and retinal vein occlusion.[1] Use during pregnancy may harm the baby.[1] It is a MEK inhibitor.[1]

    Cobimetinib was approved for medical use in the United States and Europe in 2015.[1][2] In the United Kingdom treatment for 4 weeks costs the NHS about £4,275 as of 2021.[5] This amount in the United States is about 7,300 USD.[6]

    Medical use

    Cobimetinib is approved for use in combination with vemurafenib for the treatment of advanced melanoma with BRAF mutation (either V600E or V600K) that cannot be removed by surgery or which has metastasized.[1][7]

    In the European Union, cobimetinib is indicated for use in combination with vemurafenib for the treatment of adults with unresectable or metastatic melanoma with a BRAF V600 mutation.[8]

    Atezolizumab in combination with cobimetinib and vemurafenib is indicated for the treatment of people with BRAF V600 mutation-positive unresectable or metastatic melanoma.[9] [10]

    Dosage

    It is generally take at a dose of 60 mg once per day for 3 weeks with 1 week off.[1]

    Side effects

    Common sideeffects observed in cobimetinib and vemurafenib co-treated persons in clinical trials included diarrhea, nausea, vomiting, rash, photosensitivity, and pyrexia.[11]

    Society and culture

    The brands Cotellic, Zelboraf, and Tecentriq are all marketed by Genentech.[1][9][12]

    History

    Cobimetinib was awarded orphan drug status by the FDA for malignant melanoma with BRAFV600 mutation in 2014.

    Acquired resistance to BRAF inhibitors, such as vemurafenib and dabrafenib, commonly occurs after several months of progression-free tumor response. Preclinical data indicated the involvement of MAPK pathways and MAPK-independent signaling in the developed resistance, suggesting dual inhibition of MEK and BRAF kinase as a strategy for increasing the longevity of tumor response seen with BRAF inhibition alone.

    In phase III clinical trials, the combination of cobimetinib and vemurafenib was tested in patients with BRAFV600-mutated metastatic melanoma, which resulted in significant improvement in progression-free survival in patients, but also produced some increase in toxicity. The combination increased progression-free survival to an average of 12.3 months, compared to 7.2 months for vemurafenib alone. This clinical data also showed that the combination treatment resulted in 65% survival rate of patients 17 months after beginning the treatment, increased rates from the 50% of patients on vemurafenib treatment alone. Adding cobimetinib also increased the median overall survival to 25.6 months, compared to the 18 months for vemurafenib alone.[13][11]

    Pre-clinical investigation suggests that combined use of cobimetinib with PI3K inhibition could boost the anti-cancer effects of the drug, with a synergistic response being observed in lung cancer cell lines.[14][15]

    The U.S. Food and Drug Administration (FDA) approved cobimetinib based on evidence from one clinical trial of 495 participants with melanoma containing the BRAF V600 mutation that was advanced or could not be removed by surgery. The trial was conducted at 133 sites in 19 countries including those in North America, Europe, and Australia.[16]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 "Cotellic- cobimetinib tablet, film coated". DailyMed. 5 November 2019. Archived from the original on 4 August 2020. Retrieved 19 October 2020.
    2. 1 2 3 4 "Cotellic". Archived from the original on 20 January 2021. Retrieved 6 January 2022.
    3. 1 2 Takahashi RH, Choo EF, Ma S, Wong S, Halladay J, Deng Y, et al. (January 2016). "Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans". Drug Metabolism and Disposition. 44 (1): 28–39. doi:10.1124/dmd.115.066282. PMID 26451002.
    4. ↑ Choo E, Takahashi R, Rooney I, Gates M, Deng A, Musib L (January 30, 2014). "Abstract B160: Assessing Human Absorption, Metabolism, Routes of Excretion and the Contribution of Intestinal Metabolism to the Oral Clearance of Cobimetinib, a MEK Inhibitor". Molecular Cancer Therapeutics. 12 (11 Supplement): B160. doi:10.1158/1535-7163.TARG-13-B160.
    5. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1019. ISBN 978-0857114105.
    6. ↑ "Cotellic Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 26 January 2021. Retrieved 6 January 2022.
    7. ↑ "FDA approves Cotellic as part of combination treatment for advanced melanoma". U.S. Food and Drug Administration (FDA). 10 November 2015. Archived from the original on 8 December 2015. Retrieved 2 December 2015.
    8. ↑ "Cotellic EPAR". European Medicines Agency. Archived from the original on 20 January 2021. Retrieved 21 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    9. 1 2 "Tecentriq- atezolizumab injection, solution". DailyMed. Archived from the original on 4 May 2021. Retrieved 21 September 2021.
    10. ↑ "FDA approves atezolizumab for BRAF V600 unresectable or metastatic melanoma". U.S. Food and Drug Administration (FDA). 31 July 2020. Archived from the original on 8 June 2021. Retrieved 21 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
    11. 1 2 Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. (November 2014). "Combined vemurafenib and cobimetinib in BRAF-mutated melanoma" (PDF). The New England Journal of Medicine. 371 (20): 1867–76. doi:10.1056/NEJMoa1408868. PMID 25265494. Archived (PDF) from the original on 2021-11-02. Retrieved 2021-10-05.
    12. ↑ "Zelboraf- vemurafenib tablet, film coated". DailyMed. Archived from the original on 21 March 2021. Retrieved 21 September 2021.
    13. ↑ Staton T (11 November 2015). "Ready to rumble, Novartis? Roche targets melanoma-fighting combo market with new FDA nod". FiercePharma. FierceMarkets. Questex. Archived from the original on 8 December 2015. Retrieved 2 December 2015.
    14. ↑ Heavey, Susan; Cuffe, Sinead; Finn, Stephen; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin; O'Byrne, Kenneth; Gately, Kathy (2016-11-29). "In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC". Oncotarget. 7 (48): 79526–79543. doi:10.18632/oncotarget.12755. ISSN 1949-2553. PMC 5346733. PMID 27765909.
    15. ↑ Heavey, Susan; O'Byrne, Kenneth J.; Gately, Kathy (April 2014). "Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC". Cancer Treatment Reviews. 40 (3): 445–456. doi:10.1016/j.ctrv.2013.08.006. ISSN 1532-1967. PMID 24055012. Archived from the original on 2020-03-05. Retrieved 2021-10-05.
    16. ↑ "Drug Trials Snapshots: Cotellic". U.S. Food and Drug Administration (FDA). 30 July 2020. Archived from the original on 27 October 2021. Retrieved 21 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
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