{{Short description|Chemical compound}} {{Use dmy dates|date=August 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = Cobimetinib.svg | image_class = skin-invert-image | width = | alt = | caption =
<!-- Clinical data --> | pronounce = {{IPAc-en|ˌ|k|oʊ|b|ɪ|ˈ|m|ɛ|t|ɪ|n|ɪ|b}} {{respell|KOH|bim|ET|i-nib}} | tradename = Cotellic | Drugs.com = {{Drugs.com|monograph|cobimetinib-fumarate}} | MedlinePlus = a615057 | DailyMedID = Cobimetinib | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Cotellic PI" /> | pregnancy_category = | routes_of_administration = By mouth<ref name="Cotellic FDA label" /> | class = | ATC_prefix = L01 | ATC_suffix = EE02 | ATC_supplemental =
<!-- Legal status --> | legal_AU = S4 | legal_AU_comment = <ref name="Cotellic PI">{{cite web|url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropcotel10416 |title=Products|website=guildlink.com.au}}</ref><ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2016 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | access-date=10 April 2023}}</ref> | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=Health Canada | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024}}</ref> | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Cotellic FDA label">{{cite web | title=Cotellic- cobimetinib tablet, film coated | website=DailyMed | date=5 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c387579e-cee0-4334-bd1e-73f93ac1bde6 | access-date=19 October 2020}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Cotellic EPAR" /> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = Rx-only
<!-- Pharmacokinetic data --> | bioavailability = reported from 28%<ref name="Takahashi">{{cite journal | vauthors = Takahashi RH, Choo EF, Ma S, Wong S, Halladay J, Deng Y, Rooney I, Gates M, Hop CE, Khojasteh SC, Dresser MJ, Musib L | display-authors = 6 | title = Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans | journal = Drug Metabolism and Disposition | volume = 44 | issue = 1 | pages = 28–39 | date = January 2016 | pmid = 26451002 | doi = 10.1124/dmd.115.066282 | doi-access = free }}</ref> to 46%<ref name="Cotellic FDA label" /> | protein_bound = 95%<ref name="Cotellic FDA label" /> | metabolism = Intestinal and low Liver clearance (mostly CYP3A4 oxidation and UGT2B7 glucuronidation)<ref name="Cotellic FDA label" /><ref name="Takahashi" /> | metabolites = | onset = | elimination_half-life = 44 hours (mean)<ref name="Cotellic FDA label" /> | duration_of_action = | excretion = Feces (76–77%), urine (17.9–18%) (after oral and IV administration)<ref name="Cotellic FDA label" /><ref name="Choo">{{cite journal| vauthors = Choo E, Takahashi R, Rooney I, Gates M, Deng A, Musib L |title=Abstract B160: Assessing Human Absorption, Metabolism, Routes of Excretion and the Contribution of Intestinal Metabolism to the Oral Clearance of Cobimetinib, a MEK Inhibitor|journal=Molecular Cancer Therapeutics|date=30 January 2014|volume=12|issue=11 Supplement|pages=B160|doi=10.1158/1535-7163.TARG-13-B160}}</ref>
<!-- Identifiers --> | CAS_number = 934660-93-2 | CAS_supplemental = | PubChem = 16222096 | IUPHAR_ligand = 7626 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB05239 | ChemSpiderID = 17349374 | UNII = ER29L26N1X | KEGG = D10405 | KEGG2 = D10615 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 90851 | ChEMBL = 2146883 | NIAID_ChemDB = | PDB_ligand = | synonyms = GDC-0973, XL-518
<!-- Chemical and physical data --> | IUPAC_name = (''S'')-[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone | C=21 | H=21 | F=3 | I=1 | N=3 | O=2 | 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 | StdInChI = 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 | StdInChI_comment = | StdInChIKey = BSMCAPRUBJMWDF-KRWDZBQOSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}
'''Cobimetinib''', sold under the brand name '''Cotellic''', is an anti-cancer medication used to treat melanoma and histiocytic neoplasms.<ref name="Cotellic FDA label" /><ref name="Tecentriq FDA label">{{cite web | title=Tecentriq- atezolizumab injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fa682c9-a312-4932-9831-f286908660ee | access-date=21 September 2021}}</ref> Cobimetinib is a MEK inhibitor.<ref name="Cotellic FDA label" /> Cobimetinib is marketed by Genentech.<ref name="Cotellic FDA label" />
The most common side effects include diarrhea, rash, nausea (feeling sick), vomiting, pyrexia (fever), photosensitivity (light sensitivity) reaction, abnormal results for certain liver function tests (increased levels of alanine aminotransferase, aspartate aminotransferase) and abnormal results for an enzyme related to muscle breakdown (creatine phosphokinase).<ref name="Cotellic EPAR" />
Cobimetinib was approved for medical use in the United States in November 2015.<ref>{{cite web | title=Cotellic (cobimetinib) tablet | website=U.S. Food and Drug Administration (FDA) | date=8 December 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20200709220537/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000TOC.cfm | url-status=dead | archive-date=9 July 2020 | access-date=21 September 2021 }}</ref><ref name="FDA snapshot">{{cite web | title=Drug Trials Snapshots: Cotellic | website=U.S. Food and Drug Administration (FDA) | date=30 July 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-cotellic | archive-url=https://web.archive.org/web/20190927212501/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-cotellic | url-status=dead | archive-date=27 September 2019 | access-date=21 September 2021}} {{PD-notice}}</ref><ref name="FDACotellicApproval">{{cite press release |url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm471934.htm |title=FDA approves Cotellic as part of combination treatment for advanced melanoma |date=10 November 2015 |website=U.S. Food and Drug Administration (FDA) |access-date=2 December 2015 |archive-date=8 December 2015 |archive-url=https://web.archive.org/web/20151208114107/http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm471934.htm |url-status=dead }}</ref>
== Medical use == In the United States, cobimetinib is indicated for the treatment of adults with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.<ref name="Cotellic FDA label" /> It is also indicated for the treatment of adults with histiocytic neoplasms.<ref name="Cotellic FDA label" />
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.<ref name="Cotellic EPAR">{{cite web | title=Cotellic EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cotellic | access-date=21 September 2021}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
== Adverse effects == Common adverse effects observed in cobimetinib and vemurafenib co-treated persons in clinical trials included diarrhea, nausea, vomiting, rash, photosensitivity, and pyrexia.<ref name="LarkinAscierto2014"/>
== History == Cobimetinib was granted orphan drug designation by the US Food and Drug Administration (FDA) for melanoma with BRAFV600 mutation in 2014,<ref>{{cite web | title=Cobimetinib Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=31 January 2014 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=419513 | archive-url=https://web.archive.org/web/20231002054359/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=419513 | url-status=dead | archive-date=2 October 2023 | access-date=4 July 2022}}</ref> and for histiocytic neoplasms in 2021.<ref>{{cite web | title=Cobimetinib Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=26 April 2021 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=752820 | archive-url=https://web.archive.org/web/20220704050510/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=752820 | url-status=dead | archive-date=4 July 2022 | access-date=4 July 2022}}</ref>
In phase III clinical trials, the combination of cobimetinib and vemurafenib was tested in participants with BRAFV600-mutated metastatic melanoma, which resulted in significant improvement in progression-free survival in participants, 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 participants 17 months after beginning the treatment, increased rates from the 50% of participants on vemurafenib treatment alone. Adding cobimetinib also increased the median overall survival to 25.6 months, compared to the 18 months for vemurafenib alone.<ref name="StatonFP">{{cite news| vauthors = Staton T |title=Ready to rumble, Novartis? Roche targets melanoma-fighting combo market with new FDA nod|url=http://www.fiercepharma.com/story/ready-rumble-novartis-roche-targets-melanoma-fighting-combo-market-new-fda/2015-11-11|access-date=2 December 2015|work=FiercePharma|agency=Questex|publisher=FierceMarkets|date=11 November 2015}}</ref><ref name="LarkinAscierto2014">{{cite journal | vauthors = Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A | display-authors = 6 | title = Combined vemurafenib and cobimetinib in BRAF-mutated melanoma | journal = The New England Journal of Medicine | volume = 371 | issue = 20 | pages = 1867–1876 | date = November 2014 | pmid = 25265494 | doi = 10.1056/NEJMoa1408868 | doi-access = free | hdl = 10668/2159 | hdl-access = free }}</ref>
The US 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.<ref name="FDA snapshot" />
== Research == Pre-clinical investigation suggests that combined use of cobimetinib with PI3K inhibition might boost the anti-cancer effects of cobimetinib.<ref>{{cite journal | vauthors = Heavey S, Cuffe S, Finn S, Young V, Ryan R, Nicholson S, Leonard N, McVeigh N, Barr M, O'Byrne K, Gately K | display-authors = 6 | title = In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC | journal = Oncotarget | volume = 7 | issue = 48 | pages = 79526–79543 | date = November 2016 | pmid = 27765909 | pmc = 5346733 | doi = 10.18632/oncotarget.12755 }}</ref><ref>{{cite journal | vauthors = Heavey S, O'Byrne KJ, Gately K | title = Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC | journal = Cancer Treatment Reviews | volume = 40 | issue = 3 | pages = 445–456 | date = April 2014 | pmid = 24055012 | doi = 10.1016/j.ctrv.2013.08.006 }}</ref>
== References == {{reflist}}
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Category:Azetidines Category:Benzamides Category:Cancer treatments Category:Fluorobenzene derivatives Category:Iodobenzene derivatives Category:MEK inhibitors Category:Piperidines Category:Protein kinase inhibitors Category:Drugs developed by Genentech Category:Drugs developed by Hoffmann-La Roche Category:Orphan drugs