Cobimetinib

Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma.[1][5] Cobimetinib is a MEK inhibitor.[1] Cotellic, Zelboraf, and Tecentriq are all marketed by Genentech.[1][5][6]

Cobimetinib
Clinical data
Pronunciation/ˌkoʊbɪˈmɛtɪnɪb/ KOH-bim-ET-i-nib
Trade namesCotellic
Other namesGDC-0973, XL-518
AHFS/Drugs.comMonograph
MedlinePlusa615057
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth[1]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • EU: Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
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]
Identifiers
IUPAC name
  • (S)-[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl] methanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
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

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).[2]

Cobimetinib was approved for medical use in the United States in November 2015.[7][8]

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][9]

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.[2]

Atezolizumab in combination with cobimetinib and vemurafenib is indicated for the treatment of people with BRAF V600 mutation-positive unresectable or metastatic melanoma.[5][10]

Adverse effects

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

History

Cobimetinib was granted orphan drug status by the US Food and Drug Administration (FDA) for malignant melanoma with BRAFV600 mutation in 2014,[12] and for histiocytic neoplasms in 2021.[13]

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.[14][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.[15][16]

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.[8]

References
  1. "Cotellic- cobimetinib tablet, film coated". DailyMed. 5 November 2019. Retrieved 19 October 2020.
  2. "Cotellic EPAR". European Medicines Agency. Retrieved 21 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 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. "Tecentriq- atezolizumab injection, solution". DailyMed. Retrieved 21 September 2021.
  6. "Zelboraf- vemurafenib tablet, film coated". DailyMed. Retrieved 21 September 2021.
  7. "Cotellic (cobimetinib) tablet". U.S. Food and Drug Administration (FDA). 8 December 2015. Retrieved 21 September 2021.
  8. "Drug Trials Snapshots: Cotellic". U.S. Food and Drug Administration (FDA). 30 July 2020. Retrieved 21 September 2021. This article incorporates text from this source, which is in the public domain.
  9. "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.
  10. "FDA approves atezolizumab for BRAF V600 unresectable or metastatic melanoma". U.S. Food and Drug Administration (FDA). 31 July 2020. Retrieved 21 September 2021. This article incorporates text from this source, which is in the public domain.
  11. 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.
  12. "Cobimetinib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 31 January 2014. Retrieved 4 July 2022.
  13. "Cobimetinib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 26 April 2021. Retrieved 4 July 2022.
  14. Staton T (11 November 2015). "Ready to rumble, Novartis? Roche targets melanoma-fighting combo market with new FDA nod". FiercePharma. FierceMarkets. Questex. Retrieved 2 December 2015.
  15. 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.
  16. 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.
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