Cobimetinib

File:Cobimetinib.svg
Systematic (IUPAC) name
(S)[3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl]azetidin-1-yl) methanone
Clinical data
Trade names	Cotellic
Legal status	US: ℞-only Initial U.S. Approval: 2015
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	28%
Protein binding	95%
Metabolism	Intestinal and low hepatic clearance (mostly CYP3A4)
Biological half-life	44 hours
Excretion	Feces (77%), Urine (18%) (oral and IV)
Identifiers
CAS Number	934660-93-2
ATC code	none
PubChem	CID: 16222096
DrugBank	DB05239 Y
ChemSpider	17349374
ChEBI	CHEBI:90851 Y
ChEMBL	CHEMBL2146883
Chemical data
Formula	C21H21F3IN3O2
Molecular mass	531.3 g/mol
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 (GDC-0973, XL-518, trade name Cotellic) is a MEK inhibitor developed by Exelixis and Genentech. It is used in combination with vemurafenib, a BRAF inhibitor, to treat melanoma. In November 2015, the U.S. Food and Drug Administration approved cobimetinib for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf). Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.

Cobimetinib in combination with vemurafenib is reportedly priced at $17,600 per month, or about $211,000 per year. A competing dual therapy, using dabrafenib along with trametinib, is also approved by the FDA, and is reported to cost $15,300 monthly, or $183,600 per year.

Medical use

Cobimetinib is approved for use in combination with vemurafenib (trade name Zelboraf) for the treatment of advanced melanoma that cannot be removed by surgery or which has spread to other parts of the body, provided that the melanoma has an abnormal gene, with a mutation of BRAF (either V600E or V600K).

Clinical trials

Acquired resistance to BRAF inhibitors, such as vemurafenib and dabrafenib, commonly occurs after a 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 3 clinical trials, the combination of cobimentinib and vemurafenib was tested in patients with BRAFV600-mutated metastic 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 cobimentinib also increased the median overall survival to 25.6 months, compared to the 18 months for vemurafenib alone.

Adverse effects

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

External links

• Highlights of prescribing information