|Other names||GDC-0973, XL-518|
|Drug class||MEK inhibitor|
|Side effects||Diarrhea, rash, nausea, fever, sunburns, liver problems, muscle damage|
|By mouth (tablets)|
|Typical dose||60 mg OD|
|Bioavailability||reported from 28% to 46%|
|Metabolism||Intestinal and low liver clearance (mostly CYP3A4 oxidation and UGT2B7 glucuronidation)|
|Elimination half-life||44 hours (mean)|
|Excretion||Feces (76–77%), urine (17.9–18%) (after oral and IV administration)|
|Chemical and physical data|
|Molar mass||531.318 g·mol−1|
|3D model (JSmol)|
Cobimetinib, sold under the brand name Cotellic among others, is a medication used to treat melanoma. Specifically it is used for advanced disease with either BRAF V600E or V600K mutation. It is used together with vemurafenib. Use is not recommended in the United Kingdom. It is taken by mouth.
Common side effects include diarrhea, rash, nausea, fever, sunburns, liver problems, or muscle damage. Other side effects may include bleeding, heart damage, and retinal vein occlusion. Use during pregnancy may harm the baby. It is a MEK inhibitor.
Cobimetinib was approved for medical use in the United States and Europe in 2015. In the United Kingdom treatment for 4 weeks costs the NHS about £4,275 as of 2021. This amount in the United States is about 7,300 USD.
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.
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.
It is generally take at a dose of 60 mg once per day for 3 weeks with 1 week off.
Society and culture
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.
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.
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.
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