Cobimetinib is a tyrosine kinase receptor inhibitor that is used in combination with vemurafenib as therapy for selected forms of advanced malignant melanoma. The combination of cobimetinib and vemurafenib is commonly associated with serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.
Cobimetinib (koe" bi me' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against the mitogen-activated extracellular regulated kinase (MEK), which is an important component of the kinase cascade in the mitogen activated protein kinase (MAPK) pathway (RAS-RAF-MEK-ERK). Components of the MAPK pathways are frequently mutated in patients with malignant melanoma, particularly the RAF isoform BRAF. BRAF-mutations cause a constitutive activation of the MAPK pathways, resulting in unregulated cell growth and proliferation. Inhibition of MEK has been found to be synergistic when combined with specific BRAF inhibitors as therapy of BRAF-mutated cancers. Clinical trials have shown that the addition of cobimetinib with vemurafenib (a specific BRAF-kinase inhibitor) results in improvements in survival in patients with melanoma who harbor the V600 BRAF mutation. Cobimetinib received accelerated approval for use as combination therapy with vemurafenib in the United States in 2015. Current indications are as combination therapy of metastatic or unresectable melanoma with BRAF V600E or V600K mutations. Cobimetinib is available in tablets of 20 mg under the brand name Cotellic. The recommended dose is 60 mg once daily for the first 21 days of each 28-day cycle, continued until disease progression or intolerable toxicity occurs. Side effects are common and include diarrhea, rash, photosensitivity, nausea, stomatitis, fever, alopecia and thrombocytopenia. Uncommon, but potentially severe side effects include severe diarrhea leading to dehydration and renal failure, rhabdomyolysis, cardiac toxicity, retinal detachment and embryo-fetal toxicity.
Elevations in serum aminotransferase and alkaline phosphatase levels are common during vemurafenib therapy and are even more common when it is combined with cobimetinib, abnormal liver tests occurring in 26% to 70% of treated patients and ALT values rising above 5 times the upper limit of the normal range (ULN) in 6% to 12%. Instances of clinically apparent liver injury with jaundice have also been reported during the clinical trials of cobimetinib and vemurafenib therapy, but the clinical features, course and outcomes of these episodes have not been described in detail. At least one instance of hepatocellular injury with jaundice was included in the initial safety review of cobimetinib. The MAPK pathway inhibitors as a class are often associated with transient serum enzyme elevations and more rarely with instances of clinically apparent liver injury, but the clinical features have not been described and the association with cobimetinib not clearly defined. The rate of clinically significant liver injury and hepatic failure associated with protein kinase inhibitors is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden.
Mechanism of Injury
The cause of liver injury that occurs during therapy with MAPK pathway inhibitors is not well understood, but may relate to the direct effects of inhibition of these enzymes on hepatocytes. Cobimetinibb is metabolized in the liver via the cytochrome P450 system, predominantly CYP 3A and is susceptible to drug-drug interactions with strong inhibitors or inducers of this microsomal enzyme.
Outcome and Management
Liver injury due to cobimetinib varies in severity from minor, transient serum enzyme elevations to acute symptomatic hepatitis. The product label for cobimetinib recommends monitoring of routine liver tests during treatment. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks. Restarting therapy is usually, but not always followed by recurrence of the serum enzyme elevations. There does not appear to be cross reactivity with other tyrosine kinase receptor inhibitors and, in some situations, switching to another protein kinase inhibitor may be appropriate.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Related Drugs: Trametinib, Vemurafenib
Cobimetinib – Cotellic®
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