Cobimetinib
Indications
Cobimetinib is used for:
In combination w/ vemurafenib for the treatment of adult patients w/ unresectable or metastatic melanoma w/ a BRAF V600 mutation.
Adult Dose
Melanoma
Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib
60 mg PO qDay for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity
Vemurafenib: 960 mg PO BID on days 1-28 of an every 28-day cycle
Hepatic impairment
Mild-to-severe (Child-Pugh A to C): No dosage adjustment necessary
Child Dose
Renal Dose
Renal impairment
Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
Severe (CrCl <30 mL/min): Safety and efficacy not established
Administration
May be taken with or without food.
Contra Indications
Hypersensitivity.
Precautions
Patients must have BRAF V600 mutation +ve tumour status confirmed by a validated test before treatment. Assess symptoms of new or worsening visual disturbances. Evaluate LVEF before initiation, then after the 1st mth of treatment & at least every 3 mth or as clinically indicated until treatment discontinuation. Monitor liver value abnormalities. Diarrhoea, lactose intolerance; QT prolongation. Concomitant use w/ strong/moderate CYP3A inhibitors.
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in a breastfed infant, advise women not to breastfeed during treatment and for 2 weeks after the final dose
Pregnancy-Lactation
Pregnancy
Based on findings from animal reproduction studies and its mechanism of action, cobimetinib can cause fetal harm when administered to a pregnant woman
In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9- to 1.4-times those observed in humans at the recommended human dose of 60 mg
Advise pregnant women of the potential risk to a fetus
Contraception: Advise females of reproductive potential to use effective contraception during treatment with and for 2 weeks after the final dose
Infertility: Based on findings in animals, cobimetinib may reduce fertility in females and males of reproductive potential
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions in a breastfed infant, advise women not to breastfeed during treatment and for 2 weeks after the final dose
Interactions
Increased AUC w/ strong/moderate CYP3A inhibitors & P-glycoprotein (P-gp) inhibitors. Reduced exposure w/ strong CYP3A inducers.
Adverse Effects
Side effects of Cobimetinib :
>10%
Increased creatinine (99.6%)
Increased CPK (79%)
Increased AST (73%)
Lymphopenia (73%)
Increased alkaline phosphatase (71%)
Anemia (69%)
Increased ALT (68%)
Hypophosphatemia (68%)
Increased GGT (65%)
Diarrhea (60%)
Photosensitivity (46%)
Hypoalbuminemia (42%)
Nausea (41%)
Hyponatremia (38%)
Pyrexia (28%)
Hyperkalemia (26%)
Hypokalemia (25%)
Hypocalcemia (24%)
Vomiting (24%)
Thrombocytopenia (18%)
Acneiform dermatitis (16%)
Hypertension (15%)
Vision impaired (15%)
Alopecia (15%)
Stomatitis (14%)
Hemorrhage (13%)
Chorioretinopathy (13%)
Retinal detachment (12%)
Hyperkeratosis (11%)
1-10%
Chills (10%)
Erythema (10%)
Mechanism of Action
Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2
MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation
BRAF V600E and K mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2
Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations
Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model