Melanoma, unresectable or metastatic (with BRAF V600E or V600K mutations): Oral: 60 mg once daily days 1 to 21 of each 28-day treatment cycle (in combination with vemurafenib); continue until disease progression or unacceptable toxicity (Larkin 2014).
Off-label combination: Oral: 60 mg once daily on days 1 to 21 of each 28-day treatment cycle (in combination with atezolizumab and vemurafenib) until disease progression or unacceptable toxicity; prior to initiating atezolizumab, patients should receive a 28-day treatment cycle of cobimetinib and vemurafenib (Gutzmer 2020). Refer to protocol for further information.
Missed doses: If a dose is missed or if vomiting occurs after a dose is taken, resume with the next scheduled dose (do not take an additional dose). In the clinical trial, a dose was considered missed if not taken within 4 hours of the scheduled time (Larkin 2013 [Protocol GO28141]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment is necessary.
CrCl <30 mL/minute: There is no dosage adjustment provided in the manufacturer’s labeling (has not been established).
Hepatic impairment prior to treatment: Mild, moderate, or severe impairment (Child Pugh class A, B, or C): No initial dosage adjustment is necessary.
Hepatotoxicity during treatment:
First occurrence of grade 4 lab abnormality (ALT, AST, or alkaline phosphatase >20 times ULN or total bilirubin >10 times ULN) or hepatotoxicity: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved to grade 0 or 1 within 4 weeks.
Recurrent grade 4 lab abnormality or hepatotoxicity: Permanently discontinue cobimetinib.
Refer to adult dosing.
Recommended cobimetinib dose reductions for toxicity (vemurafenib may also require dosage adjustment):
First dose reduction: 40 mg once daily.
Second dose reduction: 20 mg once daily.
Subsequent modification (if unable to tolerate 20 mg once daily): Permanently discontinue cobimetinib.
Cardiotoxicity:
Asymptomatic cardiomyopathy (absolute decrease in left ventricular ejection fraction [LVEF] >10% [from baseline] and less than the institutional lower limit of normal [LLN]): Withhold cobimetinib for 2 weeks and repeat LVEF. If LVEF ≥ LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if LVEF < LLN or absolute decrease from baseline is >10%.
Symptomatic cardiomyopathy (symptomatic LVEF decrease from baseline): Withhold cobimetinib for up to 4 weeks and repeat LVEF. If symptoms resolve and LVEF ≥ LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if symptoms persist or LVEF < LLN or absolute decrease from baseline is >10%.
Creatine phosphokinase elevation (CPK) or rhabdomyolysis:
Grade 4 CPK elevation (>10 times ULN) or any CPK elevation with myalgia: Withhold cobimetinib for up to 4 weeks; if improves to grade 3 or lower, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks.
Dermatologic toxicity:
Grade 2 (intolerable) or grade 3 or 4: Withhold or reduce cobimetinib dose.
New primary cutaneous or noncutaneous malignancies: No cobimetinib dosage modification is necessary.
Hemorrhage:
Grade 3: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks.
Grade 4: Permanently discontinue cobimetinib.
Ocular:
Serous retinopathy: Withhold cobimetinib for up to 4 weeks; if signs/symptoms improve, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved or symptoms recur within 4 weeks at the lower dose.
Retinal vein occlusion: Permanently discontinue cobimetinib.
Photosensitivity:
Grade 2 (intolerable), grade 3 or 4: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks.
Other toxicities:
Grade 2 (intolerable), or any grade 3: Withhold cobimetinib for up to 4 weeks; if improves to grades 0 or 1, resume cobimetinib at the next lower dose level. Permanently discontinue cobimetinib if not improved within 4 weeks.
Grade 4, first occurrence: Withhold cobimetinib until adverse reaction improves to grade 0 or 1 and then resume cobimetinib at the next lower dose level or permanently discontinue.
Grade 4, recurrent: Permanently discontinue cobimetinib.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Cotellic: 20 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Cotellic: 20 mg
Available through specialty pharmacies. Further information may be obtained from the manufacturer, Genentech, at 1-888-249-4918, or at http://www.cotellic.com.
Oral: May be administered with or without food. In the clinical trial, cobimetinib tablets were administered whole with water; tablets should not be chewed, cut, or crushed (Larkin 2013 [Protocol GO28141]).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Cobimetinib may cause teratogenicity, reproductive toxicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation (in combination with vemurafenib)
Cobimetinib may be confused with binimetinib, cabozantinib, capmatinib, ceritinib, crizotinib, dabrafenib, encorafenib, selumetinib, trametinib, vemurafenib.
Cotellic may be confused with cobicistat.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Percentages reported as part of combination chemotherapy regimens.
>10%:
Cardiovascular: Decreased left ventricular ejection fraction (grades 2/3: 26%), hypertension (15%)
Dermatologic: Skin photosensitivity (46% to 47%, grades 3/4: 4%; includes solar dermatitis and sunburn), acneiform eruption (16%, grades 3/4: 2%)
Endocrine & metabolic: Hypophosphatemia (68%), increased gamma-glutamyl transferase (65%; grades 3/4: 21%), hypoalbuminemia (42%), hyponatremia (38%), hyperkalemia (26%), hypokalemia (25%), hypocalcemia (24%)
Gastrointestinal: Diarrhea (60%), nausea (41%), vomiting (24%), stomatitis (14%; includes aphthous stomatitis, mucositis, and oral mucosa ulcer)
Hematologic & oncologic: Lymphocytopenia (73%, grades 3/4: 10%), anemia (69%; grades 3/4: 3%), thrombocytopenia (18%), hemorrhage (13%, grades 3/4: 1%; includes bruise, ecchymoses, epistaxis, gingival hemorrhage, hematemesis, hematochezia, hemoptysis, hemorrhoidal bleeding, hypermenorrhea, melena, menometrorrhagia, nail bed bleeding, pulmonary hemorrhage, purpura, rectal hemorrhage, rupture of ovarian cyst, subarachnoid hemorrhage, subgaleal hematoma, traumatic hematoma, uterine hemorrhage, and vaginal hemorrhage)
Hepatic: Increased serum AST (73%, grades 3/4: 7% to 8%), increased serum alkaline phosphatase (71%, grades 3/4: 7%), increased serum ALT (68%, grades 3/4: 11%)
Neuromuscular & skeletal: Increased creatine phosphokinase (79%, grades 3/4: 12% to 14%)
Ophthalmic: Visual impairment (15%, grades 3/4: <1%; includes blurred vision, decreased visual acuity), chorioretinopathy (13%, grades 3/4: <1%), retinal detachment (12%, grades 3/4: 2%; includes detachment of macular retinal pigment epithelium and retinal pigment epithelium detachment)
Renal: Increased serum creatinine (100%; grades 3/4: 3%)
Miscellaneous: Fever (28%)
1% to 10%:
Central nervous system: Chills (10%)
Dermatologic: Skin rash (grades 3/4: 16%; grade 4: 2%; rash resulting in hospitalization: 3%)
Gastrointestinal: Gastrointestinal hemorrhage (4%)
Genitourinary: Genitourinary tract hemorrhage (2%), hematuria (2%)
Hematologic & oncologic: Keratoacanthoma (≤6%), squamous cell carcinoma of skin (≤6%), basal cell carcinoma (5%)
Hepatic: Abnormal bilirubin levels (grades 3/4: 2%)
<1%, postmarketing, and/or case reports: Cerebral hemorrhage, malignant melanoma (second primary), malignant neoplasm (noncutaneous)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known hypersensitivity to cobimetinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiomyopathy: Symptomatic or asymptomatic declines in left ventricular ejection fraction (LVEF) may occur with cobimetinib. Safety has not been established in patients with baseline LVEF below the institutional lower limit of normal (LLN) or below 50%. Assess LVEF (by echocardiogram or multiple-gated acquisition [MUGA] scan) prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued. May require treatment interruption, dose reduction and/or discontinuation. Also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. The median time to first onset of LVEF decline was 4 months (range: 23 days to 13 months). Decreased LVEF resolved to >LLN or within 10% of baseline at nearly two-thirds of patients with a median time to resolution of 3 months (range: 4 days to 12 months).
• Dermatologic toxicity: Severe rash and other skin reactions (including grades 3 and 4 toxicity) may occur; some events required hospitalization. The median time to onset of grade 3 and 4 rash events was 11 days (range: 3 days to ~3 months); most patients with grades 3 and 4 rash experienced complete resolution at a median time of 21 days (range: 4 days to 17 months). May require treatment interruption, dose reduction and/or discontinuation. Photosensitivity was reported in nearly one-half of patients (may be severe). The median time to first onset of photosensitivity was 2 months (range: 1 day to 14 months); the median duration was 3 months (range: 2 days to 14 months). Photosensitivity resolved in nearly two-thirds of patients. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (≥SPF 30) when outdoors. Photosensitivity may require treatment interruption, dose reduction, and/or discontinuation.
• Hemorrhage: Hemorrhage, including major symptomatic bleeding in a critical area/organ, may occur with cobimetinib. Grade 3 to 4 bleeding has occurred. Cerebral hemorrhage, GI bleeding, reproductive system hemorrhage, and hematuria have been reported. May require treatment interruption, dose reduction, and/or discontinuation.
• Hepatotoxicity: Hepatotoxicity (including grades 3 or 4 transaminase, total bilirubin, or alkaline phosphatase elevations) may occur with cobimetinib. Monitor LFTs at baseline and monthly during treatment, or as clinically necessary. Grade 3 and 4 elevations may require treatment interruption, dose reduction, and/or discontinuation.
• Hypertension: Hypertension has been observed with cobimetinib in combination with vemurafenib, including grades 3 or 4 hypertension.
• Malignancy: New primary cutaneous malignancies may occur. Malignancies included cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA), basal cell carcinoma (BCC), and second primary melanoma. The median time to detection of first cuSCC or KA was 4 months (range: 2 to 11 months); the median time to first detection of BCC was 4 months (range: ~1 to 13 months). The time to onset of second primary melanoma (rare) was 9 to 12 months. Dermatologic exams should be performed prior to initiation, every 2 months during treatment, and for 6 months following discontinuation of cobimetinib/vemurafenib combination therapy. Suspicious lesions should be managed with excision and dermatopathologic evaluation. Dosage adjustment is not recommended for new cutaneous malignancies. Vemurafenib may be associated with the development of noncutaneous malignancy; monitor for signs/symptoms of noncutaneous malignancy during combination treatment.
• Ophthalmic effects: Ocular toxicities may occur, including serous retinopathy (fluid accumulation under retina layers). Chorioretinopathy and retinal detachment have been reported; retinal vein occlusion has also been reported (case reports); permanently discontinue if retinal vein occlusion occurs. The time to first onset of serous retinopathy ranged between 2 days to 9 months with a duration of 1 day to 15 months. Perform ophthalmic examinations regularly during treatment, and with reports of new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt treatment until visual symptoms improve; may require treatment interruption, dose reduction, and/or discontinuation.
• Rhabdomyolysis: Rhabdomyolysis and creatine phosphokinase (CPK) elevations may occur with cobimetinib. The median time to first occurrence of grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months), with a median time to resolution of 15 days (range: 9 days to 11 months). Obtain serum CPK and creatinine levels at baseline, periodically during treatment and as clinically indicated. If CPK is elevated, evaluate for signs/symptoms of rhabdomyolysis or other etiology. Depending on severity, may require treatment interruption, dose reduction, and/or discontinuation.
Other warnings/precautions:
• Appropriate use: Prior to initiating therapy, confirm BRAF V600K or V600E mutation status with an approved test; approved for use in patients with BRAF V600K and BRAF V600E mutations. Not indicated for use in patients with wild-type BRAF melanoma.
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Cobimetinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Cobimetinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Cobimetinib. Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cobimetinib. Risk X: Avoid combination
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Levoketoconazole: Cobimetinib may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Grapefruit juice may increase cobimetinib serum concentrations. Management: Avoid grapefruit juice.
Females of reproductive potential should use effective contraception during therapy and for 2 weeks after the final cobimetinib dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to cobimetinib would be expected to cause fetal harm.
It is not known if cobimetinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 2 weeks after the last cobimetinib dose.
Avoid grapefruit juice.
BRAF V600K or V600E mutation status (prior to treatment); LFTs (baseline and monthly during treatment, more frequently if clinically indicated); creatine phosphokinase (CPK) and serum creatinine (baseline and periodically during treatment, more frequently if clinically indicated); electrolytes (prior to and routinely during treatment). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multiple-gated acquisition (MUGA) scan prior to therapy initiation, 1 month after initiation, and every 3 months thereafter until cobimetinib is discontinued; also assess LVEF at ~2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as clinically indicated after a dose reduction or treatment interruption. Monitor ECG prior to and routinely during treatment.
Dermatologic exams (baseline, every 2 months during treatment, and for 6 months following discontinuation); ophthalmic examinations (baseline, regularly during treatment and with reports of new or worsening visual disturbances); monitor for signs/symptoms of dermatologic toxicity, hemorrhage, noncutaneous malignancy, photosensitivity, and rhabdomyolysis. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cobimetinib is a potent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway (Larkin 2014); it reversibly inhibits MEK1 and MEK2, which are upstream regulators of the extracellular signal-related kinase (ERK) pathway. The ERK pathway promotes cellular proliferation. MEK1 and MEK2 are part of the BRAF pathway, which is activated by BRAF V600E and K mutations. Vemurafenib targets a different kinase in the RAS/RAF/MEK/ERK pathway; when cobimetinib and vemurafenib are used in combination, increased apoptosis and reduced tumor growth occurs.
Distribution: 806 L
Protein binding: 95%; to plasma proteins
Metabolism: Hepatic; via CYP3A4 oxidation and UGT2B7 glucuronidation
Bioavailability, absolute: 46%
Half-life elimination, mean: 44 hours (range: 23 to 70 hours)
Time to peak, median: 2.4 hours (range: 1 to 24 hours)
Excretion: Feces (76%; ~7 as unchanged drug); Urine (~18%; ~2% as unchanged drug)
Hepatic function impairment: Exposure was decreased by 31% in patients with severe hepatic impairment compared to patients with normal hepatic function.
Tablets (Cotellic Oral)
20 mg (per each): $133.43
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