Cobimetinib, a potent, selective, and reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent.1
Cobimetinib is used in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation.1, 2, 25 Cobimetinib has been designated an orphan drug by FDA for the treatment of this cancer.3 An FDA-approved diagnostic test (e.g., cobas® 4800 BRAF V600 mutation test) is required to confirm the presence of the BRAF V600E or V600K mutation prior to initiation of therapy.1, 2
The current indication for cobimetinib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (coBRIM) in patients with previously untreated, unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by the cobas® 4800 BRAF V600 mutation test.1, 2 In this study, 495 patients were randomized (stratified by disease stage and geographic region) in a 1:1 ratio to receive either cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period) in combination with vemurafenib (960 mg twice daily) or placebo in combination with vemurafenib (960 mg twice daily).1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.1, 2 Patients randomized to receive placebo were not permitted to cross over to open-label cobimetinib therapy upon disease progression.1, 2 The primary end point of this study was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST).1, 2
The median age of patients enrolled in the study was 55 years; 93% of patients were white, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had elevated LDH concentrations, 10% had previously received adjuvant therapy, and less than 1% of patients had previously received therapy for brain metastases.1, 2 Most patients (86% of those with known mutation status) had BRAF V600E mutations.1
At initial analysis at a median follow-up of 7.3 months, the median duration of progression-free survival was 6.2 or 9.9 months for placebo and vemurafenib or vemurafenib and cobimetinib.2 Objective response rates (complete or partial) were higher with cobimetinib and vemurafenib compared to placebo and vemurafenib (68 versus 45%).2 Median overall survival had not been reached at the time of the analysis. 2
In a long-term extension of coBRIM, patients were followed for a median duration of 21.2 or 16.6 months for cobimetinib and vemurafenib or placebo and vemurafenib, respectively.25 Median progression-free survival was 12.3 months for patients receiving cobimetinib and vemurafenib compared with 7.2 months for those receiving placebo and vemurafenib.1 A progression-free survival benefit for cobimetinib and vemurafenib was confirmed by independent blinded review.1, 2 In addition, patients receiving cobimetinib and vemurafenib had higher objective response rates (70 versus 50%) compared with those receiving placebo and vemurafenib.1, 25 The median duration of response for patients receiving cobimetinib and vemurafenib or receiving placebo and vemurafenib was 13 or 9.2 months, respectively.1, 25 Median overall survival was 22.3 or 17.4 months, respectively, for cobimetinib and vemurafenib compared with placebo and vemurafenib.1, 25
Use of cobimetinib in combination with vemurafenib also was investigated in a phase 1b, open-label study (BRIM7) in 129 patients with unresectable stage IIIc or IV advanced melanoma with BRAF V600 mutation.19, 26 Patients enrolled in the study were either BRAF inhibitor therapy naïve (BRAF inhibitor-naïve) or had experienced disease progression during prior vemurafenib monotherapy.19, 26 Patients received cobimetinib with vemurafenib, both given in a dose-escalating regimen.26
Initial analysis reported a median progression-free survival of 2.8 months for patients who had progressed on vemurafenib, compared to 13.7 months for BRAF inhibitor naïve patients.19 Response rates were also higher among BRAF inhibitor naïve patients, with 88% achieving a complete (10%) or partial (78%) response.19 For patients who had progressed on prior vemurafenib monotherapy, none achieved a complete response and 15% had a partial response; the remainder had stable (42%) or progressive (36%) disease.19 At a later analysis, with a median follow-up of 28 or 8.4 months for BRAF inhibitor naïve or vemurafenib-experienced patients, respectively, progression-free survival rates were similar, with a median of 13.8 or 2.8 months.26 Median overall survival was 31.8 or 8.5 months for BRAF inhibitor naïve patients or vemurafenib-experienced patients, respectively.26 At 5 years, the overall survival rate was 39.2%, similar to the 3 and 4 year rates (41.5 and 39.2%, respectively), for BRAF inhibitor naïve patients.26 Among patients who had progressed on prior vemurafenib monotherapy, the 3, 4, and 5 year survival rates were the same for each year, at 14%.26
The 2023 American Society for Clinical Oncology (ASCO) guideline on systemic therapy for unresectable and/or metastatic cutaneous melanoma with BRAF mutant (V600) recommends one of the following as first-line therapy: programmed cell death protein (PD-1) inhibitors (nivolumab plus ipilimumab followed by nivolumab; or nivolumab plus relatimab; or nivolumab); or combination BRAF/MEK inhibitor therapy (dabrafenib plus trametinib; or encorafenib plus binimetinib; or vemurafenib plus cobimetinib).28 Per the ASCO guidelines, nivolumab plus ipilimumab is preferred as first-line therapy for patients with unresectable and/or metastatic BRAF mutant (V600) disease over BRAF/MEK inhibitor combination therapy.28
For patients with BRAF mutation-positive (V600) unresectable/metastatic cutaneous melanoma who progress on first-line PD-1 inhibitor therapy, combination BRAF/MEK inhibitor therapy may be offered.28 Patients with BRAF mutation-positive (V600) unresectable/metastatic cutaneous melanoma who had disease progression following combination BRAF/MEK inhibitor therapy may be offered PD-1 inhibitor therapy.28
Cobimetinib is used as a single agent for treatment of adult patients with histiocytic neoplasms.1, 27 Cobimetinib has been designated an orphan drug by FDA for the treatment of this cancer.3
The current indication for cobimetinib is based on the results of a single-center, single-arm, phase 2 trial.27 Twenty-six adult patients with histiocytic neoplasms (multi-system disease, recurrent or refractory disease, or single-system disease unlikely to benefit from conventional therapies), regardless of tumor genotype, were enrolled; patients with documented BRAF V600E mutations could be enrolled if access to a BRAF inhibitor was not available or if BRAF inhibitor therapy was discontinued due to toxicity.1 Histiocytic neoplasms present in enrolled patients included Langerhans cell histiocytosis (n=4), Rosai-Dorfman disease (n=4), Erdheim-Chester disease (n=13), xanthogranuloma (n=2), and mixed histiocytosis (n=3).1 The median patient age was 50.5 years, 65% of patients were male, and 85% were white.1 Cobimetinib was given at a dose of 60 mg once daily for 21 days and then off for 7 days, in a 28-day cycle.1 The primary outcome was best overall response rate, maintained on 2 occasions at least 4 weeks apart, as assessed by PET response criteria (PRC).1, 27 PRC-based duration of response and best overall response rate assessed using RECIST, maintained on 2 occasions at least 4 weeks apart, were also assessed.1
The median duration of follow-up was 11.4 months; with a median time to a PRC-based response of 2 months.1 The overall response rate was 76.9%, with a complete response seen in 61.5% and a partial response in 15.4% of patients, based on PRC.1 The median PRC-based duration of response was 31 months.1 The overall response rate based on RECIST was 46.2%; complete or partial response was seen in 11.5 or 34.6% of patients, respectively.1
Cobimetinib fumarate is administered orally without regard to meals.1
Store below 30°C.1
Dosage of cobimetinib fumarate is expressed in terms of cobimetinib.1
For use in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation, the recommended adult dosage of cobimetinib is 60 mg once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
For use as a single agent for the treatment of histiocytic neoplasms, the recommended adult dosage of cobimetinib is 60 mg once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
If adverse reactions occur, consider interruption of therapy, dosage reduction, and/or permanent discontinuance of cobimetinib.1 If dosage modification of cobimetinib is necessary, an initial dosage reduction to 40 mg once daily is recommended.1 If further dosage reduction is necessary, reduce the dosage to 20 mg once daily.1 Dosages less than 20 mg once daily are not recommended; permanently discontinue the drug if the 20-mg daily dosage is not tolerated.1
If grade 3 hemorrhage occurs, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when the toxicity improves to grade 1 or less.1 If the toxicity does not improve within 4 weeks of withholding cobimetinib, permanently discontinue the drug.1
If grade 4 hemorrhage occurs, permanently discontinue cobimetinib therapy.1
If an asymptomatic absolute decrease in left ventricular ejection fraction (LVEF) from baseline of more than 10% and to a level below the lower limit of normal (LLN) occurs, withhold cobimetinib therapy for 2 weeks and reassess left ventricular function; resume therapy at a reduced dosage when LVEF recovers to at least the LLN and the absolute decrease in LVEF from baseline is 10% or less.1
If a symptomatic decrease in LVEF from baseline occurs, withhold cobimetinib therapy for up to 4 weeks and reassess left ventricular function; resume therapy at a reduced dosage when symptoms resolve, LVEF recovers to at least the LLN, and the absolute decrease from baseline is 10% or less.1
If LVEF remains below the LLN, the absolute decrease from baseline remains above 10%, or symptoms persist, permanently discontinue cobimetinib therapy.1
If QT-interval prolongation occurs during combination therapy with cobimetinib and vemurafenib, dosage modifications for vemurafenib may be required.1
If intolerable grade 2 dermatologic reactions or grade 3 or 4 dermatologic reactions occur, withhold cobimetinib therapy or reduce the dose.1
Serous Retinopathy or Retinal Vein Occlusion
If serous retinopathy occurs, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when visual manifestations improve.1 If the toxicity does not improve or if symptoms recur within 4 weeks of resuming therapy at a reduced dosage, permanently discontinue the drug.1
If retinal vein occlusion occurs, permanently discontinue cobimetinib therapy.1
Liver Laboratory Abnormalities and Hepatotoxicity
For the first occurrence of grade 4 liver function test abnormalities, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when the toxicity improves to grade 1 or less.1 If liver function test abnormalities do not improve to grade 1 or less within 4 weeks of withholding therapy, permanently discontinue the drug.1
If grade 4 liver function test abnormalities recur, permanently discontinue cobimetinib therapy.1
Rhabdomyolysis and CPK Elevations
In patients who exhibit grade 4 CPK elevations or any grade of CPK elevation with concomitant myalgia, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when the toxicity improves to grade 3 or less.1 If the toxicity does not improve within 4 weeks of withholding therapy, permanently discontinue the drug.1
If intolerable grade 2 photosensitivity or grade 3 or 4 photosensitivity occurs, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when the toxicity improves to grade 1 or less.1 If the toxicity does not improve within 4 weeks of withholding therapy, permanently discontinue the drug.1
Development of New Primary Malignancies
No dosage adjustment is necessary in patients who develop new primary cutaneous or noncutaneous malignancies.1
If an intolerable grade 2 or any grade 3 adverse reaction occurs, withhold cobimetinib therapy for up to 4 weeks; resume therapy at a reduced dosage when the toxicity improves to grade 1 or less.1 If the toxicity does not improve within 4 weeks of withholding therapy, permanently discontinue the drug.1
For the first occurrence of any grade 4 adverse reaction, withhold or permanently discontinue cobimetinib therapy; if withheld, resume therapy at a reduced dosage when the toxicity improves to grade 1 or less.1 If the grade 4 adverse reaction recurs, permanently discontinue cobimetinib therapy.1
Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes
Avoid concomitant use of cobimetinib with drugs that are moderate or potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A.1 If concomitant short-term (14 days or less) therapy with a moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of cobimetinib from 60 mg once daily to 20 mg once daily.1 When concomitant use of the moderate CYP3A inhibitor is discontinued, resume the prior cobimetinib dosage of 60 mg once daily.1
In patients receiving a reduced dosage of cobimetinib (40 or 20 mg once daily), select an alternative drug with no or only mild CYP3A inhibitory activity.1
No dosage adjustment is necessary in patients with mild, moderate, or severe preexisting hepatic impairment (Child-Pugh class A, B, or C).1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 The manufacturer states that an appropriate dosage for patients with severe renal impairment has not been established.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Photosensitivity reactions, sometimes severe, have been reported in patients receiving cobimetinib.1 In the coBRIM study in patients with unresectable or metastatic melanoma, photosensitivity reactions occurred in 47% of patients receiving combination therapy with cobimetinib and vemurafenib; grade 3 reactions occurred in 4% of patients receiving combined therapy.1 The median time to first onset of photosensitivity reactions in patients receiving combined therapy was 2 months (range: 1 day to 14 months).1 The median duration of photosensitivity reactions was 3 months (range: 2 days to 14 months).1 Most patients (63%) had resolution of photosensitivity reactions.1
The manufacturer recommends that patients avoid exposure to sunlight during cobimetinib therapy.1 Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if photosensitivity reactions occur during therapy with the drug.1
When cobimetinib is used in combination with vemurafenib, the usual cautions, precautions, and contraindications associated with vemurafenib must be considered in addition to those associated with cobimetinib.1
New primary cutaneous or noncutaneous malignancies have been reported in patients receiving cobimetinib.1
In the coBRIM study in patients with unresectable or metastatic melanoma, cutaneous squamous cell carcinoma or keratoacanthoma, basal cell carcinoma, or new primary melanoma occurred in 6, 4.5, or 0.8%, respectively, of patients receiving cobimetinib in combination with vemurafenib compared with 20, 2.4, or 2.4%, respectively, of those receiving vemurafenib alone.1 In this study, the median time to detection of cutaneous squamous cell carcinoma, including keratoacanthoma, or basal cell carcinoma was 4 months in patients receiving combination therapy with cobimetinib and vemurafenib.1 Development of new primary melanoma occurred 9 and 12 months after initiation of combination therapy with cobimetinib and vemurafenib in 2 patients.1
In the coBRIM study, noncutaneous malignancies were reported in 0.8% of patients receiving cobimetinib in combination with vemurafenib compared with 1.2% of those receiving vemurafenib alone.1
Perform a dermatologic evaluation at baseline and every 2 months during monotherapy with cobimetinib or when cobimetinib is used in combination with vemurafenib.1 Continue monitoring for 6 months following discontinuance of cobimetinib, when administered in combination with vemurafenib.1 Treat suspicious cutaneous lesions and excise for pathologic evaluation as appropriate.1 Monitor for new noncutaneous malignancies when cobimetinib is used in combination with vemurafenib.1
Hemorrhage, including major hemorrhagic events (defined as symptomatic bleeding in a critical area or organ), has been reported in patients receiving cobimetinib.1 In the coBRIM study in patients with unresectable or metastatic melanoma, hemorrhage occurred in 13% of patients receiving cobimetinib in combination with vemurafenib compared with 7% of those receiving vemurafenib alone.1 Grade 3 or 4 hemorrhage was reported in 1.2% of patients receiving combination therapy compared with 0.8% of those receiving vemurafenib alone.1 An increased incidence of GI hemorrhage, reproductive system hemorrhage, or hematuria was observed in patients receiving combination therapy with cobimetinib and vemurafenib (3.6, 2, or 2.4%, respectively) compared with those receiving vemurafenib alone (1.2, 0.4, or 0.8%, respectively).1 Cerebral hemorrhage occurred in 0.8% of patients receiving combination therapy compared with none of those receiving vemurafenib alone.1 Hemorrhagic events (all grade 1 severity) occurred in 19% of patients with histiocytic neoplasms receiving cobimetinib monotherapy.1
Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if hemorrhagic events occur during therapy with the drug.1
Cardiomyopathy (defined as a symptomatic or asymptomatic decrease in left ventricular ejection fraction [LVEF]) has been reported in patients receiving cobimetinib.1 Safety of cobimetinib has not been established in patients with a baseline LVEF below the lower limit of normal (LLN) or less than 50%.1
In the coBRIM study in patients with unresectable or metastatic melanoma, grade 2 or 3 decreases in LVEF occurred in 26% of patients receiving combination therapy with cobimetinib and vemurafenib and in 19% of those receiving vemurafenib alone; temporary interruption and/or dosage modification or permanent discontinuance of therapy was necessary in 22 or 14%, respectively, of those with left ventricular dysfunction.1 The median time to first onset of left ventricular dysfunction was 4 months (range: 23 days to 13 months).1 Left ventricular dysfunction resolved (i.e., LVEF improved to above the LLN or to within 10% of baseline) in 62% of patients receiving combination therapy with cobimetinib and vemurafenib; the median time to resolution was 3 months (range: 4 days to 12 months).1
In patients with histiocytic neoplasms receiving monotherapy with cobimetinib, grade 2 or grade 3—4 decreases in LVEF occurred in 8 or 12% of patients, respectively.1 The median time to first onset of left ventricular dysfunction was 29 days (range: 22—114 days).1 Patients who experienced left ventricular dysfunction had dosage reductions or interruptions in therapy with cobimetinib, and none required permanent discontinuation.1 Left ventricular dysfunction resolved (i.e., LVEF improved to above the LLN or within 10% of baseline) in 60% of patients, with a median time to resolution of 31 days (range: 13—126 days).1
Assess LVEF prior to and 1 month after initiation of cobimetinib therapy and then every 3 months during therapy.1 If left ventricular dysfunction occurs, temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary; reassess LVEF at approximately 2, 4, 10, and 16 weeks following reinitiation of the drug and then as clinically indicated.1
Severe dermatologic reactions, sometimes requiring hospitalization, have been reported in patients receiving cobimetinib.1 In the coBRIM study in patients with unresectable or metastatic melanoma, grade 3 or 4 rash occurred in 16% (grade 4 in 1.6%) of patients receiving combination therapy with cobimetinib and vemurafenib and in 17% (grade 4 in 0.8%) of those receiving vemurafenib alone; hospitalization was required in 3.2 or 2% of patients receiving combination therapy with cobimetinib and vemurafenib or vemurafenib alone, respectively.1 The median time to onset of grade 3 or 4 rash in patients receiving combination therapy with cobimetinib and vemurafenib was 11 days (range: 3 days to 2.8 months).1 Complete resolution occurred in 95% of patients with grade 3 or 4 rash; the median time to resolution was 21 days (range: 4 days to 17 months).1 In patients with histiocytic neoplasms receiving monotherapy with cobimetinib, rash events were reported in 81% of patients; all were grade 1—2 in severity.1
Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if dermatologic reactions occur during therapy with the drug.1
Serous Retinopathy and Retinal Vein Occlusion
Ocular toxicities, such as serous retinopathy, have been reported in patients receiving cobimetinib.1, 2 In the coBRIM study in patients with unresectable or metastatic melanoma, symptomatic or asymptomatic serous retinopathy occurred in 26% of patients receiving combination therapy with cobimetinib and vemurafenib; the most common events were chorioretinopathy and retinal detachment.1 The time to initial onset of serous retinopathy ranged from 2 days to 9 months and the duration ranged from 1 day to 15 months.1 Retinal vein occlusion occurred in one patient in each treatment group.1 In patients with histiocytic neoplasms receiving monotherapy with cobimetinib, grade 2 retinopathy and grade 3 retinal vascular disorders each occurred in 4% of patients.1
Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during cobimetinib therapy.1 Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if ocular toxicities occur during therapy with the drug.1
Liver function test abnormalities have been reported in patients receiving cobimetinib.1 In the coBRIM study in patients with unresectable or metastatic melanoma, grade 3 or 4 elevations in ALT, AST, total bilirubin, or alkaline phosphatase concentrations occurred in 11, 8, 1.6, or 7%, respectively, of patients receiving combination therapy with cobimetinib and vemurafenib and in 5, 2.1, 1.2, or 3.3%, respectively, of patients receiving vemurafenib alone.1 Concurrent elevations in ALT (exceeding 3 times the upper limit of normal [ULN]) and total bilirubin concentrations (exceeding 2 times the ULN) with normal alkaline phosphatase concentrations (not exceeding 2 times the ULN) occurred in 1 of 247 patients (0.4%) receiving combination therapy with cobimetinib and vemurafenib and in none of those receiving vemurafenib alone.1 In patients with histiocytic neoplasms receiving cobimetinib monotherapy, grade 3 or 4 elevations in AST and ALT occurred in 9 and 5% of patients, respectively.1
Perform liver function tests prior to initiation of cobimetinib therapy and then monthly, or more frequently as clinically indicated, during therapy with the drug.1 Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if liver function test abnormalities occur during therapy with the drug.1
Rhabdomyolysis has been reported in patients receiving cobimetinib.1 In the coBRIM study in patients with unresectable or metastatic melanoma, grade 3 or 4 elevations of serum CPK, including asymptomatic elevations over baseline, occurred in 14% of patients receiving combination therapy with cobimetinib and vemurafenib and in 0.5% of patients receiving vemurafenib alone.1 The median time to first occurrence of grade 3 or 4 elevations in CPK concentrations was 16 days (range: 12 days to 11 months) in patients receiving combination therapy with cobimetinib and vemurafenib.1 The median time to complete resolution of elevated CPK concentrations was 15 days (range: 9 days to 11 months).1 Concurrent elevations in CPK concentrations (exceeding 10 times the baseline value) and serum creatinine concentrations (1.5 or more times the baseline value) occurred in 3.6% of patients receiving combination therapy with cobimetinib and vemurafenib and in 0.4% of patients receiving vemurafenib alone.1 In patients with histiocytic neoplasms receiving cobimetinib monotherapy, grade 2 CPK elevations occurred in 27% of patients and grade 3—4 CPK elevations occurred in 27% of patients.1
Evaluate serum CPK and creatinine concentrations at baseline, periodically during cobimetinib therapy, and as clinically indicated.1 Patients with elevated CPK concentrations should be evaluated for manifestations of rhabdomyolysis and for other potential causes.1 Temporary interruption, dosage reduction, or discontinuance of cobimetinib may be necessary if increased CPK concentrations occur during therapy with the drug.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of cobimetinib in pregnant women; however, based on its mechanism of action and animal findings, cobimetinib may cause fetal harm.1 Embryotoxicity (i.e., post-implantation loss) and teratogenicity (i.e., great vessel and eye socket abnormalities) were observed in pregnant animals receiving cobimetinib at exposure levels equivalent to 0.9-1.4 times the human exposure at the recommended dosage.1
Avoid pregnancy during cobimetinib therapy.1 Advise women of childbearing potential to use an effective method of contraception while receiving cobimetinib and for at least 2 weeks after discontinuance of therapy.1 Apprise patients of the potential hazard to the fetus if the drug is used during pregnancy.1
Cobimetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
It is not known whether cobimetinib is distributed into human milk.1 The effects of the drug on nursing infants or on the production of milk are unknown.1 Because of the potential for serious adverse reactions to cobimetinib in nursing infants, advise women not to breast-feed during cobimetinib therapy and for 2 weeks following the final dose.1
Females and Males of Reproductive Potential
Results of animal studies suggest that cobimetinib may impair female and male fertility.1 In a general toxicology study, degeneration of reproductive tissues was observed in female (apoptosis and necrosis of corpora lutea and vaginal epithelial cells) and male (testicular degeneration) animals receiving cobimetinib at exposure levels approximately 2 and 0.1 times, respectively, the human exposure at the recommended dosage.1
Avoid pregnancy during cobimetinib therapy and for at least 2 weeks after drug discontinuance.1 Advise women of childbearing potential to use an effective method of contraception while receiving cobimetinib and for at least 2 weeks after discontinuance of therapy.1
Safety and efficacy of cobimetinib have not been established in pediatric patients.1
Safety and efficacy were assessed, but were not established, in a clinical study of 55 pediatric patients 2—17 years of age with solid tumors; no new safety events were observed.1 Cobimetinib exposure at the maximally tolerated dosage in pediatric patients was lower than that observed in adult patients receiving the recommended dosage.1
Mortality from unknown cause has been observed in immature rats receiving cobimetinib (exposure level on postnatal days 10-17 of approximately 0.13-0.5 times the AUC at the recommended human adult dosage).1
Clinical studies of cobimetinib did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1
Following administration of a single 10-mg dose of cobimetinib, systemic exposure to cobimetinib was similar in individuals with mild or moderate hepatic impairment and those with normal hepatic function, but systemic exposure to cobimetinib was decreased by 31% in individuals with severe hepatic impairment.1 Cobimetinib dosage adjustment is not necessary in patients with hepatic impairment.1
Formal pharmacokinetic studies of cobimetinib have not been conducted in patients with renal impairment; however, cobimetinib undergoes minimal renal elimination.1
In a population pharmacokinetic analysis, systemic exposure to cobimetinib was similar in patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment compared with patients with normal renal function.1 Cobimetinib dosage adjustment is not necessary in patients with mild to moderate renal impairment.1 Cobimetinib has not been studied in patients with severe renal impairment; therefore, the manufacturer states that an appropriate dosage for these patients has not been established.1
Adverse effects reported in 20% or more of patients receiving cobimetinib in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation include diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.1 Laboratory abnormalities of grade 3 or 4 severity reported in 5% or more of patients receiving cobimetinib in combination with vemurafenib include elevated concentrations of CPK, elevated concentrations of aminotransferases (i.e., AST, ALT), lymphopenia, elevated concentrations of alkaline phosphatase, hypophosphatemia, elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), and hyponatremia.1
Adverse effects reported in 20% or more of patients receiving cobimetinib monotherapy for histiocytic neoplasms include acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritis, dyspepsia, vomiting, dyspnea, and urinary tract infections.1 Laboratory abnormalities of grade 3 or 4 severity reported in 5% or more of patients receiving cobimetinib monotherapy for histiocytic neoplasms include hyponatremia, elevated concentrations of CPK, hypokalemia, increased serum creatinine, elevated concentrations of AST, hypocalcemia, lymphopenia, leukopenia, and anemia.1
Cobimetinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A and uridine diphosphate-glucuronosyltransferase (UGT) 2B7.1 In vitro, cobimetinib is a substrate of CYP3A and P-glycoprotein (P-gp).1 In vitro studies also indicate that cobimetinib may inhibit CYP isoenzymes 3A and 2D6.1 In vitro, cobimetinib does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2C19 or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.1 Cobimetinib also does not inhibit P-gp in vitro at clinically relevant concentrations.1
In vitro studies indicate that cobimetinib is not a substrate or inhibitor of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3 at clinically relevant concentrations.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of cobimetinib with potent or moderate inhibitors of CYP3A may result in increased systemic exposure (AUC) of cobimetinib.1 Concomitant administration of the potent CYP3A inhibitor itraconazole (200 mg daily for 14 days) with cobimetinib (single 10-mg dose) in healthy individuals increased the peak plasma concentration and AUC of cobimetinib by 3.2- and 6.7-fold, respectively.1 Simulations suggest that steady-state concentrations of cobimetinib following concomitant administration of a reduced dosage of cobimetinib (20 mg once daily) with a moderate CYP3A inhibitor for less than 14 days are similar to steady-state concentrations attained with cobimetinib alone at a dosage of 60 mg once daily.1
Avoid concomitant use of cobimetinib with potent or moderate inhibitors of CYP3A.1 If concomitant short-term (14 days or less) therapy with a moderate CYP3A inhibitor (e.g., an anti-infective agent [e.g., erythromycin, ciprofloxacin]) cannot be avoided, the manufacturer recommends reducing the dosage of cobimetinib from 60 mg once daily to 20 mg once daily.1 When concomitant use of the moderate CYP3A inhibitor is discontinued, resume the prior cobimetinib dosage of 60 mg once daily.1 In patients receiving a reduced dosage of cobimetinib (40 or 20 mg once daily), select an alternative drug with no or only mild CYP3A inhibitory activity.1
Concomitant use of cobimetinib with potent or moderate inducers of CYP3A may result in decreased systemic exposure and reduced efficacy of cobimetinib.1 Simulations suggest that concomitant administration of a potent or moderate CYP3A inducer and cobimetinib may decrease systemic exposure of cobimetinib by 83 or 73%, respectively.1
Avoid concomitant use of cobimetinib with potent or moderate inducers of CYP3A (e.g., carbamazepine, efavirenz, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]).1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant administration of cobimetinib (60 mg once daily for 15 days) with the CYP2D6 substrate dextromethorphan (single 30-mg dose) or the CYP3A substrate midazolam (single 2-mg dose) in patients with solid tumors did not substantially alter systemic exposure to dextromethorphan or midazolam.1
Drugs Affecting Efflux Transport Systems
Cobimetinib is a substrate of the efflux transporter P-gp.1 Concomitant use of cobimetinib with drugs that inhibit P-gp may result in increased concentrations of cobimetinib.1
Drugs Affecting Gastric Acidity
Concomitant administration of the proton-pump inhibitor rabeprazole (20 mg once daily for 5 days) with cobimetinib (single 20-mg dose) under fed and fasted conditions did not result in clinically important changes in systemic exposure of cobimetinib.1
Concomitant use of cobimetinib (60 mg once daily) with vemurafenib (960 mg twice daily) did not result in clinically important pharmacokinetic interactions.1, 19, 21
Cobimetinib, a potent, selective, and reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent.1, 2, 10, 21 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1 Approximately 40-60% of cutaneous melanomas carry a BRAF mutation.4, 5, 8, 10, 11 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E);4, 6, 8, 9, 10, 11 a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K).8, 9, 10, 11 BRAF V600 mutations result in activation of the BRAF pathway that includes MEK 1 and 2.1 The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).6, 7, 8, 9, 10 Cobimetinib has demonstrated antitumor activity in mice bearing tumor xenografts that expressed BRAF V600E.1
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway.2, 14, 20 Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib).1, 2, 14, 20 In vitro, use of cobimetinib in combination with vemurafenib resulted in increased apoptosis and reduced tumor growth of melanoma cell lines testing positive for BRAF V600E compared with either drug alone.1 In addition, cobimetinib prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in mice bearing tumor xenografts.1
Following oral administration of cobimetinib in healthy individuals, the absolute bioavailability of the drug is 46%.1 Cobimetinib exhibits linear pharmacokinetics over a dose range of 3.5-100 mg.1 Following oral administration in cancer patients, median time to peak plasma concentrations of cobimetinib is 2.4 hours.1 Repeated administration of cobimetinib 60 mg daily resulted in a 2.4-fold mean cobimetinib accumulation ratio.1 Steady-state concentrations are reached within 9 days.1 Administration of a single 20-mg dose of cobimetinib with a high-fat meal did not affect systemic exposure (AUC) and peak plasma concentration of the drug in healthy individuals.1 Cobimetinib is highly bound (95%) to plasma proteins.1 Following oral administration of cobimetinib 60 mg once daily in cancer patients, the mean terminal half-life of cobimetinib was 44 hours.1 Cobimetinib is metabolized mainly by cytochrome P-450 (CYP) isoenzyme 3A and uridine diphosphate-glucuronosyltransferase (UGT) 2B7.1 Following oral administration of a single radiolabeled dose of cobimetinib, 76% of the radioactivity was recovered in feces (6.6% of the dose as unchanged drug) and 17.8% was recovered in urine (1.6% of the dose as unchanged drug).1
The pharmacokinetics of cobimetinib do not appear to be affected substantially by age (19-88 years), gender, or ethnicity.1, 21
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at http://www.ahfsdruginformation.com.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Cobimetinib is obtained through specialty pharmacies.29 Contact manufacturer or consult the Cotellic®product website [Web]for specific availability information.29
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 20 mg (of cobimetinib) | Cotellic® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech. Cotellic® (cobimetinib) tablets prescribing information. South San Francisco, CA; 2023 May. [Web]
2. Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med . 2014; 371:1867-76. [PubMed 25265494]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2023 Nov 6. [Web]
4. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med . 2011; 364:2507-16. [PubMed 21639808]
5. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med . 2010; 363:809-19. [PubMed 20818844]
6. Russo AE, Torrisi E, Bevelacqua Y et al. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol . 2009; 34:1481-9. [PubMed 19424565]
7. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med . 2011; 364:2547-8. [PubMed 21639809]
8. Liu Y, Sheikh MS. Melanoma: Molecular Pathogenesis and Therapeutic Management. Mol Cell Pharmacol . 2014; 6:228. [PubMed 25745537]
9. Ascierto PA, Kirkwood JM, Grob JJ et al. The role of BRAF V600 mutation in melanoma. J Transl Med . 2012; 10:85. [PubMed 22554099]
10. Richman J, Martin-Liberal J, Diem S et al. BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert Opin Pharmacother . 2015; 16:1285-97. [PubMed 26001180]
11. Rauschenberg R, Garzarolli M, Dietrich U et al. Systemic therapy of metastatic melanoma. J Dtsch Dermatol Ges . 2015; 13:1223-37. [PubMed 26612791]
13. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med . 2012; 366:707-14. [PubMed 22356324]
14. Sanlorenzo M, Choudhry A, Vujic I et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol . 2014; 71:1102-1109.e1. [PubMed 25440439]
15. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res . 2012; 18:263-72. [PubMed 22096025]
16. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature . 2010; 464:427-30. [PubMed 20179705]
17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med . 2012; 366:207-15. [PubMed 22256804]
18. Weeraratna AT. RAF around the edges--the paradox of BRAF inhibitors. N Engl J Med . 2012; 366:271-3. [PubMed 22256810]
19. Ribas A, Gonzalez R, Pavlick A et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol . 2014; 15:954-65. [PubMed 25037139]
20. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med . 2012; 367:1694-703. [PubMed 23020132]
21. Han K, Jin JY, Marchand M et al. Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol . 2015; 76:917-24. [PubMed 26365290]
22. Roche Pharma AG. Cotellic® (cobimetinib) tablets summary of product characteristics. Welwyn Garden City, United Kingdom. (undated) [Web]
24. Peng L, Wang Y, Hong Y et al. Incidence and relative risk of cutaneous squamous cell carcinoma with single-agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: a meta-analysis. Oncotarget . 2017; 8:83280-83291. [PubMed 29137342]
25. Ascierto P, Dreno B, Larkin J, et al. 5-year outcomes with cobimetinib plus vemurafenib in BRAFv600 mutation-positive advanced melanoma: extended follow-up of the coBRIM study. Clin Cancer Res . 2021;27:5225-5235. [PubMed 34158360]
26. Ribas A, Daud A, Pavlick A, et al. Extended 5-year follow-up results of a phase Ib study (BRIM7) of vemurafenib and cobimetinib in BRAF-mutant melanoma. Clin Cancer Res . 2020;46:46-53. [PubMed 31732523]
27. Diamond E, Durham B, Ulaner G, et al. Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature . 2019;567:521-524. [PubMed 30867592]
28. Seth R, Agarwala S, Messersmith H, et al. Systemic therapy for melanoma: ASCO Guideline update. J Clin Oncol . 2023;41(30):4794-4820. [PubMed 37579248]
29. Genentech. Cotellic® Distribution from Helpful Resources for Practice website. Undated. Accessed 2023 Oct 23. [Web]