Binimetinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent.1, 2
Binimetinib is used in combination with encorafenib for the treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation.1, 2, 3 Binimetinib has been designated an orphan drug by FDA for the treatment of this cancer.4 An FDA-approved diagnostic test is required to confirm the presence of the BRAF V600E or V600K mutation in tumor specimens prior to initiation of therapy.1, 2 22 In patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, combined therapy with binimetinib and encorafenib has been shown to prolong progression-free survival and overall survival, and increase response rate compared with vemurafenib alone.1, 2, 3
This indication for binimetinib use is based principally on the results of a randomized, open-label, phase 3 study (COLUMBUS) in patients with unresectable locally advanced or metastatic melanoma positive for V600E or V600K BRAF mutation as detected by the bioMerieux THxID® BRAF V600 mutation test.1, 2, 3 In this study, 577 patients were randomized (stratified by disease stage, Eastern Cooperative Oncology Group [ECOG] performance status, and prior immunotherapy use) in a 1:1:1 ratio to receive binimetinib 45 mg twice daily with encorafenib 450 mg once daily (binimetinib-encorafenib), encorafenib 300 mg once daily alone, or vemurafenib 960 mg twice daily.1, 2, 3 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.1, 2, 3 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent central review committee).1, 2, 3 The median age of patients randomized to the binimetinib-encorafenib or vemurafenib treatment groups was 56 years; 91% of patients were white, 59% were male, 95% had metastatic disease, 65% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 28% had elevated LDH concentrations, 45% had tumor involvement in at least 3 organs, and 3% of patients had brain metastases.1 Approximately 4% of patients enrolled in the binimetinib-encorafenib or vemurafenib treatment groups received prior therapy with an anti-programmed-death 1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody.1, 2 Most patients (88%) randomized to receive binimetinib-encorafenib or vemurafenib had BRAF V600E mutation; 11% had V600K mutation and <1% had both BRAF V600E and V600K mutations.1 Patients who had received immunotherapy in the adjuvant setting or one prior immunotherapy regimen for unresectable locally advanced or metastatic melanoma were eligible for this study; however, patients with prior exposure to BRAF or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors were not eligible to enroll in the study.1
At a median follow-up of 16.7 or 14.4 months in patients receiving binimetinib-encorafenib or vemurafenib alone, respectively, median progression-free survival was 14.9 months in patients receiving binimetinib-encorafenib compared with 7.3 months in those receiving vemurafenib.1, 2 The overall response rate was 63% for patients receiving binimetinib-encorafenib and 40% for those receiving vemurafenib; complete response was achieved in 8% of patients receiving binimetinib-encorafenib and 6% of those receiving vemurafenib.1, 2 The median duration of response in patients receiving binimetinib-encorafenib or vemurafenib alone was 16.6 or 12.3 months, respectively.1, 2 After a median follow-up of 48.8 months for the overall study population, the median overall survival was 33.6 or 16.9 months in patients receiving binimetinib-encorafenib or vemurafenib alone, respectively.1, 3 The risk for death was reduced by 39% with binimetinib-encorafenib as compared to vemurafenib alone.1, 3 In general, the overall survival benefit for combination therapy with binimetinib and encorafenib versus vemurafenib was consistent in most subgroup analyses (e.g., age, gender, race, ECOG performance status, geographic region, baseline serum LDH concentration, BRAF mutation status, disease stage, organ involvement, presence of brain metastases, prior use of first-line immunotherapy or adjuvant therapy).2, 3
The American Society of Clinical Oncology (ASCO) guidelines on systemic therapy for melanoma recommends that in the setting of unresectable or metastatic melanoma, patients with confirmed BRAF wild type cutaneous melanoma should be offered (in no particular order) ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone.200 In patients with confirmed BRAF-mutant (V600) disease, ASCO recommends offering treatment (in no particular order) with the 3 previous regimens or combination BRAF/MEK inhibitor therapy with dabrafenib plus trametinib, encorafenib plus binimetinib, or vemurafenib plus cobimetinib.200 For patients who progress after first-line therapy with programmed-death receptor-1 (PD-1) inhibitors, combination BRAF/MEK inhibitors may be offered; PD-1 inhibitors may be offered after progression on first-line combination BRAF/MEK inhibitors.200 Patients with mucosal melanoma may be offered the same treatment options as those with cutaneous melanoma; enrollment in clinical trials should be offered where possible.200
Binimetinib is used in combination with encorafenib for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.1 An FDA-approved diagnostic test is required to confirm the presence of the BRAF V600E mutation in tumor or plasma specimens prior to initiation of therapy.1 If no mutation is detected in a plasma specimen, test tumor tissue.1
This indication for binimetinib use is based principally on the results of an open-label, single-arm, multicenter, phase 2 study (PHAROS) in patients with metastatic NSCLC positive for a BRAF V600E mutation.1, 15 In this study, 98 patients received binimetinib 45 mg orally twice daily in combination with encorafenib 450 mg orally once daily in 28-day cycles; 59 patients were treatment-naïve and 39 were previously treated.1, 15 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary end point was confirmed objective response rate per RECIST version 1.1 criteria.15
The median age of enrolled patients was 70 years (range: 47 to 86 years); 88% of patients were white, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 53% were female; 57% were former smokers; 73% had an ECOG performance status of 1; and 97% had adenocarcinoma.1, 15 Results revealed an objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients.1, 15 A complete response was observed in 9 (15%) and 4 (10%) patients in the treatment-naïve and previously treated groups, respectively, with a partial response documented in 35 (59%) and 14 (36%) patients, respectively.1, 15 At the time of this analysis, the median duration of response was not estimable in the treatment naïve group and was 16.7 months in the previously treated group.1, 15 Durable responses lasting ≥12 months were seen in 59% of treatment naïve and 33% of previously treated patients.1, 15 The disease control rate after 24 weeks was 64% among treatment naïve patients and 41% in previously treated patients.15 Median progression-free survival was not estimable in the treatment naïve group and was 9.3 months in the previously treated group.15
Approximately 60% of patients with lung cancer have driver alterations (e.g., mutations in EGFR, ALK, or BRAF; ROS-1 fusions, RET fusions, MET exon 14 skipping mutations, and NTRK fusions).201 The ASCO and Ontario Health (OH; previously known as Cancer Care Ontario) 2021 guideline specifically addresses treatment of stage IV NSCLC with driver alterations, including BRAF gene alterations.201 The 2023 update to this guideline recommends that, for patients with stage IV NSCLC with a BRAF V600E mutation, clinicians may offer dabrafenib and trametinib or encorafenib and binimetinib as first-line treatment.202 If these treatment options are unavailable, clinicians may offer standard first-line therapy following the nondriver alteration guideline.202
In the second-line setting, standard first-line treatment based on the ASCO/OH nondriver mutation guideline should be offered in patients with stage IV NSCLC harboring BRAF V600E driver alterations who were previously treated with BRAF/MEK inhibitor combination therapy.202 In patients who did not receive BRAF-targeted therapy in the first-line setting, dabrafenib and trametinib or encorafenib and binimetinib may be offered.202 For patients with stage IV NSCLC with BRAF mutations other than V600E, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.202
Binimetinib is administered orally twice daily, with doses given approximately 12 hours apart; the drug can be taken without regard to meals.1
If a dose of binimetinib is missed by more than 6 hours, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1 Patients should not take extra tablets of the drug to make up for the missed dose.1
If vomiting occurs following administration of binimetinib, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.1
Store at 20-25ºC (excursions permitted between 15-30ºC).1
For use in combination with encorafenib in the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation, the recommended adult dosage of binimetinib is 45 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
If encorafenib therapy is permanently discontinued, binimetinib also should be discontinued.1 Clinicians should consult the manufacturer's labeling for information on recommended dosage modifications for encorafenib.1
Non-small Cell Lung Cancer (NSCLC)
For use in combination with encorafenib in the treatment of adults with metastatic NSCLC with a BRAF V600E mutation, the recommended adult dosage of binimetinib is 45 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
If encorafenib therapy is permanently discontinued, binimetinib also should be discontinued.1 Clinicians should consult the manufacturer's labeling for information on recommended dosage modifications for encorafenib.1
Dosage Modification for Toxicity
If adverse reactions occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of binimetinib may be required based on severity of the reaction.1 If dosage modification of binimetinib for adverse reactions is necessary, a dosage reduction to 30 mg twice daily is initially recommended.1 If a dosage of 30 mg twice daily is not tolerated, binimetinib should be permanently discontinued.1
If an asymptomatic absolute decrease in left ventricular ejection fraction (LVEF) from baseline of >10% and to a level below the lower limit of normal (LLN) occurs, binimetinib therapy should be withheld for up to 4 weeks and left ventricular function should be reassessed every 2 weeks; therapy may be resumed at a reduced dosage if the following are present: LVEF is at or above the LLN and the absolute decrease from baseline is 10% or less and the patient is asymptomatic.1 If the toxicity does not improve within 4 weeks of withholding binimetinib, the drug should be permanently discontinued.1
If symptomatic congestive heart failure or an absolute decrease in LVEF from baseline of >20% and to a level below the LLN occurs, binimetinib therapy should be permanently discontinued.1
If prolongation of QT interval occurs during combination therapy with binimetinib and encorafenib, no dosage modification of binimetinib is necessary.1
If uncomplicated deep-vein thrombosis (DVT) or pulmonary embolism (PE) occurs, binimetinib therapy should be withheld; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1 If the toxicity does not improve, the drug should be permanently discontinued.1
If life-threatening PE occurs, binimetinib therapy should be permanently discontinued.1
If symptomatic serous retinopathy or retinal pigment epithelial detachment occurs, binimetinib therapy should be withheld for up to 10 days; therapy may be resumed at the same dosage when the toxicity improves and the patient becomes asymptomatic.1 If the toxicity does not improve within 10 days of withholding therapy, therapy may be resumed at a reduced dosage or permanently discontinued.1
If grade 1 or 2 uveitis unresponsive to ocular therapy occurs, binimetinib therapy should be withheld for up to 6 weeks.1 If the toxicity improves within 6 weeks of withholding therapy, therapy may be resumed at the same or reduced dosage.1 If the toxicity does not improve within 6 weeks of withholding therapy, binimetinib therapy should be permanently discontinued.1
If grade 3 uveitis occurs, binimetinib therapy should be withheld for up to 6 weeks.1 If grade 3 uveitis improves within 6 weeks of withholding therapy, therapy may be resumed at the same or reduced dosage.1 If grade 3 uveitis does not improve within 6 weeks of withholding therapy, binimetinib therapy should be permanently discontinued.1
If retinal vein occlusion or grade 4 uveitis occurs, binimetinib therapy should be permanently discontinued.1
If grade 2 interstitial lung disease occurs, binimetinib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1 If grade 2 interstitial lung disease does not improve within 4 weeks of withholding therapy, the drug should be permanently discontinued.1
If grade 3 or 4 interstitial lung disease occurs, binimetinib therapy should be permanently discontinued.1
In patients who develop grade 2 elevations of serum aminotransferases (ALT or AST), binimetinib therapy may be continued at the same dosage for up to 2 weeks.1 If the toxicity persists, binimetinib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less or to baseline.1
For the first occurrence of grade 3 elevations of serum ALT or AST, binimetinib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 If grade 3 elevations of serum ALT or AST recur, permanent discontinuance of binimetinib should be considered.1
For the first occurrence of grade 4 elevations of serum ALT or AST, binimetinib therapy may be permanently discontinued or temporarily interrupted.1 If binimetinib therapy is temporarily interrupted, the drug should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 For recurrent grade 4 serum ALT or AST elevations, binimetinib therapy should be permanently discontinued.1
In patients who exhibit asymptomatic grade 4 creatine kinase (CK, creatine phosphokinase, CPK) elevations or any grade of CK elevation with symptoms or concomitant renal impairment, binimetinib therapy should be withheld for up to 4 weeks; therapy may be resumed 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, the drug should be permanently discontinued.1
For the first occurrence of grade 2 dermatologic reactions, binimetinib therapy should be continued at the same dosage.1 If the toxicity does not improve within 2 weeks, binimetinib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less.1 If grade 2 dermatologic reactions recur and do not improve within 2 weeks, binimetinib therapy should be withheld; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1
For the first occurrence of grade 3 dermatologic reactions, binimetinib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less.1 If grade 3 dermatologic reactions recur, binimetinib therapy should be withheld; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1
If grade 4 dermatologic reactions occur, binimetinib therapy should be permanently discontinued.1
If palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) develops during combination therapy with binimetinib and encorafenib, no dosage modification of binimetinib is necessary.1
Development of New Primary Malignancies
No dosage adjustment of binimetinib is necessary in patients who develop new primary RAS mutation-positive, noncutaneous malignancies during combination therapy with binimetinib and encorafenib.1
If grade 2 adverse reaction recurs, binimetinib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 0 or 1 or to pretreatment baseline levels.1 If the toxicity does not improve to grade 0 or 1 or to pretreatment baseline levels within 4 weeks of withholding therapy, the drug should be permanently discontinued.1
For the first occurrence of grade 3 adverse reaction, binimetinib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 0 or 1 or to pretreatment baseline levels.1 If the toxicity does not improve to grade 0 or 1 or to pretreatment baseline levels within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 If grade 3 adverse reaction recurs, permanent discontinuance of binimetinib should be considered.1
For the first occurrence of grade 4 adverse reaction, binimetinib therapy may be permanently discontinued or temporarily interrupted.1 If binimetinib therapy is temporarily interrupted, the drug should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 0 or 1 or to pretreatment baseline levels.1 If the grade 4 adverse reaction does not improve to grade 0 or 1 or to pretreatment baseline levels within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 For recurrent grade 4 adverse reactions, binimetinib therapy should be permanently discontinued.1
In patients with moderate (total bilirubin concentration exceeding 1.5 times the upper limit of normal [ULN], but no more than 3 times the ULN, with any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN, with any AST concentration) hepatic impairment, the manufacturer recommends a reduced binimetinib dosage of 30 mg twice daily.1 No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration).1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
When binimetinib is used in combination with encorafenib, the usual cautions, precautions, and contraindications associated with encorafenib must be considered in addition to those associated with binimetinib.1
New primary malignancies, both cutaneous and non-cutaneous, can occur with use of binimetinib.1 In the PHAROS study, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients receiving binimetinib in combination with encorafenib.1 Monitor patients for the development of new malignancies prior to treatment initiation, during therapy, and after discontinuation.1
Cardiomyopathy, which may manifest as a symptomatic or asymptomatic decrease in left ventricular ejection fraction (LVEF), has been reported in patients receiving binimetinib in combination with encorafenib.1, 2, 3 In the COLUMBUS study, cardiomyopathy (defined as an absolute decrease in LVEF from baseline of ≥10% and to a level below the lower limit of normal [LLN]) occurred in 7% of patients receiving binimetinib in combination with encorafenib; grade 3 left ventricular dysfunction occurred in 1.6% of patients receiving combination therapy.1 The median time to first onset of left ventricular dysfunction was 3.6 months (range: 0-21 months).1 Cardiomyopathy resolved in 87% of patients receiving combination therapy with binimetinib and encorafenib.1
Evidence of cardiomyopathy was observed in 11% of patients administered binimetinib in combination with encorafenib in the PHAROS study, with grade 3 left ventricular dysfunction occurring in 1% of patients.1 Cardiomyopathy resolved in 82% of patients.1
Safety of combination therapy with binimetinib and encorafenib has not been established in patients with a baseline LVEF below the LLN or <50%.1
LVEF should be assessed using echocardiogram or multigated radionuclide angiography (MUGA) prior to and 1 month after initiation of binimetinib and then every 2-3 months during therapy.1 Close monitoring during therapy is indicated in patients with preexisting cardiovascular risk factors.1 If left ventricular dysfunction occurs, temporary interruption followed by dosage reduction or discontinuance of binimetinib may be necessary.1
Venous thromboembolism (VTE) has been reported in patients receiving binimetinib in combination with encorafenib.1 In the COLUMBUS study, VTE occurred in 6% of patients receiving binimetinib in combination with encorafenib; 3.1% of patients receiving combination therapy developed pulmonary embolism (PE).1 In the PHAROS study, VTE was reported in 7% of patients receiving binimetinib in combination with encorafenib; 1% of patients administered this combination therapy developed PE.1
If deep-vein thrombosis (DVT) or PE occurs, temporary interruption followed by dosage reduction or discontinuance of binimetinib may be necessary.1
Serous retinopathy, retinal vein occlusion, retinal pigment epithelial detachment, and macular edema have been reported in patients receiving binimetinib in combination with encorafenib.1 Uveitis, including iritis and iridocyclitis, also has occurred in patients receiving binimetinib in combination with encorafenib.1
In the COLUMBUS study, serous retinopathy occurred in 20% of patients receiving combination therapy with binimetinib and encorafenib; macular edema and retinal detachment were reported in 6 and 8%, respectively, of patients receiving combination therapy.1 Symptomatic serous retinopathy occurred in 8% of patients receiving combination therapy with binimetinib and encorafenib; blindness was not reported in these patients.1 The median time to initial onset of serous retinopathy was 1.2 months (range: 0-17.5 months).1 Discontinuance of binimetinib therapy was not necessary in patients experiencing serous retinopathy; however, dosage modification or interruption of binimetinib therapy was necessary in 6% of patients.1
In the PHAROS study, serous retinopathy (retinal detachment) occurred in 2% of patients receiving binimetinib in combination with encorafenib, with no cases of blindness reported with the combination therapy.1 No patient permanently discontinued binimetinib due to serous retinopathy; 1% of patients required dose interruptions.1
Retinal vein occlusion is a known risk of mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors.1 In clinical trials evaluating combination therapy with binimetinib and encorafenib, retinal vein occlusion occurred in 1 of 690 patients (0.1%) with b-Raf serine-threonine kinase (BRAF) mutation-positive melanoma.1 In the COLUMBUS study, uveitis was reported in 4% of patients receiving binimetinib in combination with encorafenib.1 In the PHAROS study, uveitis was reported in 1% of patients receiving binimetinib in combination with encorafenib.1
Safety of binimetinib has not been established in patients with a history of or predisposition to retinal vein occlusion, including those with uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.1
Ophthalmologic examinations should be performed regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur; to follow new or persistent ophthalmologic findings) during binimetinib therapy.1 Patients should be monitored for visual symptoms at each visit.1 If visual disturbances are reported, ophthalmologic evaluations should be performed urgently (within 24 hours).1 Temporary interruption, dosage reduction, or discontinuance of binimetinib may be necessary if ocular toxicities occur during therapy with the drug.1
Interstitial lung disease or pneumonitis has been reported in patients receiving combination therapy with binimetinib and encorafenib.1 In clinical trials evaluating combination therapy with binimetinib and encorafenib, interstitial lung disease and pneumonitis occurred in 2 of 690 patients (0.3%) with BRAF mutation-positive melanoma.1 One patient receiving binimetinib in combination with encorafenib developed pneumonitis in the PHAROS study.1
Patients presenting with manifestations of interstitial lung disease (e.g., new or progressive pulmonary symptoms) should be evaluated.1 If a diagnosis of interstitial lung disease is confirmed, temporary interruption followed by dosage reduction or discontinuance of binimetinib may be necessary.1
Liver function test abnormalities have been reported in patients receiving combination therapy with binimetinib and encorafenib.1 In the COLUMBUS study, grade 3 or 4 elevations in ALT, AST, or alkaline phosphatase concentrations occurred in 6, 2.6, or 0.5%, respectively, of patients receiving combination therapy with binimetinib and encorafenib; grade 3 or 4 elevations in serum bilirubin were not reported.1 In the PHAROS study, grade 3 or 4 elevations in ALT, AST, or alkaline phosphatase concentrations occurred in 9%, 10%, and 3.2%, respectively, of patients receiving binimetinib in combination with encorafenib.1
Liver function tests should be performed prior to initiation of binimetinib therapy and then monthly, or more frequently as clinically indicated, during therapy with the drug.1 Temporary interruption, dosage reduction, or discontinuance of binimetinib may be necessary if liver function test abnormalities occur during therapy with the drug.1
Rhabdomyolysis has been reported in patients receiving combination therapy with binimetinib and encorafenib.1 In clinical trials evaluating combination therapy with binimetinib and encorafenib, rhabdomyolysis occurred in 1 of 690 patients (0.1%) with BRAF mutation-positive melanoma.1 In the COLUMBUS study, elevations of serum creatine kinase (CK, creatine phosphokinase, CPK) occurred in 58% of patients receiving combination therapy with binimetinib and encorafenib.1 In the PHAROS study, 41% of patients experienced CK elevations with combination therapy; however, no patient experienced rhabdomyolysis.1
Serum CK and creatinine concentrations should be evaluated at baseline, periodically during binimetinib therapy, and as clinically indicated.1 If elevated CK concentrations occur, therapy interruption followed by dosage reduction or discontinuance of binimetinib may be necessary.1
Hemorrhage has been reported in patients receiving combination therapy with binimetinib and encorafenib.1 In the COLUMBUS study, hemorrhage occurred in 19% of patients and was grade 3 or greater in 3.2% of patients receiving binimetinib in combination with encorafenib.1 The most common hemorrhagic events in patients receiving binimetinib in combination with encorafenib were GI hemorrhage, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).1 Intracranial hemorrhage was fatal in 1.6% of patients with new or progressive brain metastases receiving combination therapy with binimetinib and encorafenib.1
In the PHAROS study, hemorrhage occurred in 12% of patients receiving binimetinib in combination with encorafenib, including fatal intracranial hemorrhage in 1% of patients.1 Grade 3 or 4 hemorrhage was reported in 4.1% of patients.1 The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).1
If hemorrhagic events occur, therapy interruption followed by dosage reduction or discontinuance of binimetinib may be necessary.1
Fetal/Neonatal Morbidity and Mortality
Binimetinib may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals.1 There are no available data regarding the risk of binimetinib use in pregnant women to date.1 In animal reproduction studies, embryofetal toxicity (i.e., decreases in fetal body weight, postimplantation loss, abortion) and teratogenic effects were observed in rabbits receiving binimetinib at exposure levels of approximately 5 times the human exposure at the recommended dosa fetal ventricular septal defects and pulmonary trunk alterations were increased at exposure levels less than 8 times the human exposure.1 Skeletal anomalies also were observed in rats receiving binimetinib at exposure levels of approximately 37 times the human exposure at the recommended dosage.1
Pregnancy should be avoided during binimetinib therapy.1 The manufacturer states that pregnancy status should be verified prior to initiation of binimetinib therapy in women of childbearing potential and that such women should be advised to use effective contraception while receiving binimetinib and for at least 30 days after the last dose.1 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1
Binimetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
It is not known whether binimetinib or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to binimetinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 3 days after the last dose.1 The effects of the drug on nursing infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
Pregnancy status should be verified in women of childbearing potential prior to initiation of binimetinib therapy.1 Advise females of reproductive potential to use effective contraception during treatment and for ≥30 days after the final dose of binimetinib.1
Safety and efficacy of binimetinib have not been established in pediatric patients.1
In clinical trials evaluating binimetinib (45 mg twice daily) in combination with encorafenib (300-600 mg once daily) in patients with BRAF mutation-positive melanoma, 20% of patients were 65-74 years of age and 8% were ≥75 years of age.1 In a clinical trial of patients with BRAF V600E mutation-positive metastatic NSCLC administered binimetinib in combination with encorafenib, 63.2% of patients were ≥65 years of age and 20.4% were ≥75 years of age.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1
Systemic exposure of binimetinib is increased by 80 or 110% in individuals with moderate (total bilirubin concentration exceeding 1.5 times the ULN, but not more than 3 times the ULN, with any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN, with any AST concentration) hepatic impairment, respectively, compared with individuals with normal hepatic function;1, 5 therefore, dosage adjustment is recommended in patients with moderate or severe hepatic impairment.1
No clinically important differences in systemic exposure of binimetinib were observed between individuals with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) and those with normal hepatic function;1, 5 no dosage adjustment is necessary in patients with mild hepatic impairment.1
No clinically important differences in systemic exposure of binimetinib were observed between individuals with severe renal impairment (estimated glomerular filtration rate ≤29 mL/minute per 1.73 m2) and those with normal renal function.1
The most common adverse effects (≥25%) for binimetinib, in combination with encorafenib, for the treatment of melanoma include fatigue, nausea, diarrhea, vomiting, and abdominal pain.1
The most common adverse effects (≥25%) for binimetinib, in combination with encorafenib, for the treatment of NSCLC include fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.1
Binimetinib is metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and, to a lesser extent, by cytochrome P-450 (CYP) isoenzymes 1A2 and 2C19 to form a minor active metabolite (M3).1, 5 Binimetinib is a weak inhibitor of UGT1A.5 The drug does not demonstrate time-dependent inhibition of CYP isoenzymes 1A2, 2C9, 2D6, and 3A, and shows little to no induction of CYP2C9.1, 5
In vitro studies indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); the drug is not a substrate of organic cation transporter (OCT) 1 or organic anion transport protein (OATP) 1B1, OATP1B3, and OATP2B1.1, 5 In vitro, binimetinib is a weak inhibitor of OCT2, but does not inhibit OCT1.5
Drugs Affected by Hepatic Microsomal Enzymes
Concomitant administration of binimetinib (30 mg orally twice daily for 7 or 15 days) with the CYP3A4 substrate midazolam (single oral dose of 4 mg) did not substantially alter systemic exposure of midazolam.1, 5
Drugs Affected by Other Enzymes
Uridine Diphosphate glucuronosyltransferase
Binimetinib is a substrate of UGT1A1;6 however, in vitro studies indicate that binimetinib is unlikely to interact with drugs affecting UGT1A1.1, 5
Concomitant administration of binimetinib with the UGT1A1 inhibitor encorafenib did not substantially alter systemic exposure of binimetinib.1, 6 Pharmacokinetic simulations also suggest that concomitant administration of atazanavir (single 400-mg dose), a UGT1A1 inhibitor, and binimetinib (single 45-mg dose) does not substantially alter peak plasma concentrations of binimetinib.1, 5
Cigarette smoking has been shown to induce UGT1A1; however, cigarette smoking did not have a clinically important effect on systemic exposure of binimetinib.1
Clinically important pharmacokinetic interactions between drugs that are substrates of OCT1 or OCT2 and binimetinib are not expected during concurrent use.5
Drugs Affecting Gastric Acidity
Concomitant administration of the proton-pump inhibitor rabeprazole (20 mg once daily for 4 days) with binimetinib (single 45-mg dose) did not result in clinically important changes in peak plasma concentrations and systemic exposure of binimetinib and M3.1, 5
Binimetinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent.1, 2 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1, 7 Approximately 40-60% of cutaneous melanomas carry a b-Raf serine-threonine kinase (BRAF) mutation.2, 3, 8, 11 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E);8, 9, 11 a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K).8, 9, 11 BRAF V600 mutations result in activation of the BRAF pathway that includes MEK 1 and 2.7, 9 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).7, 8, 9 In vitro studies have demonstrated that binimetinib inhibits phosphorylation of ERK in cell-free assays and MEK-dependent phosphorylation of melanoma cells harboring BRAF mutation.1 The drug also has demonstrated inhibition of ERK phosphorylation and tumor growth in xenograft models of melanoma harboring BRAF mutation in mice.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.14 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).3, 11, 14 In vitro, use of binimetinib in combination with encorafenib resulted in increased antiproliferative activity compared with either drug alone in BRAF mutation-positive cell lines.1 The combination of binimetinib and encorafenib also has demonstrated increased inhibition of tumor growth and delayed emergence of resistance compared with either drug alone in xenograft models of melanoma harboring BRAF V600E mutation in mice.1
Following oral administration of binimetinib 45 mg twice daily, at least 50% of the dose is rapidly absorbed with peak plasma concentrations occurring in 1.6 hours.1, 5 Peak plasma concentrations and systemic exposure of binimetinib and its active metabolite (M3) are proportional to dose following single or repeated administration of the drug over the dosage range of 5-80 mg or 5-60 mg once daily, respectively.5 Repeated administration of binimetinib 45 mg twice daily resulted in a 1.5-fold binimetinib accumulation ratio.1, 5 Administration of a single 45-mg dose of binimetinib with a high-fat, high-calorie meal (approximately 150 calories from protein, 350 calories from carbohydrates, 500 calories from fat) did not affect systemic exposure of the drug in healthy individuals.1, 5 Binimetinib is highly bound (97%) to plasma proteins.1 The mean terminal half-life of binimetinib is 3.5 hours.1 Binimetinib is metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and, to a lesser extent, by N -dealkylation and amide hydrolysis by cytochrome P-450 (CYP) isoenzymes 1A2 and 2C19 to form its minor active metabolite (M3).1, 5 Following oral administration of a single radiolabeled dose of binimetinib, 62% of the radioactivity was recovered in feces (32% of the dose as unchanged drug) and 31% was recovered in urine (6.5% of the dose as unchanged drug).1 Single agent MEK inhibitor treatment is no longer recommended by experts as combination BRAF/MEK inhibition has demonstrated superior outcomes with a similar safety profile.200
The pharmacokinetics of binimetinib do not appear to be affected substantially by age (20-94 years), gender, body weight, or UGT1A1 genotype.1, 5
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.
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.
Binimetinib can only be obtained through select specialty pharmacies.21 Contact the manufacturer or consult the Braftovi® and Mektovi® website for specific availability information ([Web])21
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 15 mg | Mektovi® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Array BioPharma, Inc. Mektovi® (binimetinib) tablets prescribing information. Boulder, CO; 2023 Oct.
2. Dummer R, Ascierto PA, Gogas HJ et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol . 2018; 19:603-15.
3. Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. 2020;126:33-44.
4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 April 2. [Web]
5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210498Orig1s000: Multi-discipline review(s). From FDA website. [Web]
6. Array BioPharma, Inc. Barftovi® (encorafenib) capsules prescribing information. Boulder, CO; 2018 Jun.
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]
11. Rauschenberg R, Garzarolli M, Dietrich U et al. Systemic therapy of metastatic melanoma. J Dtsch Dermatol Ges . 2015; 13:1223-37. [PubMed 26612791]
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. Riely GJ, Smit EF, Ahn MJ, et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer. J Clin Oncol. 2023;41(21):3700-10.
21. Pfizer. Braftovi® (encorafenib) capsules and Mektovi® (binimetinib) tablets: access and patients support. From Braftovi® Mektovi® for Healthcare Professionals website. [Web]
22. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). From FDA website. Accessed 2024 Apr 2. [Web]
200. Seth R, Messersmith H, Kaur V, et al. Systemic Therapy for Melanoma: ASCO Guideline. J Clin Oncol. 2020;38(33):3947-3970.
201. Robinson AG, Temin S et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol . 2021; 39:1040-1091. [PubMed 33591844]
202. Jaiyesimi IA, Leighl NB, Ismaila N, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3. J Clin Oncol. 2024; JCO2302744.