BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

MEKTOVI is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test (see sections 4.2).

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

MEKTOVI is indicated, in combination with encorafenib, for the treatment of adult patients with metastatic non small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test. (see sections 4.2).

Patient Selection

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating MEKTOVI (see section 5.1). Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating MEKTOVI (see section 5.1). If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

Posology

The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information.

MEKTOVI may be taken with or without food (see section 5.2). Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI.

Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose.

Dose modification

The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation (see below, Table 1 and Table 2).

If encorafenib is permanently discontinued, discontinue MEKTOVI.

Dose reductions for adverse reactions associated with MEKTOVI are presented in Table 1.

Table 1: Recommended Dose Reductions for MEKTOVI for Adverse Reactions

Dosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2.

a. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

b. Dose modification of MEKTOVI when administered with encorafenib is not recommended for the following adverse reactions: palmar‑plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation.

Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib.

Duration of treatment

Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity.

Missed doses

Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI.

Vomiting

Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose.

Special populations

Elderly patients

Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI in combination with encorafenib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older (see section 5.2).

Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI in combination with encorafenib, 62 (63.2%) were 65 years of age and over and 20 (20.4%) were 75 years and over (see section 5.1).

No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients.

Hepatic impairment

Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN). Reduce the dose of MEKTOVI for patients with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment.

For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 × ULN and any AST) or severe (total bilirubin levels greater than 3 × ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily (see section 5.2).

Renal impairment

No dose adjustment is recommended for patients with renal impairment (see section 5.2).

Paediatric population

The safety and effectiveness of MEKTOVI have not been established in pediatric patients.

Method of administration

MEKTOVI is for oral use.

The tablets may be taken with or without food (see section 5.2).

Binimetinib is to be given in combination with encorafenib. For additional information on warnings and precautions associated with encorafenib treatment, see section 4.4 of encorafenib SmPC.

New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when MEKTOVI is used in combination with encorafenib.

In PHAROS, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients who received MEKTOVI in combination with encorafenib.

Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment (see section 4.2).

Cardiomyopathy

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib.

In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving MEKTOVI plus encorafenib.

Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Venous Thromboembolism

In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. In PHAROS, VTE occurred in 7% of patients receiving MEKTOVI in combination with encorafenib, including 1% of patients who developed pulmonary embolism.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Ocular Toxicities

Serous Retinopathy

In COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months).

In PHAROS, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness treated with MEKTOVI in combination with encorafenib. No patient permanently discontinued MEKTOVI due to serous retinopathy; 1% of patients required dose interruptions.

Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Retinal Vein Occlusion

RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 1 patient experienced RVO (0.1%).

The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. 

Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO (see section 4.2 and 4.8).

Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%. In PHAROS, uveitis occurred in 1% of patients receiving MEKTOVI in combination with encorafenib.

Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Interstitial Lung Disease

In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. In PHAROS, 1 patient (1%) receiving MEKTOVI with encorafenib developed pneumonitis.

Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Hepatotoxicity

Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Rhabdomyolysis

Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%). In PHAROS, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients treated with MEKTOVI in combination with encorafenib. No patient experienced rhabdomyolysis.

Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Hemorrhage

Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction (see section 4.2 and 4.8).

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose (see section 4.6).

Risks Associated with Combination Treatment

MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment.

Clinical Studies

Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar C_max of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor).

No differences in binimetinib exposure have been observed when MEKTOVI is coadministered with encorafenib.

Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam).

Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole).

In Vitro Studies

Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.

Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1).

Women of childbearing potential/Contraception in females

Based on animal data, MEKTOVI can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose.

Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action (see section 5.1), MEKTOVI can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses ≥30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses ≥10 mg/kg/day (approximately 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily).

Breast-feeding

Risk Summary

There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the last dose.

Fertility

No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs.

Binimetinib has minor influence on the ability to drive or use machines. Visual disturbances have been reported in patients treated with binimetinib during clinical studies. Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse reaction that may affect their ability to drive and use machines (see sections 4.4 and 4.8).

The following adverse reactions are described elsewhere in the labeling:

•        New Primary Malignancies (see section 4.4)

•        Cardiomyopathy (see section 4.4)

•        Venous Thromboembolism (see section 4.4)

•        Ocular Toxicities (see section 4.4)

•        Interstitial Lung Disease (see section 4.4)

•        Hepatotoxicity (see section 4.4)

•        Rhabdomyolysis (see section 4.4)

•        Hemorrhage (see section 4.4)

•        Embryo-Fetal Toxicity (see section 4.4)

•        Risks Associated with Combination Treatment (see section 4.4)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in WARNINGS AND PRECAUTIONS reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily in a randomized open-label, active‑controlled trial (COLUMBUS) (see section 5.1) or, for rare events, exposure of 690 patients with BRAF V600 mutation‑positive melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib once daily across multiple clinical trials (NCT03915951, NCT01909453).

The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure of 98 patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer to MEKTOVI 45 mg twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity in PHAROS (see section 5.1).

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS.

The COLUMBUS trial (see section 5.1) excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib.

The most common (≥25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain.

Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients.

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS^a

a. Grades per National Cancer Institute CTCAE v4.03.

b. Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm.

c. Represents a composite of multiple, related preferred terms.

Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were:

Gastrointestinal disorders: Colitis

Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity

Immune system disorders: Drug hypersensitivity

Table 4: Laboratory Abnormalities Occurring in ≥10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS^a

a.   Grades per National Cancer Institute CTCAE v4.03.

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

The safety of MEKTOVI in combination with encorafenib is described in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in an open-label, single-arm trial (PHAROS).

The PHAROS trial (see section 5.1) excluded patients with abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for MEKTOVI and encorafenib was 8.4 and 9.2 months respectively.

The most common (≥25%) adverse reactions in patients receiving MEKTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

Adverse reactions leading to dose interruptions of MEKTOVI occurred in 62% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (17%); nausea (15%); fatigue (9%); AST increased (7%); ALT increased, anemia, musculoskeletal pain, vomiting (6% each); and acute kidney injury, hemorrhage, and LV dysfunction/cardiomyopathy (5% each). Adverse reactions leading to dose reductions of MEKTOVI occurred in 33% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (8%), nausea (6%), and AST increased (5%). A total of 17% of patients receiving MEKTOVI experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI; the most common (≥2%) were diarrhea (3.1%); musculoskeletal pain, LV dysfunction/cardiomyopathy, fatigue, nausea, rash, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of MEKTOVI occurred in more than 1 patient.

Serious adverse reactions occurred in 38% of patients who received MEKTOVI in combination with encorafenib. Serious adverse reactions in ≥2% of patients included hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received MEKTOVI (45 mg twice‑daily) in combination with encorafenib, including intracranial hemorrhage and myocardial infarction (1% each).

Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.

a.   Grades per National Cancer Institute CTCAE v4.03.

b.   One Grade 5 adverse reaction of hemorrhage occurred.

c. Fatigue includes fatigue, asthenia.

d. Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema.

e. Diarrhea includes diarrhea, colitis.

f. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.

g. Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia.

h. Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, non-cardiac chest pain, neck pain.

i. Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation.

j. Pruritis includes pruritus, pruritus genital.

k. Dyspnea includes dyspnea, dyspnea exertional.

l. Cough includes cough, productive cough.

m. Dizziness includes dizziness, balance disorder.

n. Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage.

o. Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive.

Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were:

Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity

Immune system disorders: Drug hypersensitivity

a.   Grades per National Cancer Institute CTCAE v4.03.

b.   Based on the number of patients with available baseline and at least one on-treatment laboratory test.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to National Pharmacovigilance Center (NPC).

To Report side effects

·         Saudi Arabia:

·         Other GCC States

Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EE03

Mechanism of action

Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF‑mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.

Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.

Cardiac Electrophysiology

Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.

Clinical efficacy and safety

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

MEKTOVI in combination with encorafenib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no).

Patients were randomized (1:1:1) to receive MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily (MEKTOVI in combination with encorafenib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (MEKTOVI 45 mg in combination with encorafenib 450 mg) are described below.

The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare MEKTOVI in combination with encorafenib with vemurafenib. Additional efficacy measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.

A total of 577 patients were randomized, 192 to the MEKTOVI in combination with encorafenib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the MEKTOVI in combination with encorafenib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients’ tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%). 

MEKTOVI in combination with encorafenib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 7 and Figure 1.

Table 7: Efficacy Results for COLUMBUS

CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response.

a.   Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1).

b.   Log-rank test adjusted by the same stratification factors.

c.   Based on a cutoff date 82.4 months after the date of PFS analysis.

Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer

MEKTOVI in combination with encorafenib was evaluated in an open-label, multicenter, single‑arm study in patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) (PHAROS; NCT03915951). Eligible patients had a diagnosis of histologically-confirmed metastatic NSCLC with BRAF V600E mutation that was treatment-naïve or had been previously treated with 1 prior line of systemic therapy in the metastatic setting (platinum-based chemotherapy and/or anti-PD-1/PD-L1 therapies), age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Prior use of BRAF inhibitors or MEK inhibitors was not allowed.

Patients received MEKTOVI 45 mg orally twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) per RECIST v1.1 and duration of response (DoR) as assessed by independent review committee (IRC).

In the efficacy population, BRAF V600E mutation status was determined by prospective local testing using tumor tissue (78%) or blood (22%) specimens. Of the 98 patients with BRAF V600E mutation, 6 patients were enrolled into the trial based on testing of their tumor tissue specimens with the FoundationOne CDx tissue test. Of the remaining 92 patients enrolled based on local testing, 68 patients had their tumor tissue specimens retrospectively confirmed as having BRAF V600E positive status by the FoundationOne CDx tissue test. The remaining patients had either BRAF V600E negative status (n=5) or had unevaluable results (n=19) by the FoundationOne CDx tissue test. In addition, plasma samples from 81 out of 98 patients were retrospectively tested using the FoundationOne Liquid CDx assay. Of the 81 patients, 48 were confirmed positive for BRAF V600E, while 33 patients were BRAF V600E mutation negative by FoundationOne Liquid CDx assay. The remaining 17 samples had unevaluable results with FoundationOne Liquid CDx assay.

The efficacy population included 59 treatment-naïve patients and 39 previously-treated patients. Among these 98 patients, the median age was 70 years (range: 47 to 86); 53% female; 88% White, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 99% were not Hispanic or Latino; 13% were current smokers and 57% were former smokers; 73% had ECOG PS of 1; and 97% had adenocarcinoma. All patients had metastatic disease and 8% had brain metastases at baseline.

Efficacy results for patients with BRAF V600E mutation-positive metastatic NSCLC are summarized in Table 8.

Table 8: Efficacy Results for PHAROS

The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional.

Absorption

After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours.

Effect of Food

The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure.

Distribution

Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%).

Elimination

The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).

Metabolism

The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.

Excretion

Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine.

Specific Populations

Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown.

Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and Cmax) were observed in subjects with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULN and AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment (see section 2.4).

Renal Impairment: In subjects with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function.

Medicinal product interactions

Clinical Studies

Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar C_max of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor).

No differences in binimetinib exposure have been observed when MEKTOVI is coadministered with encorafenib.

Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam).

Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole).

In Vitro Studies

Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.

Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1).

Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.

No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs.

Tablet core

Lactose monohydrate

Cellulose microcrystalline (E460i)

Silica colloidal anhydrous (E551)

Croscarmellose sodium (E468)

Magnesium stearate  (E470b)

Film-coating

Polyvinyl alcohol (E1203)

Macrogol 3350 (E1521)

Titanium dioxide (E171)

Talc (E533b)

Iron oxide yellow (E172)

Iron oxide black (E172)

Not applicable.

Store below 30°C

PVC/PVDC/Alu blister containing 12 tablets. Each pack contains 84 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.