Binimetinib -The Breakthrough in Melanoma Treatment

Introduction

The drug, Binimetinib, belongs to the group of drugs known as kinase inhibitors. It is used for the treatment of certain kinds of melanoma which is a type of cancer of the skin. The melanoma that has migrated to other regions of the body and cannot be excised surgically is treated with Binimetinib along with Encorafenib. Binimetinib functions by preventing the abnormal protein from signaling the growth of cancer cells. This aids in preventing or reducing the proliferation of cancerous cells. The drug received Food and Drug Administration (FDA) approval in 2018.

For Patients

What Is Melanoma?

Melanocytes, which are skin cells, are the source of melanoma. These cells undergo malignant transformation and form melanoma. Melanomas typically occur on the skin because of melanocytes. The neural crest cells are the source of these melanocytes. However, it can develop in other organs where neural crest cells migrate, such as the gastrointestinal tract and brain. Melanomas are pink, red, purple, or skin-colored but usually, it is dark colored. Melanomas are typically black or brown. Patients with stage 0 melanoma have a 97 percent five-year relative survival rate, compared to 10 percent for those with stage IV disease. Although there is no known cause for all melanomas, exposure to ultraviolet (UV) radiation from sunlight, tanning beds, or tanning lamps increases the risk of getting the disease. By reducing UV radiation exposure, the risk of melanoma can be reduced.

What Are the Clinical Indications For Melanoma?

• Melanomas are often seen on any body part but mostly on the areas which are exposed to the sun.

• It can also occur in the body parts, like the soles and palms.

• The first signs that are present are a modification to an existing mole and the appearance of a new, pigmented growth or other uncharacteristic feature on the skin.

• The "ABCDE" memory aid from the American Academy of Dermatology can help to remember the indicators that a spot on the skin might be melanoma:

  • Asymmetry - The two halves do not match each other.

  • Border - No smooth edges.

  • Color - It has a mottled, uneven color with brown, black, gray, red, or white undertones.

  • Diameter - New growth should be present in the moles which are bigger than 0.6 millimeters.

  • Evolving - The mole spot may show changes in color, shape, and size. Additionally, moles can change over time to manifest new signs and symptoms like new itchiness or bleeding.

How Should This Medication Be Taken?

Binimetinib is available as an oral tablet. It is usually taken two times daily, with or without meals, at intervals of around 12 hours. Binimetinib should be taken every day at around the exact same time. Ask the doctor or chemist to clarify any instructions on the label of the prescription that the patient is unsure about following. Binimetinib must be taken as prescribed. It should never be taken in larger or fewer amounts or more frequently than directed by the doctor. If vomiting occurs after taking the medicine, the subsequent dose should not be taken. Continue taking the medication as usual. The treatment with Binimetinib can be stopped permanently or temporarily if the patient experienced adverse effects from the drug. The drug dosage might also be altered depending on the symptoms. The patient must inform about any changes or new symptoms they encounter during the treatment process.

What Specific Safety Measures Should Be Taken?

Before Ingestion of Binimetinib:

• If a patient has an allergy to Binimetinib and any other ingredient in Binimetinib tablets, they should inform their doctor and chemist right away. For a list of the components, consult the medication guide or speak with the chemist.

• The patient should inform the physician and chemist about any over-the-counter drugs (OTC), herbal items, vitamins and nutritional supplements they are currently using or intend to take. The dosage of the drugs may need to be changed, or the healthcare provider may need to watch for adverse effects closely.

• If the patient is expecting, wants to get pregnant, or is nursing a baby, they should inform the healthcare worker.

• Before beginning therapy, the patient must take a pregnancy test. Throughout Binimetinib therapy and for 30 days following the last dosage, the patient should use birth control to avoid becoming pregnant. Consult the doctor about birth control options. The doctor must be contacted immediately in case the patient has conceived as the fetus might suffer from Binimetinib.

• If the patient had liver or heart problems, let the doctor know.

What Are the Potential Adverse Effects of the Medication?

The list of side effects caused by the drug are:

• Tiredness.

• Pain in the abdomen.

• Diarrhea.

• Dizziness.

• Constipation.

• Nausea.

• Vomiting.

The serious side effects are listed below:

• Changes in vision or eye discomfort, puffiness, or redness.

• Fever, chills, sore throat, cough, or other symptoms of infection

• Yellow eyes or skin, black urine, malnutrition, exhaustion, or right upper stomach ache or discomfort.

• Muscular discomfort, weakness, or dark-colored or brown urine.

• Presence of blood in the stool, bruising, and bleeding.

• Difficulty in breathing and cough.

• Shortness of breath, edema of ankle and feet, fast heartbeat, or dizziness.

How Is Medicine Stored and Disposed Of?

The medicine must be kept in the original and tightly secured container. It should not be stored in a place where there is excessive heat and moisture, especially in the bathroom. If a desiccant (drying agent) has been supplied, do not remove it from the bottle. All the medical supplies must be stored in a place that is out of children’s reach and as well as sight. Medicines like eye drops, inhalers, patches, eye drops, creams, and pill reminders can be opened easily by children, and hence extra measures should be taken to keep them away from children. Safety caps must be secured immediately after using the medication. Unused prescriptions must be discarded with caution. The medication should however be never disposed of in the bathroom. The ideal approach to get rid of the medicines is via a drug take-back program. More information regarding the take-back program can be provided by the chemist or the recycling department of the city. One can also visit the FDA (Food and Drug Administration) website on safe disposal of medicines to find out more about the take-back program.

For Doctors

Mechanism of Action

Mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activity are both reversibly inhibited by the drug Binimetinib. The extracellular signal-related kinase (ERK) pathway is upstream-regulated by MEK proteins. Binimetinib suppressed ERK phosphorylation in cell-free assessments, as well as the survival and MEK-dependent phosphorylation of BRAF-mutant human melanoma lines of cells, in vitro. Additionally, in BRAF-mutant mouse xenograft models, Binimetinib reduced in vivo ERK phosphorylation and tumor development.

Two distinct kinases in the RAS/RAF/MEK/ERK cascade are the targets of Binimetinib and Encorafenib. Coadministration of Encorafenib and Binimetinib led to higher activity against proliferation in vitro in BRAF mutation-positive cell lines and higher anti-tumor activity concerning tumor inhibition of growth in BRAF V600E mutant human melanoma xenograft research in mice when compared to either drug alone. In addition, when used together rather than either treatment alone, Binimetinib and Encorafenib prevented the development of resistance in mouse xenografts of BRAF V600E mutant human melanoma.

Pharmacodynamics

• Cardiac Electrophysiology - There was no clinically significant QT prolongation when Binimetinib of dosage 45 mg was administered twice daily.

Pharmacokinetics

Both healthy individuals and patients with solid tumors were used to study the pharmacokinetics of Binimetinib. After administering the drug twice daily, the accumulation was 1.5 times greater, and the coefficient of variation (CV %) of the area under the concentration-time curve (AUC)

was less than 40 percent at a constant state. Binimetinib's systemic exposure is roughly dosage proportionate.

• Absorption - At least 50 percent of the Binimetinib dosage was absorbed after oral administration, with a median time to the highest level (Tmax) of around 1.6 hours.

• Effect of Food - In healthy participants, when a single dose of the drug (45 mg) was given along with a high-calorie and high-fat meal that included around 500 calories from fats, 150 calories from protein sources, and 350 calories from carbohydrates, it was found that there was no effect on the exposure of Binimetinib.

• Distribution - The blood-to-plasma ratio of Binimetinib is 0.72, and 97 percent of it is bound to proteins found in human plasma. Binimetinib's apparent distribution volume has a geometric mean (CV %) of 92 liters (45 percent).

• Elimination - The apparent clearance (CL/F) of Binimetinib is 20.2 liters/hour (24 percent), and the average (CV %) terminal half-life (t1/2) is 3.5 hours (28.5 percent).

Non-clinical Toxicology

There have not been any investigations on the carcinogenic effects of Binimetinib. Studies analyzing chromosomal abnormalities in mammalian cells reverse mutations in bacteria, and rat bone marrow micronuclei concluded that Binimetinib was not genotoxic. Fertility studies to understand the effect of Binimetinib on animals have not been conducted. Toxicology studies when conducted on monkeys and rats showed no significant results in the reproductive organs of females and males.

Supply and Storage of the Drug

The drug Binimetinib comes packed in bottles containing 180 tablets. The drug is oval in shape, yellow to dark yellow in color, biconvex, and unscored. The tablets are film-coated and debossed with 15 on one side and stylized A on the other side of the tablet. The drug is available in a potency of 15 milligrams (mg).

The transportation of the drug is allowed between 59 degrees Fahrenheit to 86 degrees Fahrenheit. The recommended temperature range for drug storage is 68 degrees Fahrenheit to 77 degrees Fahrenheit.

Drug Interaction

There have been no reported clinically significant medication interactions with Binimetinib.

Use in Specific Populations

• Pregnancy

  • Risk Summary - The data available from studies on animal reproduction and the mechanism of action of the drug, established that Binimetinib can harm the fetus when given to pregnant women. Clinical information on the use of Binimetinib during pregnancy is not currently available.

  • Animal Data - In research studies it was found that oral administration of Binimetinib during organogenesis was shown to be embryotoxic and abortifacient in rabbits. The doses established for embryotoxicity and abortifacient were five times the human dosage of 45 mg two times a day. The expectant mothers must be informed about the potential fetal danger.

• Lactation - There is no information on whether Binimetinib or its active metabolite is present in human milk during lactation. The data also showed that the drug has no impact on milk production as well as on infants who are breastfed. Since the drug can cause significant adverse effects in newborns who are breastfed, women are advised to refrain from breastfeeding during the treatment with Binimetinib as well as for three days following the final dosage of Binimetinib.

• Potentially Reproductive Male and Female

  • Pregnancy Testing - Before starting treatment with Binimetinib, the reproductive potential of the females must be established, and they should be told about the damage it can cause to the fetus.

  • Contraception - Binimetinib can cause harm to the fetus and hence women are recommended not to get pregnant during the treatment. Hence, women are encouraged to use effective contraception during and after 30 days of stopping the treatment with Binimetinib.

• Pediatric Population - In pediatric patients, the efficacy and safety of Binimetinib have not been shown established.

• Geriatric Population - 20 percent of the 690 individuals who were BRAF mutation-positive melanoma patients and were treated with Binimetinib at a dose of 45 mg two times daily in conjunction with Encorafenib at dosages ranging from 300 mg to 600 mg once a day across many clinical studies were 65 to 74 years old. Nearly, 8 percent of these individuals were 75 years of age or older. No difference was seen in the efficacy and safety of the drug for older and younger patients.

• Hepatic Impairment - Individuals with moderate to severe hepatic impairment may have a greater amount of Binimetinib. Patients who have mild hepatic impairment should not adjust their dosage for Binimetinib. If a patient has a moderate or severe hepatic impairment, they should take less Binimetinib.

Overdosage

Since Binimetinib binds 97 percent with the plasma proteins, it is highly unlikely that hemodialysis will effectively treat overdosing with Binimetinib.

Warnings and Precautions

• Cardiomyopathy - Treatment with Binimetinib along with Encorafenib has been reported to cause cardiomyopathy in patients. Cardiomyopathy manifests as left ventricular failure (LVF). It may be associated with symptomatic or asymptomatic reduction in ejection fraction.Reduction in left ventricular ejection fraction can be diagnosed with MUGA (multi-gated acquisition scan) or ECG (echocardiography). Before starting the treatment with Binimetinib, one month after starting treatment, and then after every two to three months while on treatment, ejection fraction should be evaluated by echocardiography or MUGA scan. Patients having a baseline ejection fraction that is either lower than 50 % are not safe while using Binimetinib in conjunction with Encorafenib. When using Binimetinib, patients with cardiovascular risk factors need to be closely watched. Depending on how severe the adverse reaction is, the decision on keeping the drug on hold, lowering the dosage, and stopping the drug should be taken.

• Venous Thromboembolism - In a research study, 3.1 percent of patients who received Binimetinib together with Encorafenib experienced a pulmonary embolism, while six percent of patients experienced venous thromboembolism (VTE). Depending on how severe the adverse reaction is, the decision on keeping the drug on hold, lowering the dosage, and stopping the drug should be taken.

• Ocular Toxicities:

  • Serous Retinopathy - In a research study, it was found that 20 percent of individuals receiving Binimetinib and Encorafenib experienced serous retinopathy. Eight percent experienced retinal detachment and six percent experienced macular edema. Eight percent of individuals with symptomatic serous retinopathy experienced no occurrences of blindness. Serous retinopathy did not cause any patients to stop using Binimetinib.

  • Six percent of patients needed dosage stoppage or dose reductions.

  • The ophthalmological examination should be conducted on the patient upon every visit. The doctor should conduct routine ophthalmologic exams to check for any new or worsening vision problems and to monitor any lingering or new ophthalmologic abnormalities. Depending on how severe the adverse reaction is, the decision on keeping the drug on hold, lowering the dosage, and stopping the drug should be taken.

  • Retinal Vein Occlusion - Retinal vein occlusion (RVO) is the adverse response to MEK inhibitors. It can happen to individuals receiving Binimetinib in conjunction with Encorafenib. Safety data of Binimetinib for RVO is not available. Also, there is no safety data available for individuals who have uncontrolled glaucoma or hyperviscosity syndromes which are the risk factors for RVO. Ophthalmological evaluation should be performed for individuals who have reported a loss of vision or disturbance in vision within 24 hours. Binimetinib is stopped permanently in patients with RVO.

  • Uveitis - Patients receiving Binimetinib and Encorafenib together have reported developing uveitis, including iridocyclitis and iritis. According to a research study, the incidence of uveitis was reported in four percent of the patients who were treated with Binimetinib along with Encorafenib.

• Interstitial Lung Disease (ILD) - Examine any developing or new lung symptoms or findings for the presence of ILD. Depending on how severe the adverse response is, withhold, lower the dose, or stop the drug permanently. Interstitial lung disease (ILD), including pneumonitis, emerged in individuals with melanoma who tested positive for the BRAF mutation and were using Binimetinib with Encorafenib.

• Hepatotoxicity - When Binimetinib and Encorafenib are used together, hepatotoxicity might happen. As per the data for a study, the incidence of Grade 3 or 4 elevations in liver function laboratory tests was 2.6 percent for aspartate aminotransferase (AST), six percent for alanine aminotransferase (ALT), and 0.5 percent for alkaline phosphatase in patients taking Binimetinib in conjunction with Encorafenib. Grade 3 or grade 4 rise of serum bilirubin was not reported for any patient. Laboratory tests for livers should be monitored before starting the treatment with Binimetinib, during the treatment, and clinically whenever indicated.

• Rhabdomyolysis - When Binimetinib and Encorafenib are used together, rhabdomyolysis might occur. In a research study, 58 % of patients receiving Binimetinib and Encorafenib treatment saw an increase in blood CPK (creatine phosphokinase) test results. Rhabdomyolysis has been documented in one patient out of 690 patients when treated with Binimetinib and Encorafenib for BRAF mutation-positive melanoma patients. CPK and creatinine levels are monitored before starting the treatment with Binimetinib, during the treatment, and whenever clinically indicated. Depending on how severe the adverse reaction is, the decision on keeping the drug on hold, lowering the dosage, and stopping the drug should be taken.

• Hemorrhage - When Binimetinib and Encorafenib are used together, bleeding might happen. In a research study, it was found that 19 percent of patients taking Binimetinib in conjunction with Encorafenib reported hemorrhage. 3.2 percent of patients experienced hemorrhage of grade 3 or above.1.6 percent of patients experienced fatal cerebral hemorrhage along with the presence of developing or new brain metastases. The most common hemorrhage reported was gastrointestinal hemorrhage including rectal hemorrhage (4.2 %), hematochezia (3.1 %), and hemorrhoidal hemorrhage (1 % of all hemorrhagic events). Depending on how severe the adverse reaction is, the decision on keeping the drug on hold, lowering the dosage, and stopping the drug should be taken.

• Embryo-Fetal Toxicity - Based on the results from animal research and its mechanism of action, it was concluded that Binimetinib can damage an unborn child when given to a pregnant woman. It was also found that Binimetinib was embryotoxic and abortifacient. Inform mothers about the potential danger to an unborn child. Encourage sexually active females to use effective contraception while taking Binimetinib and for at least 30 days following the last dosage.

Clinical Trial Study and Drug Efficacy:

In individuals with unremovable or metastatic melanoma with a BRAF V600-activating mutation, combination regimens targeting BRAF and MEK (Encorafenib plus Binimetinib, Dabrafenib plus Trametinib, or Vemurafenib plus Cobimetinib) are now advised as first-line treatment. Patients with metastatic or incurable melanoma are seeing better results because of the development of BRAF and MEK inhibitors. Encorafenib with Binimetinib is a very well-tolerated drug combination that has been found to increase PFS (progression-free survival) and OS (overall survival).