MEKTOVI

Binimetinib (Binimetinib) instructions

Common name: Bimetinib

Trade name: Mektovi

All names: Bimetinib, Bemetinib, Binimetinib, Mektovi

Indications:

Bimetinib is a kinase inhibitor used in combination with encofenib to treat patients with BRAF Patients with unresectable or metastatic melanoma with V600E or V600K mutations.

Dosage:

The recommended dose is 45 mg orally twice daily in combination with encofenib until disease progression or unacceptable toxicity.

Adverse reactions:

>10%:

Cardiovascular: peripheral edema (13%), hypertension (11%)

Central nervous system: fatigue (43%), dizziness (15%)

Dermatology: rash (22%)

Endocrine and metabolism: elevated gamma-glutamyl transferase (45%), hyponatremia (18%)

Gastrointestinal: nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), constipation (22%)

Hematology and oncology: anemia (36%, grade 3/4: 4%), bleeding (19%, grade 3/4: 3%), leukopenia (13%), lymphocytosis Cytopenia (13%, grade 3/4: 2%), neutropenia (13%, grade 3/4: 3%)

Liver: increased serum alanine aminotransferase (29%), increased serum aspartate aminotransferase (27%), increased serum alkaline phosphatase (21%)

Neuromuscular and skeletal: increased creatine phosphokinase in blood samples (5 8%)

Ophthalmology: visual impairment (20%), retinal pigment changes (≤20%, retinal pigment epithelial dystrophy), retinopathy (≤20%, serous: retinal detachment 8%, macular edema 6%)

Kidney: increased serum creatinine (93%)

Others: fever (18%)

1% - 10%:

Cardiovascular disease: reduced left ventricular ejection fraction (7%), venous thromboembolism (6%), pulmonary embolism (3%)

Gastrointestinal tract: colitis (<10%), hematochezia (3%), hemorrhoidal bleeding (1%)

Hematology and oncology: rectal bleeding (4%)

Hypersensitivity: allergy (<10%)

Neuromuscular and skeletal: lipid Inflammation (<10%)

Ophthalmic: Uveitis (4%)

<1%:

Postmarketing or case reports: Interstitial lung disease, pneumonia, retinal vein occlusion, rhabdomyolysis

Undefined frequency:

Cardiovascular: Left ventricular dysfunction

Central nervous system: headache

Contraindications:

None.

Precautions:

Cardiotoxicity: Cardiomyopathy (manifested by left ventricular dysfunction with symptomatic or asymptomatic reduced ejection fraction) has been reported in patients treated with bimetinib and encofenib. Grade 3 left ventricular dysfunction has been reported. The median time to first onset of any grade of left ventricular dysfunction was 3.6 months (range: up to 21 months). Most patients had resolution of their cardiomyopathy. Assess ejection fraction (by echocardiogram or MUGA scan) before starting treatment, one month after starting treatment, and then every 2 to 3 months during treatment. Closely monitor patients with cardiovascular risk factors receiving bimetinib. Depending on the severity, cardiomyopathy may require treatment interruption, dose reduction, or permanent discontinuation.

Gastrointestinal Toxicity: Bimetinib has moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Bleeding: Combining bimetinib and encofenib may cause bleeding, including grade ≥3 bleeding. The most common bleeding events are gastrointestinal in nature and include rectal bleeding, bloody stools, and hemorrhoidal bleeding. Fatal intracranial hemorrhage (in the setting of new or progressive brain metastases) has also been reported. Depending on the severity of bleeding, treatment interruption, dose reduction, or permanent discontinuation may be necessary.

Hepatotoxicity: Concomitant use of bimetinib and encofenib may cause hepatotoxicity; Grade 3 or 4 increases in ALT, AST, and alkaline phosphatase have been reported, but no Grade 3 or 4 increases in total bilirubin have been reported. Monitor liver function tests prior to initiation of treatment, monthly during treatment, and as clinically indicated. Depending on severity, treatment interruption, dose reduction, or permanent discontinuation of treatment may be necessary. At baseline, a dose reduction is recommended in patients with moderate or severe hepatic impairment.

Ocular toxicity: Combination of bimetinib and encofenib can cause serous retinopathy (including retinal detachment and macular edema). Symptomatic serous retinopathy has been reported, but no blindness has occurred. In clinical studies, some patients required treatment interruption or dose reduction due to serous retinopathy, although drug discontinuation was not required. The median time to onset of the first serous retinopathy event (all grades) was 1.2 months (range: up to 17.5 months). Retinal vein occlusion (RVO) is a known adverse effect of MEK inhibitors and may be related to the combined use of bimetinib and encofenib. The safety of bimetinib has not been established in patients with a history of RVO (retinal vein occlusion) or risk factors for RVO (retinal vein occlusion), including a history of uncontrolled glaucoma or hyperviscosity or hypercoagulability syndrome. Uveitis, including iritis and iridocyclitis, has been reported in patients receiving dual therapy. Assess visual symptoms at each visit; perform regular eye exams to check for new or worsening visual disturbances (and follow up on new or ongoing eye exam results). Perform ophthalmic evaluation on patients with acute vision loss or other visual impairment reported within 24 hours. Depending on severity, ocular toxicity may require treatment interruption, dose reduction, or permanent discontinuation of treatment. Permanently discontinue bimetinib in patients with documented RVO (retinal vein occlusion).

Pulmonary Toxicity: Interstitial lung disease (ILD), including pneumonitis, in patients with BRAF mutation-positive melanoma treated with bimetinib and encofenib. Evaluate new or progressive unexplained pulmonary symptoms for possible ILD (interstitial lung disease). Depending on severity, treatment interruption, dose reduction, or permanent discontinuation may be necessary.

Rhabdomyolysis: Elevated CPK (serum creatine phosphate kinase) is common. Monitor CPK (serum creatine phosphate kinase) and creatinine levels before starting treatment and periodically during treatment. Depending on severity, treatment interruption, dose reduction, or permanent discontinuation may be necessary.

Thromboembolism: Depending on severity, thromboembolism may require treatment interruption, dose reduction, or permanent discontinuation.

Combination therapy: Combination use with encofenib (BRAF inhibitor) may produce other toxicities. If encofenib is permanently discontinued, discontinue bimetinib.

Fetal toxicity: May cause fetal harm. Advise females of reproductive potential at risk to the fetus and to use effective contraception.

Storage:

Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15°C to 30°C (59°F to 86°F).

Mechanism of action:

Bimetinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activity. MEK protein is an upstream regulator of the extracellular signal-related kinase (ERK) pathway. In vitro, bimetinib inhibited ERK phosphorylation in cell-free assays and inhibited BRAF-mutant melanoma cells. Bimetinib and encotinib can target two different kinases in the RAS, RAF, MEK, and ERK pathways. The combination had greater antiproliferative activity against BRAF mutation-positive cells in vitro than either agent alone. In mice, BRAF V600E mutant melanomas also produced greater antitumor activity.

Safety and efficacy:

COLUMBUS is a randomized, active-controlled, open-label, multicenter trial. The trial mainly evaluated bimetinib combined with encofenib in the treatment of BRAF Efficacy of unresectable or metastatic melanoma positive for V600E or V600K mutations: median progression-free survival (mPFS) in the bimetinib plus encofenib combination group versus vemurafenib group was 14.9 months VS 7.3 months, the combination group more than doubled the PFS; the objective response rate (ORR) was 63% VS 40%; the duration of response (DOR) was 16.6 months VS 12.3 months. The trial's PFS and OS data show that in the field of targeted melanoma treatment, new drug combinations have "unprecedented advantages" over traditional single drugs.