Pharmacologic Class
- Targeted therapy – MEK inhibitor (Mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor).
- Used in combination with BRAF inhibitors for BRAF V600–mutant cancers.
Indications
- Unresectable or metastatic melanoma with BRAF V600E or V600K mutation, in combination with encorafenib (Braftovi®).
- Investigational/ongoing trials: other solid tumors with MAPK pathway mutations.
Mechanism of Action
- Inhibits MEK1/2, downstream kinases in the RAS–RAF–MEK–ERK signaling pathway.
- Blocks abnormal MAPK signaling caused by BRAF mutations, preventing tumor cell proliferation and survival.
- Synergy with BRAF inhibitors: reduces resistance and paradoxical pathway activation.
Dosing
- 45 mg PO twice daily (in combination with encorafenib).
- Taken with or without food.
- Dose adjustments required for adverse effects (to 30 mg BID or 15 mg BID if needed).
Key Toxicities & Adverse Effects
- Cardiac: Decreased LVEF, cardiomyopathy.
- Ocular: Retinal pigment epithelial detachment (RPED), retinal vein occlusion (rare).
- GI: Diarrhea, nausea, vomiting, abdominal pain.
- Skin: Rash, photosensitivity, acneiform eruptions.
- Musculoskeletal: Elevated CK, myopathy.
- Hepatic: Elevated AST/ALT.
- Other: Fatigue, edema, dyspnea.
Monitoring
- LVEF (Echocardiogram or MUGA): Baseline, after 1 month, then q2–3 months.
- Ophthalmologic exam: At baseline, for visual symptoms, and periodically.
- CK & CPK: At baseline and periodically.
- LFTs: Regularly during therapy.
- Skin exam: For rash or new malignancies.
Drug Interactions
- Substrate of UGT1A1 → caution with UGT inducers/inhibitors.
- Minimal CYP interactions compared to encorafenib.
- QT prolongation risk increases with other QT-prolonging agents.
Clinical Pearls
- Not used as monotherapy → rapid resistance develops if used without a BRAF inhibitor.
- Synergistic effect with encorafenib → prolongs PFS and reduces cutaneous toxicities compared to BRAF monotherapy.
- Ocular toxicities are class effects of MEK inhibitors (binimetinib, trametinib, cobimetinib).
- Cardiotoxicity risk: needs close monitoring of EF, especially in patients with cardiac history.
In practice:
- Melanoma regimen: Binimetinib 45 mg PO BID + Encorafenib 450 mg PO daily.
- In clinical trials for CRC, binimetinib was tested with encorafenib + cetuximab, but the FDA-approved CRC regimen excludes binimetinib (only encorafenib + cetuximab).