Pharmacologic Class
- Targeted therapy – BRAF kinase inhibitor
- Selectively inhibits mutated BRAF V600E kinase.
Indications
- Metastatic melanoma with BRAF V600E or V600K mutation
→ Used in combination with binimetinib (MEK inhibitor). - Metastatic colorectal cancer (CRC) with BRAF V600E mutation
→ Used in combination with cetuximab. - Investigational/ongoing trials: other solid tumors with BRAF V600 mutations.
Mechanism of Action
- Inhibits mutated BRAF kinase → blocks abnormal activation of the MAPK/ERK pathway → reduces tumor cell proliferation.
- Less paradoxical activation of MAPK pathway compared to earlier BRAF inhibitors (e.g., vemurafenib, dabrafenib).
Dosing
- Melanoma (with binimetinib):
- Encorafenib 450 mg PO once daily (with or without food).
- Binimetinib 45 mg PO twice daily.
- Colorectal cancer (with cetuximab):
- Encorafenib 300 mg PO once daily.
- Dose adjustments may be required for toxicity (graded by CTCAE).
Key Toxicities & Adverse Effects
- Dermatologic: Rash, photosensitivity, alopecia, new primary cutaneous malignancies (SCC, keratoacanthoma).
- GI: Nausea, vomiting, diarrhea, abdominal pain.
- Musculoskeletal: Arthralgia, myalgia.
- Cardiac: QT prolongation (dose-related).
- Ocular: Uveitis, retinal pigment epithelial detachment (especially with binimetinib).
- Other: Fatigue, pyrexia (less frequent than with dabrafenib).
Monitoring
- Before starting: Confirm BRAF V600 mutation status (must be positive).
- ECG & electrolytes: Monitor QTc at baseline and periodically.
- Dermatologic exam: Before, during, and after therapy for skin cancers.
- Ophthalmologic exam: If visual changes occur.
- LFTs & renal function: Periodically.
Drug Interactions
- CYP3A4 substrate → avoid strong inducers (e.g., rifampin, carbamazepine) and inhibitors (e.g., ketoconazole, clarithromycin).
- May affect agents that prolong QTc.
- Use caution with other targeted therapies in combination.
Clinical Pearls
- Always combine with a MEK inhibitor (binimetinib) in melanoma to reduce resistance and paradoxical MAPK pathway activation.
- In CRC, must be combined with cetuximab – monotherapy is ineffective due to EGFR feedback activation.
- Has a longer dissociation half-life than other BRAF inhibitors, which may contribute to more durable inhibition.
- Compared to dabrafenib + trametinib, encorafenib + binimetinib tends to have lower incidence of pyrexia but more GI side effects.