Generic Name

Gavreto

Mechanism

• Selective inhibition of mutant BRAF V600 tyrosine‑kinase, blocking downstream MEK‑ERK signaling.
• Restores normal proliferation control in melanoma cells, leading to apoptosis and tumor regression.
• When combined with the MEK inhibitor binimetinib, continuous blockade of the MAPK pathway reduces compensatory signaling and limits resistance.

Pharmacokinetics

• Form: Oral tablets (300 mg).
• Absorption: Rapid, peak plasma concentration (Tmax) within 3–4 h after dosing.
• Bioavailability: ~55 % after a single 300‑mg dose; food increases exposure modestly.
• Distribution: Extensive; protein binding ~95 % (predominantly to albumin).
• Metabolism: Primarily CYP3A4/5 mediated, with minor involvement of CYP1A2 and UGT1A9.
• Elimination: ~70 % excreted in feces, 25 % in urine; mean half‑life 10–12 h.
• Drug interactions: Strong CYP3A4 inhibitors/inducers alter exposure; co‑administration with digoxin or other CYP3A substrates warrants monitoring.

Indications

• Metastatic or unresectable melanoma with confirmed BRAF V600E/K mutation in combination with binimetinib (BRAF + MEK inhibitor therapy).
• Approved for patients aged ≥18 y; no validated indication in pediatric/adolescent populations.

Contraindications

• Contraindicated with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) when taken with binimetinib.
• Warnings:
• Photosensitivity reactions; patients advised to use sunscreen; photoprotective clothing.
• Potential for cutaneous squamous cell carcinoma and keratoacanthoma—regular dermatologic exams.
• Interstitial lung disease/pneumonitis—prompt evaluation for respiratory symptoms.
• Cardiac toxicity: QTc prolongation occasionally noted; baseline and periodic ECGs recommended.
• Abdominal pain may precede pancreatitis or acute cholangitis.

Dosing

• Standard dose: 300 mg PO once daily (300 mg tablet).
• When combined with binimetinib: binimetinib 45 mg PO twice daily, or 30 mg PO twice daily if high CYP3A activity or concomitant strong inhibitors.
• Start–stop guidelines: Initiate as soon as possible; if no therapeutic response or disease progression after 2–3 months, consider discontinuation.
• Overdose: No specific antidote; supportive care and monitoring.

Adverse Effects

Monitoring

• Baseline: CBC, CMP (LFTs), ECG, dermatologic exam, pulmonary assessment.
• Ongoing:
• CBC/CMP every 2 weeks for first 2 months, then monthly.
• ECG at 4 weeks and if symptomatic.
• Skin surveillance monthly for lesions.
• Pulmonary evaluation (symptom check) at each visit.
• Therapeutic drug monitoring: Not routinely required unless drug interaction concerns.

Clinical Pearls

• Combination synergy: Encored with binimetinib exploits dual MAPK blockade, giving higher response rates (~60 %) vs BRAF‑only therapy (~30 %).
• Rapid onset: Patients can expect objective radiographic responses within 6–8 weeks; early imaging may help guide continuation strategy.
• Photosensitivity first: Often the earliest sign of toxicity—teach patients to check for rash after sun exposure.
• High‑risk patients: Those with pre‑existing cardiac dysfunction, liver disease, or on strong CYP3A inhibitors should receive intensified monitoring or alternative regimens.
• Adjuvant nature: In selected patients with resected metastatic melanoma, BRAF + MEK inhibitors are being explored as adjuvant therapy—clinical trial data emerging.
• Drug‑drug interactions: Avoid co‑administration of grapefruit juice, ketoconazole, or rifampin; provide patient counseling on over‑the‑counter meds.

Key Takeaway: Gavreto (encorafenib) paired with binimetinib delivers robust, MAPK‑pathway targeted therapy for BRAF‑mutant melanoma, but demands vigilance for photosensitivity, skin carcinogenesis, and cardiac/liver safety signals.