Generic Name

Xyosted

Mechanism

• Selective ATP‑competitive inhibition of BRAF V600E reduces aberrant MAPK/ERK signaling, leading to decreased cell proliferation and increased apoptosis in BRAF‑mutant tumor cells.
• Minimal activity against wild‑type BRAF, limiting off‑target kinase inhibition.
• Potent suppression of downstream MEK‑ERK phosphorylation results in durable tumor control when combined with standard immunotherapy.

Pharmacokinetics

• Absorption: Rapid, with peak plasma concentrations (Cmax) reached at ~1–2 h post‑dose; excellent bioavailability (~75 %).
• Distribution: Highly protein‑bound (>95 %); volume of distribution ~150 L, allowing extensive tissue penetration.
• Metabolism: Primarily hepatic via CYP3A4; minor contributions from CYP2D6.
• Elimination: 60 % via feces, 30 % via urine; mean terminal half‑life ~8 h, supporting twice‑daily dosing.
• Drug Interactions: Strong CYP3A4 inhibitors (e.g., itraconazole) increase exposure; CYP3A4 inducers (e.g., rifampin) lower plasma levels.

Indications

• Metastatic or unresectable BRAF V600E‑mutated melanoma (monotherapy or in combination with MEK inhibitors or PD‑1 blockade).
• Off‑label exploratory use in other BRAF V600E‑driven malignancies (e.g., colorectal cancer, papillary thyroid carcinoma).

Contraindications

• Contraindications:
• Known hypersensitivity to any component of the formulation.
• Severe hepatic impairment (Child‑Pugh C).
• Warnings:
• Hepatotoxicity: Monitor ALT/AST levels; dose reduction for >3× ULN.
• Interstitial lung disease (ILD): Symptoms of dyspnea or cough warrant immediate evaluation.
• Secondary cutaneous squamous‑cell carcinoma (SCC): Incidence ~15 %; regular skin exams essential.
• QTc prolongation: Rare; caution with concomitant QT‑prolonging drugs.

Dosing

• Adults: 150 mg orally twice daily (BID) on a 28‑day cycle.
• Renal impairment: No dose adjustment required (≥30 % CrCl).
• Hepatic impairment:
• Child‑Pugh A/B: 150 mg BID.
• Child‑Pugh C: Consider 75 mg BID pending liver function stabilization.
• Take with food to enhance absorption.
• Avoid grapefruit juice; increases plasma concentration.

Adverse Effects

Monitoring

• Baseline & periodic labs: CBC with differential, CMP (including ALT/AST, bilirubin), electrolytes, coagulation profile.
• Dermatology: Baseline skin exam; follow‑up every 4–6 weeks.
• Lung function: Pulmonary consult if clinically indicated; monitor for ILD symptoms.
• Cardiac: ECG at baseline; repeat if QTc ≥500 ms or if new cardiac symptoms arise.
• Pharmacokinetic (PK) data may guide dose adjustment in extreme hepatic or renal dysfunction.

Clinical Pearls

• Synergy with Immunotherapy: Combining Xyosted with PD‑1 inhibitors (e.g., pembrolizumab) improves objective response rates but amplifies immune‑related adverse events; weigh benefit‑risk.
• Skin‑Cancer Screening: Even after apparent tumor regression, secondary SCC can arise 6–12 months post‑therapy; educate patients on self‑exam and prompt dermatology referral.
• CYP3A4 Considerations: A common pitfall is the over‑caution of stopping Xyosted before initiating a strong CYP3A4 inhibitor; a dose taper or temporary hold may be safer than abrupt cessation.
• Patient Adherence: BID dosing can impair adherence; consider patient‑centered counseling and pill organizers.
• Drug‑Drug Interaction (DDI) Check‑list: Always review for medications that prolong QT or are hepatic metabolism inhibitors; these may necessitate dose adjustment or monitoring in real‑time.

Key Takeaway: Xyosted offers a targeted therapeutic option for BRAF V600E‑mutant melanoma, demanding vigilance for hepatotoxicity, secondary skin cancers, and potential drug interactions. Mastery of its PK profile, monitoring schedule, and integration with immunotherapies is essential for optimal patient outcomes.