Selpercatinib

• Metastatic RET fusion-positive non-small cell lung cancer (NSCLC): For adult patients whose disease has progressed after prior platinum-based chemotherapy or who are intolerant to such treatment.
• Advanced or metastatic RET-mutant medullary thyroid cancer (MTC): In adults and pediatric patients 12 years and older requiring systemic therapy.
• Advanced or metastatic RET fusion-positive differentiated thyroid cancer: In adults and pediatric patients 12 years and older who are refractory to radioactive iodine therapy.
• Off-label uses: Investigational treatment in other RET-altered solid tumors.

• Route: Oral administration.
• Adults: 160 mg orally twice daily, with or without food.
• Pediatrics (≥12 years): Weight-based dosing, typically 120 mg/m² orally twice daily.
• Dose adjustments: Required for adverse events such as hepatotoxicity, hypertension, or QT prolongation. Temporary interruption followed by dose reduction is recommended if severe toxicity occurs.
• Special populations:
• Hepatic impairment: Moderate or severe impairment requires dose adjustment and close monitoring.
• Renal impairment: No specific adjustment recommended; monitor for toxicity in severe renal impairment.

Selpercatinib is a potent and selective inhibitor of the RET tyrosine kinase receptor. RET gene alterations, including fusions and mutations, lead to constitutive activation of RET signaling, promoting cancer cell proliferation and survival. Selpercatinib binds to the ATP-binding site of RET, inhibiting its kinase activity, thereby blocking downstream signaling pathways that drive tumor growth and survival, resulting in tumor cell apoptosis and disease control.

• Absorption: Rapid, with peak plasma concentration approximately 2 hours after oral dosing.
• Bioavailability: Moderate; food intake does not significantly affect absorption.
• Distribution: Widely distributed; plasma protein binding ~95%.
• Metabolism: Mainly metabolized by CYP3A4 enzymes in the liver to inactive metabolites.
• Elimination half-life: Approximately 32 hours, supporting twice-daily dosing.
• Excretion: Primarily eliminated via feces (~69%) and urine (~24%).

• Pregnancy: No adequate human studies; animal data indicate potential fetal risk. Use only if benefits justify potential risks.
• Lactation: Unknown if excreted in human milk; breastfeeding is not recommended during treatment and for at least one week after the last dose.

• Primary class: Antineoplastic agent.
• Subclass: Selective RET kinase inhibitor.

• Hypersensitivity to Selpercatinib or any excipients.
• Severe hepatic impairment without possibility for dose adjustment and monitoring.

• Hepatotoxicity: Monitor liver function tests; discontinue or adjust dose if severe elevation occurs.
• Hypertension: Regular blood pressure monitoring is essential; treat hypertension as clinically indicated.
• QT interval prolongation: Monitor ECG and electrolytes; avoid coadministration with other QT-prolonging drugs.
• Bleeding risk: Use cautiously in patients with bleeding disorders or on anticoagulants.
• Hypersensitivity reactions: Discontinue therapy if severe hypersensitivity occurs.
• Close monitoring of patients for adverse effects is mandatory.

• Common: Fatigue, dry mouth, diarrhea, constipation, hypertension, elevated liver enzymes, peripheral edema, rash, headache.
• Serious (less frequent): Hepatotoxicity, QT prolongation, severe hypertension, hemorrhage, hypersensitivity reactions.

• CYP3A4 inhibitors (e.g., ketoconazole): Increase Selpercatinib plasma levels, potentially increasing toxicity risk; dose adjustment or avoidance advised.
• CYP3A4 inducers (e.g., rifampin): Decrease Selpercatinib plasma concentrations, reducing efficacy; coadministration should be avoided or dosing adjusted.
• Avoid concomitant use of other drugs that prolong QT interval or significantly affect blood pressure without close monitoring.

• FDA approval for treatment of RET fusion-positive NSCLC, RET-mutant MTC, and RET fusion-positive thyroid cancers, including pediatric indications (≥12 years).
• Guidelines emphasize genetic testing for RET alterations to guide therapy.
• Updated safety monitoring recommendations for liver function and cardiac status included in recent clinical protocols.

• Store at controlled room temperature: 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light; keep container tightly closed.
• No refrigeration or special reconstitution required.
• Keep out of reach of children.