Selpercatinib

Selpercatinib

FDA-Approved Indications

  1. NSCLC (non-small cell lung cancer):
    • Adults with RET fusion–positive NSCLC.
  2. Medullary thyroid cancer (MTC):
    • Adults and pediatric patients (≥2 years) with RET-mutant MTC requiring systemic therapy.
  3. Thyroid cancer (other than MTC):
    • Adults and pediatric patients (≥2 years) with RET fusion–positive thyroid cancer who require systemic therapy and are refractory to radioactive iodine (if appropriate).
  4. Solid tumors (tumor-agnostic approval, 2022):
    • Adults with locally advanced or metastatic RET fusion–positive solid tumors that progressed on prior therapy and lack alternative treatments.

Dosing

  • Adults & Pediatrics ≥12 years (based on weight):
    • <50 kg: 120 mg PO BID
    • ≥50 kg: 160 mg PO BID
  • Children 2–11 years: weight-based oral solution dosing (FDA approved 2025, not widely adopted yet).

Administration:

  • Take with or without food.
  • Avoid grapefruit.
  • Swallow capsules whole (do not crush or chew).

Key Toxicities

  • Hepatotoxicity (↑AST/ALT) → monitor LFTs.
  • Hypertension (can be severe) → monitor BP regularly.
  • QT interval prolongation → ECG and electrolytes monitoring.
  • Hemorrhagic events (rare but serious).
  • Hypersensitivity reactions (fever, rash, arthralgia, myalgia, thrombocytopenia).
  • Diarrhea, constipation, fatigue, dry mouth, edema (common).

Drug–Drug Interactions

  • CYP3A4 substrate:
    • Avoid strong CYP3A inhibitors (e.g., ketoconazole) → ↑ toxicity.
    • Avoid strong CYP3A inducers (e.g., rifampin) → ↓ efficacy.
  • P-gp substrate.
  • Acid-reducing agents:
    • Avoid PPIs.
    • If H2 antagonists → give selpercatinib 2h before or 10h after.
    • If antacids → give selpercatinib 2h before or after.

Monitoring

  • LFTs (baseline, then q2 weeks × 3 months, monthly thereafter).
  • BP at baseline and regularly.
  • ECG and electrolytes (K, Mg, Ca) if QT risk.
  • Assess for hemorrhage, hypersensitivity.
  • Response via imaging.

Clinical Pearls

  • Highly selective RET inhibitor → less off-target toxicity compared to multikinase inhibitors (like cabozantinib or vandetanib).
  • Used as first-line in RET+ NSCLC and MTC.
  • CNS activity – effective against brain metastases.
  • Dose modifications required for hepatic impairment and toxicities.
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