Osimertinib

• Class: Tyrosine kinase inhibitor – EGFR inhibitor, third-generation, irreversible.

Mechanism of Action (MOA)

• Irreversibly binds mutant EGFR tyrosine kinase, including:

  • Exon 19 deletions
  • Exon 21 L858R mutations
  • T790M resistance mutation (common after first-generation EGFR TKIs).
• Inhibits downstream signaling (RAS/RAF/MEK/ERK, PI3K/AKT).
• Spares wild-type EGFR, reducing some skin and GI toxicities compared to first-generation TKIs.

Clinical Uses

• NSCLC with EGFR activating mutations – first-line therapy.

• NSCLC with T790M mutation – after progression on first- or second-generation EGFR TKIs.
• Effective against CNS metastases due to good blood-brain barrier penetration.

Dosing (Adults)

• 80 mg orally once daily, with or without food.

• Dose adjustments:
  • Reduce to 40 mg daily in severe hepatic impairment.
  • Avoid strong CYP3A4 inhibitors/inducers; adjust as needed.

Toxicities

• Dermatologic: Rash, dry skin, pruritus (less severe than erlotinib/gefitinib).

• Diarrhea – usually mild to moderate.
• QT prolongation – monitor ECG, especially with other QT-prolonging drugs.
• Interstitial lung disease (ILD) / pneumonitis – rare but serious.
• Fatigue, anorexia.
• Cardiac toxicity: rare heart failure.

Monitoring

• Skin: manage rash and dry skin.

• ECG and electrolytes for QT interval monitoring.
• Liver function tests periodically.
• Pulmonary symptoms: monitor for ILD/pneumonitis.
• Drug interactions: CYP3A4 substrates, inhibitors, inducers.

Summary

Osimertinib (Tagrisso®) is a third-generation, irreversible EGFR TKI targeting activating EGFR mutations and T790M resistance mutations. Key concerns are rash, diarrhea, QT prolongation, and rare ILD, with good CNS penetration making it valuable for brain metastases.