Osimertinib

• EGFR-Mutated Non-Small Cell Lung Cancer
• T790M Resistance Mutation NSCLC
• Adjuvant Lung Cancer Treatment

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat EGFR-mutated non-small cell lung cancer (NSCLC). It is specifically designed to target both EGFR-sensitizing mutations and the T790M resistance mutation.

Mechanism of Action

Osimertinib selectively and irreversibly inhibits EGFR:

• Targets EGFR exon 19 deletions and exon 21 L858R mutations: Most common sensitizing mutations
• Targets T790M resistance mutation: Develops in ~60% of patients progressing on first/second-generation EGFR TKIs
• Spares wild-type EGFR: Improved safety profile vs first-generation TKIs
• CNS penetration: Effectively crosses blood-brain barrier for brain metastases

By irreversibly binding to the EGFR ATP-binding site, osimertinib blocks downstream signaling pathways (RAS-RAF-MEK-ERK, PI3K-AKT) that promote cancer cell survival and proliferation.

Available Formulations

Osimertinib is available as oral tablets:

• 40 mg tablets
• 80 mg tablets

Can be taken with or without food. If unable to swallow, tablets can be dispersed in water.

Medical Uses

FDA-Approved Indications:

• First-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations
• Treatment of metastatic EGFR T790M mutation-positive NSCLC in patients who progressed on prior EGFR TKI therapy
• Adjuvant treatment after tumor resection in early-stage (IB-IIIA) NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations

Dosing Guidelines

Metastatic NSCLC:

• 80 mg once daily until disease progression or unacceptable toxicity

Adjuvant Treatment:

• 80 mg once daily for 3 years or until disease recurrence or unacceptable toxicity

Dose Modifications:

• Reduce to 40 mg for adverse reactions
• Permanently discontinue for certain severe toxicities (ILD, QTc >500 ms, symptomatic heart failure)

Important Safety Information

Warnings and Precautions:

• Interstitial lung disease (ILD)/Pneumonitis: Occurs in ~3-4%; can be fatal. Withhold for suspected ILD; discontinue if confirmed
• QTc prolongation: Monitor ECG and electrolytes
• Cardiomyopathy: Monitor LVEF at baseline and during treatment
• Keratitis: Refer to ophthalmology if symptoms occur
• Embryo-fetal toxicity: Can cause fetal harm

Contraindications:

• No specific contraindications listed, but avoid in patients with severe hypersensitivity to osimertinib

Drug Interactions

• Strong CYP3A4 inducers (rifampin, phenytoin): Reduce osimertinib exposure; avoid or increase osimertinib dose to 160 mg if unavoidable
• CYP3A4 inhibitors: No dose adjustment needed (modest effect)
• BCRP substrates (rosuvastatin): Increased exposure; monitor for toxicity
• QT-prolonging drugs: Avoid combination; if necessary, monitor ECG frequently
• Proton pump inhibitors: No significant interaction (unlike some other EGFR TKIs)

Special Populations

• Hepatic Impairment:
  • Mild to moderate: No adjustment needed
  • Severe: Reduce to 40 mg once daily
• Renal Impairment: No adjustment for mild to severe; not studied in ESRD
• Pregnancy: Avoid; can cause fetal harm. Use effective contraception during and for 6 weeks (women) or 4 months (men) after
• Lactation: Avoid breastfeeding during treatment and for 2 weeks after