Osimertinib — Drug Monograph

Osimertinib (Tagrisso) — EGFR-Mutant NSCLC Overview

Osimertinib (Tagrisso) is a third-generation, irreversible EGFR tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) driven by activating EGFR mutations — chiefly exon 19 deletions and the L858R exon 21 point mutation. It also targets the T790M resistance mutation that limits first- and second-generation EGFR TKIs, and its strong CNS penetration makes it effective against brain metastases. This monograph summarizes osimertinib indications, the standard osimertinib dose, mechanism of action across EGFR exon 19 deletions and L858R, adverse effects, drug interactions, and monitoring requirements.

Indications (FDA / NCCN)

• First-line metastatic NSCLC with EGFR exon 19 deletions or L858R mutations (FLAURA)
• T790M-positive metastatic NSCLC that progressed on a prior EGFR TKI
• Adjuvant therapy after resection of EGFR exon 19 del / L858R NSCLC (ADAURA)
• NCCN-preferred first-line EGFR TKI for exon 19 del / L858R NSCLC

Dosing

• Standard dose: 80 mg orally once daily
• Adjuvant (ADAURA): 80 mg once daily for up to 3 years
• Take with or without food; may be dispersed in ~50 mL water for NG tube
• Strong CYP3A4 inducers (e.g. rifampin) lower levels ~80% — avoid

Monitoring

• EGFR mutation testing (tissue or liquid biopsy) before starting
• Baseline + periodic ECG for QTc; correct electrolytes
• LVEF (echo/MUGA) at baseline and ~every 3 months
• Monitor for interstitial lung disease / pneumonitis and LFTs

Brand names: Tagrisso

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Third-generation irreversible EGFR TKI. Covalently binds and inhibits mutant EGFR kinase domain (classical sensitizing mutations: exon 19 deletions and L858R exon 21) and the resistance mutation T790M (which confers resistance to 1st and 2nd generation EGFR TKIs). Has superior CNS penetration compared to earlier EGFR TKIs due to lower P-gp efflux. Spares wild-type EGFR at pharmacologically relevant concentrations.

FDA Indications

• First-line treatment of metastatic NSCLC with exon 19 deletions or L858R EGFR mutations (FLAURA trial)
• T790M mutation-positive metastatic NSCLC — progressed on or after EGFR TKI therapy
• Adjuvant treatment of NSCLC with exon 19 or L858R EGFR mutations following tumor resection (ADAURA trial)

Common Side Effects

• Diarrhea
• Rash (acneiform/papulopustular)
• Dry skin and pruritus
• Nail toxicity (paronychia)
• Mucositis
• Fatigue
• Decreased appetite

Clinical Pearl

Osimertinib is the preferred first-line EGFR TKI because it covers both classical sensitizing mutations and T790M resistance, and has superior CNS penetration (reduces brain metastasis risk significantly — FLAURA showed 52% reduction in CNS progression). For acquired resistance to osimertinib, the C797S mutation is the most common molecular mechanism; MET amplification is the most common bypass mechanism (~15%).

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC