Osimertinib vs Gefitinib

## Overview

Gefitinib (Iressa) was the first EGFR TKI approved for NSCLC and validated EGFR-targeted therapy as a concept. Osimertinib has superseded it in first-line treatment. Gefitinib remains a rational second choice where osimertinib is unavailable.

## Mechanism of Action

Both inhibit EGFR tyrosine kinase. Gefitinib is a first-generation reversible ATP-competitive inhibitor; osimertinib is a third-generation irreversible Cys797-binding inhibitor with T790M activity.

## Clinical Evidence

IPASS trial (gefitinib vs chemotherapy in EGFR-selected Asian patients): established EGFR TKIs as first-line in EGFR-mutated NSCLC (2009). FLAURA (osimertinib vs erlotinib or gefitinib): osimertinib significantly superior in PFS and OS.

## CNS Penetration

Osimertinib has substantially better CNS penetration (CSF:plasma ~33%) vs. gefitinib (<1%). Given high brain metastasis rates in EGFR-mutated NSCLC, this is a critical difference.

## Key Takeaways

- Gefitinib: historical 1st-line; now replaced by osimertinib
- Osimertinib: current standard (FLAURA), CNS penetrant, T790M active
- Gefitinib used when osimertinib unavailable or cost-prohibitive