Osimertinib vs Afatinib

## Overview

Afatinib (Gilotrif) is a second-generation, irreversible pan-ErbB TKI blocking EGFR, HER2 (ErbB2), and HER4. Osimertinib is a third-generation EGFR-selective irreversible TKI. Afatinib's broader ErbB inhibition provides benefit in specific EGFR exon 20 insertion mutations and uncommon EGFR mutations where osimertinib has less data.

## Mechanism of Action

Both covalently bind ErbB family kinases. Afatinib: pan-ErbB (EGFR + HER2 + HER4), Cys797 in EGFR. Osimertinib: primarily EGFR (and to some extent HER2), but with higher selectivity for mutant vs. WT EGFR than afatinib.

## Clinical Evidence

LUX-Lung 3 and 7 (afatinib): established afatinib as first-line in EGFR-mutated NSCLC. LUX-Lung 8 (afatinib vs erlotinib in squamous NSCLC with EGFR expression): afatinib superior. FLAURA (osimertinib): superior OS vs erlotinib/gefitinib; afatinib not directly compared.

## Uncommon EGFR Mutations

Afatinib has specific approval for uncommon EGFR mutations (exon 18–21) based on data from the Global Rare Mutations registry. Osimertinib's activity in uncommon mutations is more limited. For certain uncommon mutations (G719X, S768I, L861Q), afatinib is guideline-recommended.

## Toxicity

Afatinib inhibits WT EGFR strongly, causing significant diarrhea (80–100%), rash (89%), and mucositis. Osimertinib has better mutant selectivity, causing less severe diarrhea and rash.

## Key Takeaways

- Osimertinib: standard first-line for classical Exon 19 del/L858R; superior CNS; less toxicity
- Afatinib: preferred for certain uncommon EGFR mutations (G719X, S768I, L861Q)
- Pan-ErbB inhibition: afatinib has HER2/HER4 activity not shared by osimertinib