- EGFR
- EGFR exon 20 insertion mutations
Approximately one third of the 1.8 million patients worldwide who are diagnosed with NSCLC each year have a mutation in their EGFR gene (EGFRm), equating to 600,000 people[1][2][3][4]
The frequency of EGFR mutations in NSCLC varies across geographies – with higher figures reported in Asia (~49%) and lower figures reported in Europe (~13%) (fig. 1)[5]
Figure 1. Frequency of EGFR mutations by geography
All EGFR mutations; N= 57 studies; 56,462 patients.[5]
Melosky et al. 2021.[5]
A diverse array of EGFR mutations have been identified in NSCLC (fig. 2), which predominantly occur in regions encoding the protein’s tyrosine kinase domain (exons 18–22).[6][7]
Common “classical” EGFR mutations (deletions in exon 19 and the L858R point mutation in exon 21) account for the majority (~85%) and confer sensitivity to EGFR-TKIs – so they can represent an actionable diagnosis.[6]
The remaining 15% of EGFR mutations are the “uncommon” mutations – of which, EGFR exon 20 insertion (ex20ins) mutations are the most common. In fact, EGFR exon 20 insertion mutations are the third most common activating EGFR mutation in NSCLC.[6] Unfortunately, these mutations generally confer intrinsic, primary resistance to currently approved EGFR-TKIs.[7][8]
Figure 2. Pie chart showing the frequencies of EGFR driver mutations in NSCLC
Data were acquired from COSMIC databases. Data were filtered to contain only mutations from adenocarcinoma. The common resistance mutations T790M and C797S were filtered out.[6]
Adapted from Harrison et al. 2020.[6]
EGFR-TKIs interact with the ATP-binding pocket of EGFR’s tyrosine kinase domain.[7] They function as competitive inhibitors of ATP.[7]
Mutations in the ATP binding pocket (exons 18–21) therefore have the potential to alter the binding affinity of EGFR not only for ATP but also for EGFR-TKIs – meaning different EGFR mutations have different levels of sensitivity to treatment with EGFR-TKIs (fig. 3).[7]
Figure 3. Deletions, substitutions/point mutations, and insertions activate EGFR even in the absence of a ligand, changing the shape of the EGFR-TKI binding pocket and ultimately impacting interactions with EGFR-TKIs[7][9]
Exon 19 deletions occur close to the N-terminal side. They shorten the protein and “pull” the C-helix, exposing the ATP-binding pocket – the site of interaction with EGFR-TKIs.[7]
Substitution/point mutations destabilise the inactive form of EGFR and can cause conformational changes that expose the ATP-binding pocket – the site of interaction with EGFR-TKIs.[7]
Exon 20 insertion mutations add an extra portion of protein near the C-terminal side, “pushing” the C-helix.[7] These mutations are generally insensitive to treatment with EGFR-TKIs due to steric hindrance at the EGFR-TKI binding site.[10]
Adapted from Ferguson KM et al. 2003, and Vyse S, Huang PH. 2019.[7][9]
Data have suggested that a third-generation EGFR-TKI may demonstrate clinical activity in some patients who have EGFRm ex20ins NSCLC, though this requires further evaluation.[11]
Watch an expert review on EGFR in NSCLC with Matthew Krebs (UK), Antonio Passaro (Italy), Joshua Bauml (USA), and Luis Paz-Ares (Spain), on our Janssen Oncology medical education resource
ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; EGFRm, mutated EGFR; EGFR-TKI, EGFR-tyrosine kinase inhibitor; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer.
CP-223640