The incidence of NSCLC with EGFR mutations varies across geographies[1][2][3][4]

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]

Frequency of EGFR mutations by geography

Figure 1. Frequency of EGFR mutations by geography
All EGFR mutations; N= 57 studies; 56,462 patients.[5]
Melosky et al. 2021.[5]

There are many different EGFR mutation types in NSCLC – most of which impact the structure of the EGFR-TKI binding pocket[6][7]

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, EGFRexon 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]

Pie chart

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]

Find out who EGFR ex20ins mutations strike.

Mechanism of action of EGFR-TKIs

EGFR-TKIs interact with the ATP-binding pocket of EGFR’s tyrosine kinase domain.[7] They function as competitive inhibitors of ATP.[7]

The three most common activating EGFR mutations have different impacts on the ATP binding pocket, so they have different responses to currently approved EGFR-TKIs[6][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]

Deletion & Insertion

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]

Various European treatment guidelines (including in Germany and Italy) recommend against the use of first- and second-generation EGFR-TKIs in EGFRm ex20ins NSCLC due to their poor efficacy.[12][13] For these patients, conventional chemotherapy is favoured.[14]

Find out how EGFR exon 20 insertion mutations are escaping treatment with EGFR-TKIs.

A summary of key EGFRmutations (including ex20ins mutations) and their sensitivity or resistance to different generations of EGFR-TKIs[7][8][10][11][15][16][17][18][19]


Next-generation sequencing (NGS) is emerging as a reliable strategy capable of testing simultaneously for multiple alterations, including EGFR exon 20 insertion mutations, using only a single tissue sample.[20]

Make EGFR exon 20 insertion mutations unmissable. Test with next-generation sequencing (NGS).

Want to find out more about emerging treatment options for patients who have EGFRm NSCLC?

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

Discover more about EGFR exon 20 insertion mutations and NSCLC here:

Who do EGFR ex20ins mutations strike?
What impact do EGFR ex20ins mutations have on lives?
How can NGS help you to find EGFR ex20ins mutations?

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.