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Example clinical scenario

A 50-year-old woman who has never smoked is diagnosed with metastatic lung cancer (non-small cell). Somatic testing via a multi-target next-generation sequencing (NGS) panel reveals an EGFR variant: deletion of exon 19.

EGFR-variant lung cancer (non-small cell)

The EGFR gene

  • Variants in EGFR exons 18-24 (which code for the tyrosine kinase (TK) domain) may cause constitutive receptor activation.
  • Around 80%-90% of such variants are the ‘common’ variants L858R and Del19 (deletion of exon 19).
  • The major ‘uncommon’ variants include exon 20 insertions, and G719X, S768I and L861Q variants.
  • Different variants result in heterogeneous tertiary protein structure and variable sensitivity to EGFR TK inhibitors (TKIs). Many registration trials limited patients to those with the ‘common’ variants.

Clinical characteristics

  • EGFR variants are more common in adenocarcinomas in East-Asian individuals (present in 30%-50%) compared with those in the European population (present in 10%-20%).
  • EGFR variants are more common in women than men.
  • Patients with EGFR variants are younger and more likely to be never, light or ex-smokers compared with EGFR wild-type patients.
  • Presence of in-frame EGFR exon 20 insertions are associated with de novo resistance to current clinically available EGFR inhibitors and correlate with poor patient prognosis.

What do you need to do?

Management of the current cancer

  • The presence of a sensitising EGFR variant makes patients eligible for TKI therapy.
  • Three generations of EGFR TKI exist. They differ in terms of receptor specificity, affinity for the wild-type receptor and reversibility:
    • first-generation, reversible, EGFR TKIs (such as erlotinib);
    • second generation, irreversible, ErbB and EGFR TKI (such as afatinib); and
    • third generation, irreversible, EGFR TKI (osimertinib).
  • Guidance exists for first-line therapy. All three generations are licensed; their heterogeneous characteristics result in varying toxicity and efficacy profiles, however.
  • It is important to note that some uncommon EGFR variants (non-L858R or del19) are less sensitive to EGFR TKIs and specialist advice may be needed.

Following progression on first-line therapy

  • After progression on first- or second-generation therapy, around 50% of patients test positive for the T790M variant.
  • T790M variants can be assayed using a recent tumour biopsy (test directory request code M4.1: Multi-target NGS panel-small variant – EGFR, ALK, BRAF, KRAS; or M4.4: EGFR hotspot tumour) or circulating free DNA testing (M4.5: EGFR hotspot ctDNA). The latter is less sensitive, and a confirmatory test is needed (if feasible) following a negative result.
  • Osimertinib has activity following T790M-mediated resistance to first-line therapy and is approved by NICE as an option for treating EGFR T790M mutation-positive locally advanced or metastatic lung cancer (non-small cell) that has has progressed after first-line treatment with an EGFR TKI.
  • Osimertinib resistance may be caused by the C797S mutation, which disrupts the cysteine at the 797 position necessary for osimertinib binding.
  • Presence of an EGFR exon 20 insertion may confer eligibility for second-line treatment (after first-line platinum chemotherapy) with the EGFR inhibitor mobocertinib, which is being made available by the NHS in England through an early national access agreement following a Project Orbis licence.


For clinicians


For patients

Cancer Research UK: About targeted cancer drugs – see section on erlotinib, gefitinib or afatinib

Tagged: Lung cancer

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2023
  • Authors: Dr Amit Samani
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh