Results: Patient with lung cancer (non-small cell) and a somatic (tumour) EGFR variant

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

The EGFR gene

• Variants in EGFR exons 18 to 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 limit patient access 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 in men.
• Patients with EGFR variants are younger and are more likely to be never, light or ex-smokers compared with EGFR wild-type patients.
• Presence of in-frame EGFR exon 20 insertions is associated with de novo resistance to current clinically available EGFR inhibitors and correlates with poor patient prognosis.

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; however, their heterogeneous characteristics result in varying toxicity and efficacy profiles.
• 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 (National Genomic Test Directory request code M4.1 Multi-target NGS panel – small variant (EGFR, ALK, BRAF, KRAS, MET), or M4.4 EGFR hotspot tumour) or circulating tumour DNA (ctDNA) 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 progressed after first-line treatment with an EGFR TKI.
• Osimertinib resistance may be caused by the C797S variant, which disrupts the cysteine at the 797 position necessary for osimertinib binding.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

For clinicians

• European Society for Medical Oncology: Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow up (PDF, 71 pages)
• NHS England: National Genomic Test Directory
• NICE: All products on lung cancer
• NICE: Guidance relevant to lung cancer

References:

• Passaro A, Mok T, Peters S and others. ‘Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations‘. Journal of Thoracic Oncology 2020: volume 16, issue 5, pages 764–773. DOI: 10.1016/j.jtho.2020.12.002

For patients

• Cancer Research UK: Targeted and immunotherapy treatment for lung cancer