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

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.

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.

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

• ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) – includes recommendations for molecular testing and treatment
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Guidance relevant to lung cancer – many guidelines related to treatments following somatic (tumour) molecular testing
• NICE: Pathways for lung cancer – see advanced non-squamous (stages IIIB and IV) lung cancer: EGFR-TK mutation

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 2021: volume 16, issue 5, pages 764-73. doi: 10.1016/j.jtho.2020.12.002

For patients

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