What is the significance of Epidermal Growth Factor Receptor (EGFR) exon 19 deletion?

From the Guidelines

EGFR exon 19 deletion is a specific genetic mutation that makes non-small cell lung cancer (NSCLC) tumors responsive to targeted therapy with EGFR tyrosine kinase inhibitors (TKIs), with osimertinib being the preferred first-line treatment option at a dose of 80mg daily. This mutation involves the removal of a small portion of the gene in exon 19, leading to constant activation of the EGFR protein, driving cancer cell growth and survival 1. The presence of this mutation is clinically significant because it predicts a favorable response to EGFR TKIs, resulting in improved survival and tumor shrinkage compared to traditional chemotherapy 1.

Key Points

• EGFR exon 19 deletion is a common mutation in NSCLC, particularly in never/light smokers, women, and patients with adenocarcinoma histology and East Asian ethnicity 1.
• Patients with this mutation typically undergo molecular testing of their tumor tissue or liquid biopsy to confirm the presence of the mutation before starting treatment 1.
• EGFR TKIs, such as osimertinib, erlotinib, gefitinib, and afatinib, specifically block the abnormal signaling from the mutated EGFR protein, resulting in improved outcomes 1.
• Side effects of EGFR TKIs may include skin rash, diarrhea, and rarely, pneumonitis, which should be monitored during treatment 1.
• Most patients eventually develop resistance to these medications, usually after 9-13 months of treatment, highlighting the need for ongoing monitoring and potential treatment adjustments 1.

Treatment Recommendations

• Osimertinib is the preferred first-line treatment option for patients with EGFR exon 19 deletion, at a dose of 80mg daily 1.
• Other EGFR TKIs, such as erlotinib, gefitinib, and afatinib, may also be considered as first-line treatment options, although osimertinib is generally preferred due to its improved efficacy and safety profile 1.
• For patients who develop resistance to first-line EGFR TKIs, subsequent treatment options may include chemotherapy, amivantamab, or other targeted therapies, depending on the specific resistance mechanism and patient characteristics 1.

From the FDA Drug Label

EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA) ... 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by CTA. In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions

EGFR exon 19 deletion refers to a specific type of mutation in the epidermal growth factor receptor (EGFR) gene, where a portion of the gene is deleted. This mutation is associated with non-small cell lung cancer (NSCLC) and is a predictor of response to certain treatments, such as erlotinib 2.

• Key points:
  • Exon 19 deletion is a type of EGFR mutation
  • Associated with NSCLC
  • Predictor of response to certain treatments, such as erlotinib
  • 66% of patients in the study had exon 19 mutation deletions 2

From the Research

Definition of EGFR Exon 19 Deletion

• EGFR exon 19 deletion (19del) is a sensitive mutation of the epidermal growth factor receptor (EGFR) observed in non-small cell lung cancer (NSCLC) 3.
• It consists of a large number of variants and is associated with the sensitivity of EGFR tyrosine kinase inhibitors (TKIs) treatment 4.
• Exon 19 deletion is the most common activating mutation in advanced non-small cell lung cancer (NSCLC) and predicts sensitivity to EGFR TKIs treatment 4.

Clinical Significance of EGFR Exon 19 Deletion

• Patients with EGFR exon 19 deletion have been shown to have favorable overall survival after first-line gefitinib therapy in advanced non-small cell lung cancer patients 5.
• The presence of exon 19 deletion is an independent prognostic factor of favorable progression-free survival (PFS) and overall survival (OS) in patients receiving first-line gefitinib treatment 5.
• However, different exon 19 deletions may have varying responses to EGFR TKIs, with some studies suggesting that patients with deletions starting from E746 may have better OS than those with deletions starting from L747 3.

Subtypes of EGFR Exon 19 Deletion

• There are different subtypes of EGFR exon 19 deletion, including delE746_A750 and uncommon deletions 6.
• The frequency of uncommon deletions of exon 19 can be as high as 36% 6.
• Patients with E746_A750del, the most common 19del subtype, may have a higher frequency of acquired T790M mutation when treated with first- or second-generation EGFR-TKIs compared to those with other 19del subtypes 3.