Background: The rare EGFR mutations that occur in exon 18 involve missense mutations (G719X and E709X), insertion-deletion mutations (ie, E709_T710delinsX), and other molecular subtypes. In total, these mutations account for approximately 3-5% of EGFR alterations in NSCLC. Little is currently known about exon 18 mutations, with most literature based on small retrospective studies. These alterations do not to respond well to first-generation EGFR TKIs.
- Clinical Features Associated: smoking/no smoking history, no sex predilection, adenocarcinoma histology
Detection Methods: PCR, NGS
Most Common Alterations:
The most common exon 18 mutation is G719X (A, C, D, S, or V), followed by E709X, E709_T710delinsX, and finally other subtypes. Studies have shown the best response with second-generation EGFR TKIs. G719X has shown the greatest response to afatinib and neratinib (Nerlynx, Puma Biotechnology) with ORRs of 77.8% and 75%, respectively.
FDA-Approved Targeted Therapy:
- Afatinib (Gilotrif, Boehringer Ingelheim):
- Second-generation irreversible EGFR TKI granted broadened approval by the FDA in the first-line setting for patients with metastatic NSCLC positive for uncommon EGFR mutations (including S768I, L861Q and/or exon 18 G719X). The approval was based on a subset of patients from LUX-LUNG 2, 3, and 6 clinical trials. An ORR of 66% was found with 52% of patients experiencing duration of response of 12 months or longer and an ORR of 77.8% in patients with exon 18 G719X mutation.
- Most Common Adverse Events: diarrhea, rash, dry skin, decreased appetite, vomiting, fatigue, sore mouth, skin infection around the nails, itchy skin, shortness of breath
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