• Literature review: Classic EGFR activating mutations in exons 19 and 21 confer sensitivity to EGFR TKIs
• Exon 20 mutations may account for up to 4% of all EGFR mutations and are resistant to clinically achievable doses of reversible and irreversible EGFR TKIs

Unlike exon 19 deletions and exon 21 point mutations (L858R), exon 20 insertions have previously been considered clinically resistant to EGFR TKIs, and this first-ever collection of published cases confirmed that observation by demonstrating only 1 partial response to erlotinib or gefitinib among 20 patients with this abnormality. Importantly, the presence of an exon 20 insertion does not mean that an EGFR TKI should not be considered at some point, and most investigators will approach this situation as they would a “pan-wild-type” tumor, turning first to chemotherapy with or without a biologic agent and then considering a TKI in the second-line setting and beyond.