EGFR mutant non-small cell lung cancer (NSCLC) is defined by activating mutations in the epidermal growth factor receptor (EGFR) gene. Around 15-20% of adenocarcinomas in Western populations and up to 50% in East Asian populations are EGFR mutant. The classic profile is adenocarcinoma histology, female sex, never-smoker or light-smoker status, and East Asian ancestry. The most frequent mutations are exon 19 deletions (45-50%, most common, with the best response to osimertinib-class TKIs) and the exon 21 L858R point mutation (40-45%). Less common sensitizing mutations include exon 18 G719X, exon 20 S768I, and exon 21 L861Q. Exon 20 insertions confer resistance to older TKIs but respond to amivantamab and mobocertinib. The EGFR T790M mutation is a resistance mutation that remains sensitive to osimertinib.
EGFR mutations cause constitutive activation of the receptor, driving constant downstream signaling (RAS/RAF/MAPK, PI3K/AKT, JAK/STAT) that promotes tumor proliferation, survival, and angiogenesis. Tyrosine kinase inhibitors (TKIs) — erlotinib, gefitinib, and afatinib (first/second generation), dacomitinib (second generation), and osimertinib (third generation) — block the ATP binding pocket and prevent receptor phosphorylation. In EGFR mutant NSCLC, TKIs deliver higher response rates (60-80% vs 30%), longer progression-free survival (10-19 vs 5-6 months), and better quality of life than chemotherapy. The FLAURA trial established osimertinib's superiority over erlotinib and gefitinib in the first-line setting.
Current standard of care: (1) First-line metastatic EGFR mutant NSCLC — osimertinib (active across all sensitizing mutations, in T790M-resistant disease, with strong brain metastasis penetration; the FLAURA2 trial showed longer PFS when combined with chemotherapy). Alternatives include erlotinib with or without bevacizumab/ramucirumab, afatinib, or dacomitinib. (2) After osimertinib resistance — MET amplification (amivantamab + lazertinib or capmatinib), C797S mutation, and histologic transformation (SCLC or squamous) may emerge; biopsy plus NGS is recommended. Some patients benefit from T-DXd (HER2+), sacituzumab govitecan, or chemotherapy + bevacizumab + atezolizumab. (3) Exon 20 insertions — amivantamab (EGFR-MET bispecific antibody) and mobocertinib are dedicated options. (4) Adjuvant setting — in resectable stage IB-IIIA EGFR mutant NSCLC, osimertinib for 3 years following adjuvant chemotherapy improved DFS and OS (ADAURA trial). (5) Locally advanced — chemoradiotherapy followed by osimertinib consolidation is being evaluated in place of durvalumab (LAURA trial showed positive results). Brain metastases occur in 30-40% of EGFR mutant NSCLC, and osimertinib provides intracranial control through blood-brain barrier penetration.