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Review these downloadable slides on the molecular heterogeneity of atypical EGFR mutations in NSCLC and the implications for biomarker testing and personalized first-line treatment selection. Current guideline recommendations, tissue- and plasma-based molecular testing strategies, and clinical trial evidence supporting targeted therapies for uncommon EGFR mutations, including G719X, S768I, and L861Q, as well as EGFR exon 20 insertions, are highlighted. Key findings from the ACHILLES, UNICORN, CHRYSALIS-2, PAPILLON, and WU-KONG28 trials support the efficacy of afatinib, osimertinib, amivantamab plus lazertinib, amivantamab plus chemotherapy, and sunvozertinib in molecularly defined patient populations. Practical considerations for individualized treatment selection include mutation subtype, CNS involvement, treatment-related toxicity, and patient preferences.