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Uncommon mutations account for 10-15% of epidermal growth factor receptor (EGFR) mutations in patients with non-small-cell lung cancer (NSCLC). However, in spite of the wealth of knowledge of the clinical significance and tyrosine kinase inhibitor (TKI) sensitivity of these mutations, acquisition of deeper insights is limited by the paucity of case reports and cohort studies of the exceptionally rare mutations, including compound mutations. In the present case, we describe the clinical efficacy of icotinib and osimertinib in a metastatic lung adenocarcinoma patient carrying a highly uncommon EGFR L858R/D761Y compound mutation. The progression-free survival (PFS) with osimertinib treatment was much longer than that with icotinib (19 mo vs 8.2 mo), and the overall survival (OS) has currently exceeded three years. To the best of our knowledge, this is the first report of durable osimertinib response in an NSCLC patient with a rare EGFR L858R/D761Y mutation.