Uncommon epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are heterogeneous and show variable prevalence and clinical responses to EGFR-tyrosine kinase inhibitors. We investigated the characteristics of uncommon EGFR mutations and the clinical efficacy of afatinib in patients. In this multicenter, retrospective study, we analyzed patients with NSCLC and uncommon EGFR mutations; these were categorized according to their incidence: (1) major uncommon

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... s (G719X and L861Q), (2) compound mutations, and (3) minor uncommon mutations (exon 20 insertion, S768I, and de novo T790M). Sixty-four patients (9.1%, 64/703) with uncommon EGFR mutations were identified in 16 South Korean institutes. Afatinib demonstrated activity against major uncommon (median time of treatment [TOT]: 20.3 months, 95% CI: 5.0-27.9; overall survival (OS): 30.6 months, 95% CI: 33.5–34.0) and compound mutations (median TOT: 11.9 months, 95% CI: 3.6–9.6; OS: 29.1 months, 95% CI: 12.1–65.4). Minor uncommon mutations showed unfavorable responses to afatinib (median TOT: 3.8 months, 95% CI: 2.1–4.2; OS: 8.5 months, 95% CI: 4.7–18.2). S768I mutation was present in 14 patients (1.99%, 14/703). Median TOT and OS were not significantly different between S768I and resistant exon 20 mutations. Afatinib is active in patients with NSCLC harboring major uncommon and compound EGFR mutations.