Introduction: EGFR mutations are key oncogenic drivers in lung adenocarcinoma (LUAD), predominantly affecting Asian, nonsmoking, and female populations. Although common mutations, such as exon 19 deletions and L858R, respond well to tyrosine kinase inhibitors (TKIs), uncommon EGFR mutations and compound variants exhibit variable treatment responses. This study aims to compare clinical characteristics and molecular profiles of patients with common, uncommon, and compound EGFR mutations, assessing their implications for therapy outcomes. Methods: We analyzed a multi-cohort genomic dataset of 19,163 patients with LUAD (5,212 with EGFR mutations), categorizing mutations into common, uncommon, and compound classes. Patient demographics, mutational signatures, and tumor microenvironment factors were assessed, with particular attention to smoking status and concomitant alterations in KRAS and TP53. Treatment outcomes were analyzed by time under treatment as a surrogate measure of TKI efficacy. Results: Uncommon EGFR mutations, comprising 8.9% of EGFR-altered cases, were significantly more frequent among smokers and associated with tobacco-related mutational signatures. Compared with common EGFR-mutant cases, tumors harboring uncommon EGFR mutations reported higher rates of EGFR amplifications, KRAS, and TP53 mutations. Uncommon mutations also exhibited higher tumor mutational burden and distinct transcriptional profiles linked to cell cycle activity. Median time on treatment with TKIs was notably shorter in patients with uncommon mutations (4.1 mo) than those with common and compound mutations (10.9 mo and 12.4 mo, respectively). Conclusions: This study underscores the clinical and molecular heterogeneity of EGFR mutation classes in LUAD, highlighting the unique profile of uncommon mutations, particularly their association with smoking and co-mutations in KRAS and TP53. Comprehensive molecular testing, including next-generation sequencing, is crucial to identify these uncommon mutations and inform therapeutic decisions. Further investigation into the role of immunotherapy in patients with uncommon EGFR mutations is warranted given the tobacco-related molecular signatures and high tumor mutational burden associated with this subgroup. (c) 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).