EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is based on sporadic reports and need validation with larger cohorts.We identified EGFR C797X-mutant NSCLC patients from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles, and assessed associations between clinical outcomes and C797X status.365 EGFR C797X-mutant cases were categorized into four subtypes base on allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients showed the worst progression-free survival (PFS) on both prior (median 7.7 months) and subsequent treatment (median 1.0 month) and overall survival (median 3.9 months). In subsequent treatments, in cis patients showed superior PFS with combined brigatinib and cetuximab (median 11.0 months) compared with other regimens (P = 0.005), while in trans patients exhibited variable outcomes with combined first/second- and third-generation EGFR inhibitor (PFS range: 0.7 -8.1 months, median 2.6 months). Notably, subtype switching was observed after subsequent treatments, predominantly towards the in cis subtype.Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscape and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.