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Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M -negative resistance., Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M + ) and -negative (T790M - ) disease., Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M - tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M - tumors. Almost half of resistant tumors were further classified as immune hot , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M - and T790M + disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients., Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential., (©2021 The Authors; Published by the American Association for Cancer Research.)

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.