The molecular landscape of EGFR-mutated non-small cell lung cancer (NSCLC) has evolved substantially with the widespread adoption of the third-generation covalent EGFR tyrosine kinase inhibitor (TKI) osimertinib as first-line therapy for tumors harboring classical EGFR mutations, along with the expanded use of next-generation sequencing (NGS). Consequently, patterns of acquired resistance have shifted: the once-predominant EGFR-T790M resistance mutation associated with first-generation EGFR TKIs has decreased in incidence, while EGFR-C797S has emerged as a major resistance mechanism following front-line third-generation EGFR TKI therapy. In parallel, increasing evidence highlights differential therapeutic responses to first-line third-generation EGFR TKIs between tumors with EGFR-L858R and EGFR-Ex19del mutations. Comprehensive genomic profiling through NGS continues to refine our understanding of the spectrum of classical, non-classical, and bypass resistance alterations, particularly those involving or co-occurring with C797S. Using paired tissue and plasma samples, we provide real-world evidence characterizing the molecular landscape of classical and non-classical EGFR mutations, as well as bypass signaling alterations that include C797S. We further describe the activity profile of WSD0922-FU, a molecule specifically designed to address the evolving EGFR mutational landscape, supported by translational data spanning preclinical to clinical studies. Our data demonstrate that WSD0922-FU exhibits potent activity not only against classical EGFR mutations and on-target resistance mechanisms following osimertinib-including C797S-but also against a range of non-classical EGFR alterations affecting both intracellular and extracellular domains (Q701L, E709X, L718X, G719X, S768I, V769M, L792X, V834X) as well as EGFRvIII. Collectively, these findings inform the clinical development strategy for WSD0922-FU as a potential first-line therapy for classical EGFR mutations, a second-line option for patients with CNS metastases after osimertinib, and a targeted treatment for tumors harboring C797S following osimertinib resistance.