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While first- and second-generation EGFR inhibitors (EGFRi) have shown success against EGFR mutant non-small cell lung cancer (NSCLC), the emergence of resistance mechanisms has prevented long-term treatment for many patients. The third-generation inhibitor osimertinib, the current standard of care, is still prone to resistance. Combined with the failure of several late-stage candidates it is clear a novel approach is required. We have developed a transomic analysis platform, PROSPER (Protein Regulation with Objective Seeking Powerful Evidence Retrieval), employing an integrated analysis of genomics, transcriptomics, proteomics, and phosphoproteomics, termed transomics. This proprietary analysis allows us to interpret complex biological relationships and provide a functional map of the biochemical drivers of disease. We investigated the effects of a cross-section of EGFRi in a panel of EGFR mutant lung cancer cell lines and performed a transomics analysis to identify key differences between different EGFRi and drive novel drug discovery to circumvent resistance to EGFR-targeted drugs. Seven drugs, both approved and unapproved EGFRi, were evaluated against three NSCLC cell lines. The cell lines expressed wild-type EGFR (as a control), Ex19del activating mutation (to model EGFR mutant NSCLC), or L858R activating mutation plus T790M gatekeeper mutation (to model a subtype of EGFRi resistant NSCLC). Approved drugs included erlotinib, afatinib (first- and second-generation EGFRi, respectively), and osimertinib (third-generation drug that can overcome the T790M gatekeeper mutation that confers resistance to earlier drugs). The remaining drugs (maverlertinib, naquotinib, olmutinib, rociletinib) are unapproved third-generation inhibitors. The concentration required to inhibit cell growth (IC50) was determined after a 72 h incubation and viability was assessed by CellTiter-Glo. For the transomic analyses, the same drugs were incubated for 24 h with the IC50 concentration and cells were harvested for genomic, transcriptomic, proteomic and phosphoproteomic analyses. The subsequent analysis revealed striking differences between the seven drugs. Principal component analysis shows two distinct clusters between approved and unapproved drugs. Furthermore, the transomic signature for the third-generation approved drug osimertinib was significantly different to that for the drug olmutinib which failed clinical development due to toxicity. Transomic analysis of EGFRi has the potential to identify important differences between successful drugs, drugs that failed in clinical development, and to identify non-EGFR targets that may overcome resistance to current drugs. This hypothesis is currently being investigated across various resistant and undruggable cancers to unlock novel therapeutic targets. Citation Format: Christopher J. Nicholson, Arudhir Singh, Caitlin Westberg Brown, Simon P. Fricker, Jon Hu, Samantha Dale Strasser. An integrated transomics approach reveals significant differences between EGFR inhibitors with the potential to identify novel targets to overcome EGFR resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB063.