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BACKGROUND: Non-small cell lung cancer (NSCLC) represents 80% of lung cancers, the second leading cause of cancer deaths globally. Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are genomic drivers in a molecular sub-type of NSCLC that is sensitive to tyrosine kinase inhibitors (TKIs). Third-generation, irreversible TKIs, such as osimertinib and lazertinib, have become standard of care and are now widely used as first-line therapy in EGFR-driven metastatic NSCLC. However, resistance invariably arises during treatment. The C797S mutation is the most frequent on-target resistance mechanism in response to third-generation TKIs when used in the first-line setting. There are currently no approved therapies for patients who progress with a C797S mutation. Although first-generation TKIs inhibit EGFR with a C797S mutation, they carry liabilities of 1) insufficient selectivity over wild-type (WT) EGFR, which precludes maximal target coverage and results in dose-limiting adverse events; and 2) limited brain penetration. METHODS: BLU-701 activity was tested in biochemical assays for EGFR mutants and EGFR WT. Cellular activity was evaluated by a phosphorylation specific EGFR AlphaLisa assay in WT cell lines or those expressing EGFR mutations. The in vivo antitumor activity of BLU-701 was assessed in a PC9 ex19del cell line-derived tumor xenograft (CDX) model. RESULTS: We have developed an orally available, single-digit nanomolar, brain-penetrant, WT-sparing, reversible EGFR inhibitor that is active against the C797S resistance mutation. BLU-701 is equally potent against both the sensitizing mutations ex19del and L858R, and the resistance double mutants ex19del/C797S and L858R/C797S. BLU-701 is brain penetrant (Kpu,u >0.9) and demonstrates a selectivity over WT EGFR that compares favorably with osimertinib. Oral administration of BLU-701 to PC9 ex19del tumor-bearing mice resulted in strong and prolonged pathway suppression and tumor regression at tolerated doses. CONCLUSION: Due to its potent pharmacological activity and selectivity for mutant EGFR, BLU-701 has the potential to demonstrate activity in first-line and resistance settings as a single agent and in combination therapy, addressing potential tumor heterogeneity. The pre-clinical data described here supports the clinical development of BLU-701 in EGFR-driven NSCLC. Citation Format: Chiara Conti, John Campbell, Rich Woessner, Jian Guo, Yoav Timsit, Maria Iliou, Scott Wardwell, Alison Davis, Sharon Chicklas, John Hsieh, Meredith Eno, Omar Ahmad, Dilinie Fernando, Kevin Barvian, Joseph Kim, Steven Kazmirski, Emanuele Perola, Tom Dineen, Victoria Brown, Timothy Guzi, Ayşegül Özen, Faith Stevison, Caitlin Utt, Clare Medendorp, Robert Meissner, Marion Dorsch, Klaus Hoeflich. BLU-701 is a highly potent, brain-penetrant and WT-sparing next-generation EGFR TKI for the treatment of sensitizing (ex19del, L858R) and C797S resistance mutations in metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1262.