BDTX-1535, a fourth generation EGFR inhibitor, targeting intrinsic and acquired resistance mutations in NSCLC

Background: The classical mutations of the epidermal growth factor receptor (EGFR) in NSCLC are the exon 19 del and exon 21 (L858R) mutations. The 3rd generation EGFR tyrosine kinase inhibitor (TKI), osimertinib, has become the first-line treatment of choice for NSCLC patients with these mutations. Resistance to 3rd generation TKIs can be driven by gain of secondary EGFR alterations, e.g., substitution at cysteine-797 to serine (C797S). Real world evidence shows that in addition to C797S, other EGFR alterations are also acquired upon osimertinib treatment, including kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. In addition to the classical mutations, NSCLC tumors express a wide spectrum of primary kinase domain mutations including G719X in exon 18, S768I in exon 20, and L861Q in exon 21, which confer intrinsic resistance to approved TKIs. NCCN guidelines recommend the use of afatinib or osimertinib, however, there remains a need for an EGFR TKI that targets these mutations with high potency, good tolerability, and CNS penetration. Our MAP platform allowed us to select MasterKey inhibitor BDTX-1535, a 4th-generation CNS penetrant EGFR TKI, that potently and selectively targets multiple intrinsic and acquired resistance EGFR alterations. Materials and Methods: BDTX-1535 preclinical exposure was evaluated across species, and PK and Kpuu values were calculated in brain and plasma. Antitumor activity was assessed across a broad range of mouse PDX and allograft models. Results: BDTX-1535 is a potent and selective, CNS penetrant, wild type sparing, irreversible EGFR TKI targeting Exon 18–21 alterations which are associated with intrinsic or acquired resistance to 3rd generation EGFR inhibitors. These include a broad range of kinase domain EGFR mutations (e.g., C797S, L718Q, G724S, S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. Mouse xenograft and allograft studies showed that BDTX-1535 consistently achieves regression of tumors carrying these mutations at well tolerated doses without significant EGFR wild type associated toxicities. BDTX-1535 is orally bioavailable with a CNS Kpuu of 0.55 and 0.48 in rat and dog, respectively, and active in an intracranial PDX model. Conclusions: BDTX-1535 is a 4th generation CNS penetrant EGFR TKI discovered using the MAP platform which allows MasterKey targeting of EGFR alterations associated with intrinsic or acquired resistance to 3rd generation EGFR TKIs, while sparing wild type EGFR. This broad spectrum coverage of resistance mutations in conjunction with CNS penetration properties allows BDTX-1535 to address a key unmet medical need in EGFR mutant lung cancer. BDTX-1535 is currently under phase I clinical investigation (NCT05256290). Conflict of interest: Ownership: Black Diamond Therapeutics