Abstract P02-04: BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases

Abstract

Abstract NSCLC accounts for approximately 85% of lung cancer cases worldwide. NSCLC harboring EGFR mutations constitutes 10-20% of all lung cancer cases in Europe and North America, and up to 50% of those in Asia. The majority (80-90%) of these mutations are either Exon19del or L858R. Uncommon EGFR mutations, of which G719X, S768I and L861Q are amongst the most frequent, account for 10-20% of EGFR mutations in NSCLC. Additionally, secondary EGFR mutations such as C797S that emerge during treatment with osimertinib occur in ~10% of patients. Current generation EGFR inhibitors with efficacy against common, uncommon and/or resistance mutations are either poorly brain penetrant or do not have broad spectrum activity against multiple mutations. BDTX-1535 is an irreversible, spectrum selective MasterKey inhibitor of common, uncommon and resistance EGFR mutations such as G719X and C797S that occur in NSCLC (IC50<10nM). BDTX-1535 is differentiated from many EGFR inhibitors by its CNS-penetrating properties. BDTX-1535 has a Kpuu, defined as the ratio of the unbound brain tissue concentration over the unbound plasma concentration, of 0.8 in rat. In studies of EGFR Exon19del+C797S, BDTX-1535 achieved pEGFR suppression exceeding 24 hours in vitro and following a single dose in vivo. BDTX-1535 has demonstrated robust tumor growth inhibition and regressions in multiple pre-clinical models, including PDX intracranial models. Thus, BDTX-1535 has potential to treat patients with NSCLC harboring a broad range of mutations, both common and uncommon, as well as those associated with resistance to the current standard of care TKIs. The CNS penetrating properties may help to treat CNS metastases or to prevent them from occurring. BDTX-1535 is currently being evaluated in IND-enabling studies. Citation Format: Matthew C. Lucas, Melinda S. Merchant, Matthew O'Connor, Carl Cook, Sherri Smith, Anthony Trombino, Wu-Yan Zhang, Irache Visiers, Kate Tith, Reza Foroughi, Nigel Waters, Iwona Wrona, Michael Pickard, Sudharshan Eathiraj, Karsten Witt, Christopher Roberts, Rachel Humphrey, Elizabeth Buck. BDTX-1535, a CNS penetrant MasterKey inhibitor of common, uncommon and resistant EGFR mutations, demonstrates in vivo efficacy and has potential to treat osimertinib-resistant NSCLC with or without brain metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-04.