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Mini Oral session

27MO - BDTX-1535, a CNS penetrant, irreversible inhibitor of intrinsic and acquired resistance EGFR mutations, demonstrates preclinical efficacy in NSCLC and GBM PDX models.


07 Mar 2022


Mini Oral session


Matthew Lucas


Annals of Oncology (2022) 33 (suppl_1): S13-S23. 10.1016/annonc/annonc840


M.C. Lucas1, M. Merchant2, M. O'Connor3, S. Smith4, A. Trombino4, W. Zhang2, J. Simon2, S. Eathiraj2, N. Waters2, E. Buck5

Author affiliations

  • 1 Black Diamond Therapeutics, New York/US
  • 2 Black Diamond Therapeutics, Cambridge/US
  • 3 Black Diamond Therapeutics, 11795 - Stony Brook/US
  • 4 Black Diamond Therapeutics, 2142 - Cambridge/US
  • 5 Black Diamond Therapeutics, 10014 - New York/US


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Abstract 27MO


EGFR is a potent oncogene commonly altered in cancers including NSCLC and GBM. NSCLC driven by canonical EGFR mutations can be treated by inhibitors including osimertinib. However, there is an unmet need to treat NSCLC tumors with acquired drug resistance mutations including C797S, or tumors expressing non-canonical EGFR mutations that are intrinsically resistant to these agents. We have revealed how EGFR oncogenic mutations in GBM drive a conformational structure that promotes formation of a covalently linked homodimer. Reversible inhibitors can promote this oncogenic dimer and result in paradoxical stimulation. Effective targeting of the full spectrum of EGFR mutants in NSCLC and GBM requires a CNS-penetrant agent that is not only potent and selective, but also irreversible to circumvent paradoxical activation.


The in vitro activity and irreversible binding of BDTX-1535 was studied. CNS exposure was assessed in rats and dogs. Antitumor activity was assessed across a broad range of mouse PDX, including intracranial, models.


BDTX-1535 is an orally available, CNS penetrant, potent and selective irreversible inhibitor of EGFR mutations and amplification. As well as canonical EGFR mutations, it potently inhibits intrinsic resistance mutations that are inadequately controlled by approved EGFR inhibitors (e.g., G719X). It retains irreversible activity against acquired resistance mutations to 3rd generation EGFR TKIs (e.g., L858R/C797S). BDTX-1535 potently suppresses phosphorylation of EGFR mutants for greater than 24h following a single oral dose. Broad antitumor efficacy is achieved across NSCLC/GBM PDX tumors expressing a family of EGFR oncogenic mutations. BDTX-1535 exhibits a CNS Kpuu of 0.58 and 0.48 in rat and dog, respectively, and achieves survival benefit in a PDX intracranial murine model of GBM.


The preclinical characterization of BDTX-1535 supports potential for effectively treating NSCLC and GBM patients expressing mutations that are inadequately addressed by current EGFR inhibitors. BDTX-1535 is currently under phase I clinical investigation in NSCLC and GBM patients expressing targeted oncogenic EGFR mutations.

Legal entity responsible for the study

Black Diamond Therapeutics.


Black Diamond Therapeutics.


M.C. Lucas, A. Trombino, S. Eathiraj: Financial Interests, Personal, Stocks/Shares: Black Diamond Therapeutics; Financial Interests, Personal, Full or part-time Employment: Black Diamond Therapeutics. M. Merchant, M. O'Connor, S. Smith, W. Zhang, J. Simon, N. Waters, E. Buck: Financial Interests, Personal, Full or part-time Employment: Black Diamond Therapeutics; Financial Interests, Personal, Stocks/Shares: Black Diamond Therapeutics.

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