Background: EGFR genetic alterations, including mutation and amplification, are very common in glioblastoma multiforme (GBM), however, no targeted therapy has been approved for this disease. EGFR oncogenic mutations in GBM promote EGFR oncogenic covalent homodimer formation which leads to paradoxical activation and renders reversible inhibitors ineffective. An effective EGFR inhibitor in GBM must meet four conditions: 1. Highly potent and selective against a broad range of extracellular domain mutations and amplified EGFR, 2. Wild-type EGFR sparing, 3. Irreversible binding to circumvent paradoxical activation, 4. High CNS penetration. Our MAP discovery platform led to the identification of MasterKey inhibitor BDTX-1535, an irreversible 4th-generation CNS penetrant EGFR tyrosine kinase inhibitor (TKI) that potently and selectively targets a broad range of EGFR alterations in GBM.

Materials and Methods: BDTX-1535 preclinical exposure was evaluated in multiple species in plasma and brain. Antitumor activity was assessed across a broad range of mouse PDX and allograft models, including an intracranial PDX. 2540 tumors were sequenced with the Tempus xT NGS assay. Mutational frequencies and co-expression status of oncogenic EGFR variants were assessed. The relationship between treatment history and oncogenic EGFR mutational frequency was analyzed.

Results: BDTX-1535 is a small molecule that irreversibly inhibits a spectrum of EGFR alterations expressed in GBM together with EGFR amplification, while sparing inhibition of normally expressed wild type EGFR. BDTX-1535 avoids efficacy limiting paradoxical activation that can occur with reversible EGFR inhibitors. BDTX-1535 exhibits good oral bioavailability and a CNS Kpuu of 0.55 and 0.48 in rat and dog, respectively, comparing favorably with other CNS penetrant TKIs. Tumor regression and survival advantage were observed across all tumor models with EGFR amplification or mutation, including in an intracranial PDX model. EGFR mutations and amplification are commonly expressed in GBM. Consistent with published data, EGFR mutations, variants, and copy number gain were frequently coexpressed. For example, among tumors expressing EGFRvIII, ∼95% coexpressed at least one other variant, and among tumors expressing EGFRvVI, ∼45% co-expressed at least one other variant. Within a subset of GBM patients with longitudinal sequencing data, oncogenic EGFR mutations were expressed and persisted following front-line treatment.

Conclusions: BDTX-1535 is a potent, CNS penetrant, irreversible small molecule EGFR inhibitor that shows efficacy against a broad range of extracellular domain mutations and EGFR amplification found in GBM patients. RWE findings demonstrate a heterogeneous EGFR mutational profile in GBM patients, with persistent prevalence over time. BDTX-1535 is currently in a phase I clinical study (NCT05256290).

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