Data from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer

AbstractPurpose: Resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting C797S mutation. Patients and Methods: Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the efficacy of BBT-176 both in vitro and in vivo. Patient cases are derived from an ongoing phase 1 clinical trial (NCT04820023). Results: The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S protein were measured at 4.36, 1.79 and 5.35 nM, respectively (vs. 304.39, 124.82, and 573.72 nM, for osimertinib). IC50 values of BBT‑176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183 and 202 nM, respectively (vs 869, 1134, 2799, and 2685 nM for osimertinib). N-Ethyl-N-nitrosourea (ENU) mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT‑176 effectively suppressed the growth of BBT-176-resistant clones. BBT‑176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients from harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiological improvements. Conclusions: BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKIs.