Data from BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer

Abstract

<div>AbstractPurpose:<p>Resistance to third-generation EGFR inhibitors including osimertinib arises in part from the C797S mutation in <i>EGFR</i>. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting the C797S mutation.</p>Patients and Methods:<p>Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells, and patient-derived xenografts expressing mutant <i>EGFR</i>s were used to test the inhibitory potency and the anticancer efficacy of BBT-176 both <i>in vitro</i> and <i>in vivo</i>. Patient case data are also available from an ongoing phase I clinical trial (NCT04820023).</p>Results:<p>The half maximal inhibitory concentration (IC<sub>50</sub>) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S proteins were measured at 4.36, 1.79, and 5.35 nmol/L, respectively (vs. 304.39, 124.82, and 573.72 nmol/L, for osimertinib). IC<sub>50</sub> values of BBT–176 against Ba/F3 cells expressing <i>EGFR</i> 19Del/C797S, <i>EGFR</i> 19Del/T790M/C797S, <i>EGFR</i> L858R/C797S, and <i>EGFR</i> L858R/T790M/C797S were 42, 49, 183, and 202 nmol/L, respectively (vs. 869, 1,134, 2,799, and 2,685 nmol/L for osimertinib). N-ethyl-N-nitrosourea mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the <i>EGFR</i> 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 harboring <i>EGFR</i> 19Del/T790M/C797S in blood showed tumor shrinkage and radiologic improvements.</p>Conclusions:<p>BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKI, with early clinical efficacy and safety.</p></div>