BAY 2927088: The first non-covalent, potent, and selective tyrosine kinase inhibitor targeting EGFR exon 20 insertions and C797S resistance mutations in NSCLC

Background: EGFR exon 20 insertion mutations represent a distinct subset of EGFR-mutant lung cancer with poor prognosis generally associated with resistance to several EGFR tyrosine kinase inhibitors. Despite the recent advances with the approval of amivantamab and mobocertinib, there remains a high unmet need for more effective and better tolerated agents targeting exon 20 insertions that can improve response rates and response durability. Results: Here we present BAY 2927088, the first reversible small molecule inhibitor selectively targeting EGFR exon 20 insertion mutations. BAY 2927088 is highly potent against EGFR exon 20 insertions in biochemical and cellular assays, and displays strong, ∼40-fold selectivity for EGFR exon 20 insertion mutants relative to wild-type EGFR. Both potency and selectivity were validated in vivo in cell line-derived xenografts as well as in patient-derived xenograft models carrying different EGFR exon 20 insertion mutations. BAY 2927088 is also highly active against the classical EGFR exon 19 del and L858R activating mutations with >1000-fold selectivity vs. wild-type EGFR in Ba/F3 cellular models. Importantly, BAY 2927088 retains potent activity in the presence of the EGFR C797S resistance mutation due to its non-covalent binding mode. Conclusions: The strong potency and improved selectivity of BAY 2927088 offer the prospect of a wider therapeutic window in the clinic and potentially a favorable safety profile with improved combinability compared to available EGFR exon 20 insertion targeted therapies. BAY 2927088 is currently being evaluated in a first-in-human, phase I clinical trial in patients with EGFR mutant NSCLC (NCT05099172). The study will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of BAY 2927088. Conflict of interest: Ownership: shareholder of Bayer. Corporate-sponsored Research: employee of Bayer.