STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.

PURPOSE: Commonly occurring oncogenic mutations in EGFR render non-small cell lung cancers sensitive to approved EGFR-targeted drugs. EGFR in-frame exon 20 insertion (ex20ins) mutants are, however, less sensitive to such drugs. The efficacy of existing medicines may in part be limited by their selectivity for ex20ins mutations relative to wild-type EGFR, which is important for epithelial tissue homeostasis. EXPERIMENTAL DESIGN: We solved high-resolution crystal structures of clinically frequent ex20ins mutants to better understand how to achieve mutant-selective inhibition. Analyses of these structures demonstrate targetable ex20ins-mutant-biased dynamic protein states. To exploit these findings, we designed STX-721, an irreversible EGFR/ERBB2 ex20ins-mutant-selective inhibitor, and characterized its activity relative to clinical phase benchmarks across multiple preclinical assays. RESULTS: Structural analyses predict that STX-721 takes advantage of ex20ins-mutant-selective dynamic states. In carefully benchmarked biochemical, biophysical, and cellular assays, STX-721 demonstrated superior ex20ins-mutant selectivity relative to other tested benchmark clinical phase compounds and achieved ex20ins-mutant-selective tumor regression in vivo. CONCLUSIONS: These data highlight that STX-721 shows a high level of mutant EGFR selectivity across human preclinical cancer models and may provide an improved clinical efficacy versus adverse event profile relative to existing drugs.