Abstract 1470: Preclinical activity of the first reversible, potent and selective inhibitor of EGFR exon 20 insertions

Several targeted therapeutic options exist for non-small cell lung cancer (NSCLC) patients whose tumors harbor mutations of EGFR, including L858R, exon 19 deletions, and the acquired resistance mutation, T790M. However, there is no approved targeted therapy for patients with EGFR exon 20 insertions, highlighting an ongoing unmet medical need. Here, we describe a potent and selective inhibitor of EGFR exon 20 insertion mutants with decreased activity on the wild-type EGFR for an improved therapeutic window. Our compound, BAY-568, exhibits greater than 20-fold selectivity for EGFR exon 20 insertions compared to wild-type EGFR in isogenic Ba/F3 models and in cancer cell lines endogenously expressing EGFR exon 20 insertions. This activity is also observed in xenograft models in vivo, correlating with reductions in phospho-EGFR and phospho-Erk in tumors but not skin samples from treated mice. BAY-568 furthermore has even greater activity towards the “classical” erlotinib-sensitive mutations, L858R and exon 19 deletions. Importantly, our compound is reversible, differentiating it from other investigational compounds currently in clinical trials. Consistent with this, the presence of a C797S mutation, typically found in patients with acquired resistance to osimertinib, has no effect on the activity of BAY-568. Taken together, these results demonstrate the ability of BAY-568 to kill cancer cells harboring exon 20 insertions and other EGFR mutations with decreased activity on wild-type EGFR, irrespective of C797S mutation status. Citation Format: Franziska Siegel, Stephan Siegel, Keith Graham, Bethany Kaplan, Kirstin Petersen, Ulf Boemer, Uwe Eberspaecher, Daniel Korr, Ursula Moenning, Detlev Suelzle, Jens Schroeder, Florian Prinz, Sabine Zitzmann-Kolbe, Gizem Karsli-Uzunbas, Timothy Lewis, Mario Hermsen, Andrew Cherniack, Franz von Nussbaum, Knut Eis, Matthew Meyerson, Heidi Greulich. Preclinical activity of the first reversible, potent and selective inhibitor of EGFR exon 20 insertions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1470.