Abstract 4035: Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer

HER2 mutations are potent oncogenic drivers in various cancer indications. In NSCLC, about 2% of patients carry either a HER2 exon20 insertion mutation or a HER2 point mutation. With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. However, there remains a high unmet need for more effective and better tolerated therapies with the potential to improve response rates and response durability. BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, phase I clinical trial in patients with EGFR mutant NSCLC (NCT05099172). Here, we present the preclinical activity profile of BAY 2927088 in HER2 mutant NSCLC. BAY 2927088 shows strong antiproliferative activity in an isogenic Ba/F3 cell line panel of HER2 exon20 insertion mutations as well as HER2 point mutations. BAY 2927088 is highly potent on the most frequent HER2 exon20 insertion mutations A775insYVMA and G776del insVC, as well as in the HER2 point mutations S310F, S335C, and L755S, among others. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA. The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations. Citation Format: Franziska Siegel, Gizem Karsli-Uzunbas, Kristyna Kotynkova, Quinn McVeigh, Stephan Siegel, Daniel Korr, Volker Schulze, Markus Berger, Georg Beckmann, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4035.