Abstract 5610: BAY 2927088: a novel treatment option for patients with NSCLC with <i>HER2</i> mutations

Abstract Lung cancer is the most prevalent tumor type worldwide, and despite advancements in providing patients with improved therapies, the 5-year overall survival rate is still only 5.8%. About 2-4% of patients with non-small cell lung cancer (NSCLC) carry either a HER2 exon20 insertion or a HER2 point mutation, which are potent oncogenic drivers. The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki was the first targeted treatment option to be approved for patients with HER2-mutant NSCLC. However, there is still a significant unmet need for more effective and better tolerated therapies with the potential to improve response rates and response durability. Here we present preclinical data for BAY 2927088, a highly potent and selective tyrosine kinase inhibitor targeting HER2. BAY 2927088 shows potent in vitro antiproliferative activity in tumor cell lines carrying HER2 mutations, and strongly blocks HER2 phosphorylation, thereby inhibiting HER2-mediated downstream MAPK signaling. We also confirmed the strong anti-tumor activity of BAY 2927088 in in vivo models with HER2 exon20 insertions. To further explore the therapeutic potential of BAY 2927088, we evaluated combination treatment with current standard-of-care therapies in NSCLC in vitro and in vivo. In addition, we profiled BAY 2927088 vs. other HER2 tyrosine kinase inhibitors by pooled screening of 866 barcoded human cancer cell lines to identify additional oncogenic dependencies and patient populations that might benefit from treatment with BAY 2927088. We found that BAY 2927088 was also active in a subset of HER2-amplified breast and gastroesophageal cancer cell lines. Single-agent BAY 2927088 is currently being evaluated in clinical trials in patients with NSCLC with HER2 mutations. Preliminary results demonstrate efficacy and safety in pretreated patients (NCT05099172, NCT06452277). Citation Format: Franziska Siegel, Kristýna Kotýnková, Gizem Karsli-Uzunbas, Thibaud Jourdan, Melanie Berthold, Stephan Siegel, Daniel Korr, Markus Berger, Haruna Tomono, Sawyer Andersen, Daniel Denney, Jérémie Mortier, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. BAY 2927088: a novel treatment option for patients with NSCLC with HER2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5610.