Abstract 3779: LY4050784, a selective inhibitor of SMARCA2, demonstrates synergistic activity in combinations with pembrolizumab or KRAS inhibitors

Abstract SMARCA4 alterations occur in approximately 10% of NSCLC and are associated with worse overall survival [1]. SMARCA4 mutations, which also occur in multiple cancer types, create a dependency on SMARCA2, resulting in synthetic lethality when SMARCA2 is selectively inhibited [2]. LY4050784 (FHD-909) is a selective SMARCA2 inhibitor that has demonstrated robust synthetic lethality with single-agent tumor regressions across multiple murine xenograft models of SMARCA4 mutated NSCLC [3]. A phase 1 study of LY4050784 is ongoing (NCT06561685). Of note, SMARCA4 deficiency frequently co-occurs with KRAS mutations in NSCLC and has been shown to result in poor clinical outcomes upon treatment with KRAS inhibitors or with immune checkpoint inhibitors [1, 4]. Here, we report the synergistic activity of LY4050784 in combination with standard-of-care agents and several novel KRAS inhibitors that are currently in development. To assess the combination benefits of LY4050784 in NSCLC, we evaluated combination treatments with chemotherapies, pembrolizumab, and KRAS inhibitors in vitro and in vivo using preclinical SMARCA4-mutant human cancer models. LY4050784 demonstrated robust activity in vitro and in vivo when combined with standard lung cancer chemotherapies (paclitaxel, cisplatin, and pemetrexed). Additionally, we evaluated LY4050784 in combination with pembrolizumab in a humanized KRAS- and SMARCA4-mutant lung cancer xenograft model. Here, LY4050784 sensitized the tumors to pembrolizumab resulting in synergistic combination benefit, while pembrolizumab alone had no effect on tumor growth as compared to the vehicle control. Finally, we explored the activity of LY4050784 in combination with both mutant-selective KRAS G12C and G12D inhibitors (olomorasib and LY3962673, respectively) and the isoform-selective pan-KRAS inhibitor LY4066434. In SMARCA4 and KRAS co-mutated lung, pancreatic, and colon cancer models, the KRAS inhibitors resulted in synergistic increases in activity both in vitro and in vivo when combined with LY4050784. These results demonstrate that LY4050784 exhibits robust antitumor activity in combination with chemotherapy, pembrolizumab, and multiple KRAS inhibitors in preclinical models of SMARCA4-mutant cancers. Investigation of these combinations clinically is warranted. Alessi et al., 2021, doi: 10.1016/j.jtho.2021.03.024 Hoffman et al., 2014, doi: 10.1073/pnas.1316793111 Lee, J.Y. et al. Poster presented at the AACR Annual Meeting; April 8, 2024; San Diego, CA Negrao et al., 2023, doi: 10.1158/2159-8290.CD-22-1420. Citation Format: Nathan A. Brooks, Shuang Chen, Candace Langan, Bryan Perria, Bonita D. Jones, Hai Hu, Mia Lei, Renan Escalante Chong, Wei Zheng, Rowena Almonte-Baldonado, Xiaodong Huang, Robert Stephen Flack, Janice Y. Lee, Kevin Wilson, Anke Klippel, Laurie LeBrun. LY4050784, a selective inhibitor of SMARCA2, demonstrates synergistic activity in combinations with pembrolizumab or KRAS inhibitors [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 3779.