Abstract 4434: Ficerafusp alfa reverses acquired resistance to the KRAS-G12C inhibitor sotorasib in KRAS-G12C-mutated lung tumors

Abstract Approximately 15% of non-small cell lung cancer patients present with a KRAS-G12C mutation and do not respond to anti-Epidermal Growth Factor Receptor (anti-EGFR) therapy1. Recent approvals of KRAS-G12C inhibitors (G12Ci) such as sotorasib (AMG510) and adagrasib have improved treatment responses and overall survival rates2. One of the mechanisms associated with acquired resistance and subsequent relapse after prolonged treatment with G12Ci is linked to overexpression of TGF-β3. Increased TGF-β is associated with immune suppression and epithelial-mesenchymal transition (EMT), contributing to increased metastasis3, 4. Ficerafusp alfa, a bifunctional antibody targeting EGFR and TGF-β within the tumor microenvironment, may enhance treatment efficacy when combined with G12Ci by overcoming drug resistance. Lung cancer cell lines NCI-H1792 (KRAS-G12C+/−) and NCI-H1373 (KRAS-G12C−/−), both characterized by high EGFR and TGF-β levels, were cultured with sotorasib for over 6 weeks to induce resistance. Resistant NCI-H1792 cells were treated with sotorasib, cetuximab (anti-EGFR antibody), ficerafusp alfa, or their combinations. Treatments were assessed in 2D culture and 3D spheroid-PBMC co-cultures, measuring cytotoxicity and gene expression changes via Nanostring analysis (in 2D model). Additionally, sotorasib-resistant NCI-H1373 cells were used in a subcutaneous xenograft model to evaluate treatment efficacy in vivo. Results demonstrated that combining sotorasib with ficerafusp alfa showed better efficacy over sotorasib alone and sotorasib in combination with cetuximab in sotorasib-resistant NCI-H1792 tumor cells in vitro. Additionally, in the 3D spheroid-PBMC co-culture assay, our combination reduced overall spheroid area. Nanostring analysis showed downregulation of TGF-β signalling, EMT, and metastatic pathways in the sotorasib and ficerafusp alfa group compared to sotorasib plus cetuximab. In vivo, TGF-β ELISA analysis revealed higher TGF-β levels in sotorasib-resistant NCI-H1373 tumors compared to the parental tumors. The combination of sotorasib with ficerafusp alfa resulted in a significant reduction in sotorasib-resistant NCI-H1373 tumors over sotorasib in combination with cetuximab. This study reinforces the hypothesis that TGF-β plays an important role in acquired resistance to G12Ci. Our findings suggest that combining G12Ci with ficerafusp alfa could overcome G12Ci drug-resistance in KRAS-G12C-mutated lung cancer. References 1.Lim TKH, et al., Lung Cancer. 2023. PMID: 37683526 2.Huang et.al., Signal Transduct Target Ther. 2021. PMID: 34776511 3.Tsai YS, et al., J Clin Invest. 2022. PMID: 34990404 4.Adachiet.al., Clin Cancer Res. 2020. PMID: 32900796 Citation Format: Veena Somasundaram, Shiv Ram Krishn, Reshmi Nair, Pradip Nair, Rachel L. Salazar. Ficerafusp alfa reverses acquired resistance to the KRAS-G12C inhibitor sotorasib in KRAS-G12C-mutated lung tumors [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 4434.