Abstract 5617: Development of an initial triple combination therapy targeting EGFR, AXL, and FGFR for EGFR-mutated non-small cell lung cancer

Abstract Background: Based on our prior preclinical research, a clinical trial is currently underway to assess the safety and efficacy of combining the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib with the AXL inhibitor ONO-7475 in treatment-naive patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Japan (jRCT2051210045). However, even with this combined treatment, the development of acquired resistance is expected in clinical settings. Therefore, we aimed to establish a multidrug combination therapy from the first-line setting to eliminate such resistance. Methods: We investigated adaptive resistance mechanisms to the combination of osimertinib and ONO-7475 and developed a novel therapeutic strategy to overcome them using in vitro and in vivo experiments. Results: In an siRNA screening assay, knockdown of fibroblast growth factor receptor 1 (FGFR1) significantly inhibited cell viability in the presence of osimertinib plus ONO-7475. The combination of osimertinib and ONO-7475 activated FGFR1 through the upregulation of FGF2 via the c-Myc pathway. In cell-based assays, triple combination therapy with the pan-FGFR inhibitor BGJ398, along with osimertinib and ONO-7475, significantly enhanced cell apoptosis by increasing the proapoptotic factor Bim and inhibited cell viability compared to the combination of osimertinib and ONO-7475 alone. In cell line-derived xenograft (CDX) models, the combination of osimertinib, ONO-7475, and BGJ398 substantially suppressed tumor regrowth. No apparent adverse effects were observed during this treatment. Conclusions: Our findings demonstrate that the FGF2-FGFR1 signaling pathway contributes to adaptive resistance to the combination of osimertinib and ONO-7475 in EGFR-mutated NSCLC with high AXL expression. The triple combination therapy of osimertinib, ONO-7475, and BGJ398 showed safety and prevented tumor regrowth in CDX models, suggesting that this regimen has the potential to improve outcomes for patients with EGFR-mutated NSCLC. Citation Format: Ryota Nakamura, Tadaaki Yamada, Tomoko Yasuhiro, Ryohei Kozaki, Koichi Takayama. Development of an initial triple combination therapy targeting EGFR, AXL, and FGFR for EGFR-mutated non-small cell lung cancer [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 5617.