Abstract 1228: Selective FGFR4 inhibitor Irpagratinib (ABSK011) exhibits broad synergistic and combinatory anti-tumor effects with other therapeutic agents in preclinical HCC models

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, ranking as the sixth most prevalent cancer and the third leading cause of death worldwide. Approved therapeutic drugs, including chemotherapy, anti-angiogenesis agents and immunotherapy-based combination regimen (atezolizumab plus bevacizumab), have shown suboptimal clinical benefits for patients with HCC. There are critical unmet medical needs for additional therapeutic options to address this challenge. Deregulation of FGF19-FGFR4 signaling accounts for roughly 30% of HCC and plays a pivotal role in driving HCC tumorigenesis. To date, several FGFR4 inhibitors have advanced to the clinical stage for the treatment of HCC patients. Among them, a recently discovered novel and highly selective inhibitor, Irpagratinib (ABSK011), has demonstrated the potential to become a first-in-class or best-in-class FGFR4 inhibitor. It showed promising anti-tumor activity in an ongoing phase Ib clinical study, with an ORR of 40.7% observed in FGF19 overexpressed late line HCC patients in cohorts treated with BID regimens. To further expand the therapeutic potential of irpagratinib, we carried out an array of combination treatments and revealed its broad synergistic effects with various immune and targeted agents in treating HCC. Methods: We evaluated the combination effects of Irpagratinib with a variety of therapeutic agents, covering both targeted and immune-oncology agents, in preclinical HCC in vivo models. The tested agents, including lenvatinib, atezolizumab plus bevacizumab, anti-PD-(L)1, SHP2 inhibitors and EGFR antagonists, were assessed across a range of preclinical models, such as cell-derived or patient-derived xenografts, engineered syngeneic models and humanized models. Results: Synergistic anti-tumor effects of irpagratinib were observed in combination with the indicated agents, demonstrating more profound effects than either single agent alone in the selected preclinical in vivo models. This resulted in significant effects on inducing tumor regression or inhibiting tumor progression. Conclusions: In summary, these findings collectively illustrate very broad synergistic anti-tumor effects of irpagratinib when combined with various other therapeutic agents. These results may pave the road for potential novel combinatory therapeutic strategies that could expand the utility of irpagratinib and provide innovative and more effective therapies to HCC patients. Citation Format: Nannan Zhang, Bin Shen, Zhidong He, Cheng Dai, Jie Wang, Jie Zhang, Manqi Liu, Yongxian Zhang, Zhui Chen. Selective FGFR4 inhibitor Irpagratinib (ABSK011) exhibits broad synergistic and combinatory anti-tumor effects with other therapeutic agents in preclinical HCC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1228.