Abstract 3014: ASN-7350, a highly selective FGFR2/3 dual inhibitor, for FGFR2/FGFR3 driven solid tumors

Alterations in fibroblast growth factor receptors (FGFRs) are recognized as oncogenic drivers in numerous human cancers. Several FGFR inhibitors, with similar potencies against FGFR1-3 or FGFR1-4, have been approved and demonstrated modest clinical benefits in FGFR-altered urothelial carcinoma and bile duct cancer. The clinical benefit was limited partly due to FGFR1- and FGFR4-mediated side effects. In addition, FGFR2/3 acquired resistance mutations after initial response to pan-FGFR inhibitor limit the long-term clinical efficacy as well. 60% of patients develop these secondary FGFR2 kinase domain mutations in FGFR2-altered cholangiocarcinoma, and 13-25% of patients develop FGFR3 resistance mutations in urothelial carcinoma. ASN-8639 and ASN-7350 were designed to address these challenges in treating multiple solid tumors harboring FGFR2/3 alterations. ASN-7350 is a novel, highly selective, and potent non-covalent FGFR2/3 inhibitor (IC50 < 5 nM in kinase assays). It showed greater than 200-fold selectivity for FGFR3 over FGFR1/4 in cellular assays. The prodrug ASN-8639 is in preclinical developed to improve the pharmacokinetic profile of ASN-7350. ASN-8639 was efficiently converted to ASN-7350 and showed dose-proportional increases in exposure and clinically acceptable oral bioavailability across four different species. ASN-7350 was more potent in inhibiting FGFR3 wt/mut signaling than competitor compounds. Its cell killing potency was 10× stronger compared to a reference compound currently in clinical development in cell lines harboring FGFR3-TACC3 fusion or erdafitinib-resistant FGFR3-V555M mutation, and meanwhile with a better the cellular selectivity of FGFR3 over FGFR1 and FGFR4. ASN-8639 demonstrated significant anti-tumor efficacy in cancer model of RT112 with FGFR3-TACC3 fusion and erdafitinib-resistant mutations of FGFR3-V555M. ASN-7350 also exhibited high potency against FGFR2. It produced comparable activity to a reference FGFR2 inhibitor in clinical development in multiple FGFR2-altered cell lines. Notably, ASN-8639 was more efficacious than reference FGFR2 inhibitor in the endometrial tumor model with erdafitinib-resistant FGFR2-N549K mutation at the same dose. These findings support the further clinical development of ASN-8639 as a potential best-in-class FGFR2/3 dual inhibitor for the treatment of bladder, endometrial, and other solid tumors with FGFR2/3 aberrations. Citation Format: Qiaoling Sun, Jingmin Guan, Haifeng Song, Jing Lv, Peng Zeng, Mengyuan Wang, Yonghui Yu, Shuai Luo, Jinna Yu, Liang Wu, Tielin Wang, Alice Chen. ASN-7350, a highly selective FGFR2/3 dual inhibitor, for FGFR2/FGFR3 driven solid 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 3014.