Abstract LB227: ALK201, a first-in-class FGFR2b-targeting antibody-drug conjugate for patients with FGFR2b+ gastric cancer and other solid tumors

Abstract Background: Fibroblast growth factor receptor-2b (FGFR2b) is a receptor tyrosine kinase mainly expressed on epithelial cells and involved in numerous cellular functions. Overexpression of FGFR2b in solid tumors, especially gastric cancer, is associated with poor prognosis, making it a compelling candidate for targeting therapy. Methods: ALK201 consists of a humanized high-affinity FGFR2b-targeting antibody, a proprietary, hydrophilic and cleavable linker, and Exatecan, a topoisomerase I inhibitor. Binding properties and mechanism of actions of ALK201 were evaluated in a panel of in vitro studies. ALK201 was evaluated for in vivo anti-tumor effects in xenograft model of gastric cancer cell line SNU-16 and patient-derived xenograft (PDX) models across multiple tumor types. Pharmacokinetic (PK) profile of ALK201 was characterized in rats and non-human primates (NHP). GLP toxicology studies of AK201 were also conducted in rats and NHPs. Results: ALK201 bound human FGFR2b specifically and cross-reacted with FGFR2b from cynomolgus monkey, mouse and rat. ALK201 blocked FGF7/10-FGFR2b interaction and inhibited downstream phospho-ERK activation, comparable to Bemarituzumab. In addition, ALK201 demonstrated favorable antibody dependent cell mediated cytotoxicity (ADCC) on FGFR2b-expressing gastric cancer cells KATOIII with primary human NK cells. ALK201 showed efficient internalization, potent killing of FGFR2b+ tumor cells, and a strong bystander killing activity. ALK201 significantly inhibited tumor growth in SNU16 model, as well as in Bemarituzumab-resistant PDX models of gastric, breast and squamous non-small cell lung cancer. Moreover, ALK201 had a favorable PK profile in both rats and cynomolgus monkeys with limited payload shedding. ALK201 also exhibited a good safety profile in GLP toxicology studies, showing STD10>150 mg/kg in SD rats and HNSTD of 60 mg/kg in cynomolgus monkeys. The main adverse event profiles in monkeys included anemia, decreased erythrocytes in the bone marrow smears of some animals without significant abnormality in the histopathological examination of bone marrow, minimal to mild decrease cellularity of lymphocytes in the immune system, and minimal atrophy in eye cornea (only observed in the high dose group, 60 mg/kg). At the end of the recovery period, those abnormalities were fully recovered. Conclusions: In summary, preclinical results indicated that ALK201 is an effective candidate for the treatment of solid tumors expressing FGFR2b with a tolerable safety profile. The phase I/II clinical study including dose escalation and dose expansion to evaluate the safety, tolerability, PK and anti-tumor activity of ALK201 in adult participates with advanced solid tumor is ongoing (NCT06656390). Acknowledgments: We thank Dr. Sheng Yao for editorial assistance and his willingness to sponsor the abstract. Citation Format: Jiajia Pan, Hongwang He, Li Li, Jun Wang, Xiaolin Wang, Kehua Fan, Hui Feng. ALK201, a first-in-class FGFR2b-targeting antibody-drug conjugate for patients with FGFR2b+ gastric cancer and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB227.