Abstract 1960P
Background
FGFR-inhibitors (FGFRi) show antitumor activity in cancers driven by FGFR genetic alterations (GA). Derazantinib (DZB) is in Phase 2 development for UC (NCT04045613), erdafitinib (ERDA) is FDA approved for advanced UC with FGFR GA. Clinical safety profiles of different FGFRi have not been compared head-to-head. Non-controlled studies suggest adverse events (AE), such as hyperphosphatemia, gastrointestinal AE, fatigue and dry eye, as common FGFRi class effects, while absence or lower rates of drug-related retinopathy, stomatitis, hand-foot-syndrome or nail toxicity were reported for DZB vs ERDA. Here we report whole transcriptome changes for DZB and ERDA in various safety relevant target tissues in nude mice bearing UC-PDX.
Methods
DZB (75 mg/kg) or ERDA (30 mg/kg) at optimal efficacious doses, or vehicle, was given daily PO (21 d) to mice bearing UC PDX (BL3479; n=3/group). Flash frozen target tissues (eye, foot/nail, cheek, lung, liver) underwent RNA sequencing (SureSelect XT RNA, Agilent) to compare transcriptome profiles (expression difference vs vehicle) and assess shared or compound-specific changes.
Results
Shared gene expression changes were consistent with canonical FGFR biology; including genes involved in tissue repair or remodeling. DZB-specific changes included keratin gene downregulation (lung) and collagen/extracellular matrix suppression (foot/nail). ERDA-specific changes included downregulation in crystallin genes (eye) potentially associated with retinal toxicity, and increase in oral epithelium stress, turnover/repair genes (cheek) potentially associated with mucositis.
Conclusions
Shared gene expression changes observed with DZB and ERDA reflect canonical FGFR biology and shared AEs. Several compound-specific gene expression changes map to reported AE profile differences between ERDA and DZB, e.g. retinal toxicity and mucositis. Molecular dissection of target tissues via RNA sequencing may provide a new tool to interpret shared target biology and compound-specific toxicity profiles between different FGFRi.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Basilea Pharmaceutica International Ltd.
Funding
Basilea Pharmaceutica International Ltd.
Disclosure
P. McSheehy, S. Anderson, S. Braun, M. Engelhardt, L. Kellenberger, H. Lane: Shareholder/Stockholder/Stock options, Full/Part-time employment: Basilea Pharmaceutica International Ltd. J. Guo, K. Beebe, J.R. Eisner, M. Milburn: Shareholder/Stockholder/Stock options, Full/Part-time employment: GeneCentric Therapeutics, Inc.