Kim Stuyckens1, Ruben Faelens1, Wei Zhu2, Juan Jose Perez Ruixo1, Mayumi Mukai3, Oliver Ackaert1
1Department of Clinical Pharmacology & Pharmacometrics, Johnson & Johnson, 2Department of Clinical Pharmacology & Pharmacometrics, Johnson & Johnson, 3Department of Clinical Pharmacology & Pharmacometrics, Johnson & Johnson
Objective Erdafitinib (Balversa ®) is a selective pan–fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, approved to treat adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3 genetic alterations. The erdafitinib exposure-response (ER) analyses conducted based on Phase 2 study1) illustrated how serum phosphate (PO4) was a better biomarker to describe efficacy and safety than erdafitinib PK-based exposure. Exposure–response analyses were conducted to confirm the relationship between selected efficacy and safety endpoints and serum phosphate level, as a potential biomarker of efficacy and safety, and to confirm if the proposed erdafitinib dose (starting with 8 mg/day and PO4-based titration) applied in Phase 3 study (BLC3001) was adequate in terms of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from BLC3001-Cohort 1 (266 patients; 136 patients receiving erdafitinib and 130 receiving chemotherapy) was used for the exposure-efficacy analysis, and data from 3 studies including BLC3001 (814 patients; 529 patients receiving erdafitinib, 112 receiving chemotherapy and 173 patients receiving immunotherapy) were used to analyze the exposure-safety analysis. The exposure-efficacy relationship and exposure-safety relationship were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Average serum PO4 concentrations up to week 6, up to event, and time dependent serum PO4 were evaluated and compared for the efficacy endpoints OS and PFS. For ORR, average serum PO4 up to week 6 was evaluated as exposure metric. Safety endpoints were adverse events selected based on their clinical relevance, occurrence (>10%), and degree of severity (Grade 3). Average serum PO4 concentration up to event (PO4,avg,event) was selected as the exposure metric for safety analysis. Results The exposure-efficacy analyses showed that patients with higher serum PO4 levels showed better OS (hazard ratio 0.53 [95% CI 0.44–0.65] per mg/dL of PO4; p <0.001), PFS (hazard ratio 0.69[0.60–0.79]per mg/dL of PO4; p<0.001), and ORR (odds ratio 1.84[1.43–2.37per mg/dL of PO4; p<0.001). Exposure-safety analyses showed that the incidence of Grade =2 eye disorders (excluding central serous retinopathy), nail disorders, and skin disorders was significantly increased with higher PO4, but the incidence of Grade =1 central serous retinopathy and Grade =2 gastrointestinal disorders had no association with PO4 concentrations, despite them being known class effects of FGFR inhibitors. Conclusions The totality of the efficacy data, safety data, and ER analyses showed that the recommended dose regimen with pharmacodynamically-guided uptitration as implemented in BLC3001 showed an overall favorable benefit-risk in patient with mUC.
1. Dosne AG, et al. Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma. Cancer Chemo ther Pharmacol. 2022;89(2):151-64.
Reference: PAGE 33 (2025) Abstr 11314 [www.page-meeting.org/?abstract=11314]
Poster: Drug/Disease Modelling - Oncology