Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma

Cancer Chemother Pharmacol. 2022 Feb;89(2):151-164. doi: 10.1007/s00280-021-04381-4. Epub 2022 Jan 3.


Background: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib.

Methods: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, 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). Safety endpoints were adverse events typical for FGFR inhibitors.

Results: Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46-0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67-0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02-1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4.

Conclusions: The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib's therapeutic benefit/risk ratio.

Clinical trial registration number: NCT02365597.

Keywords: Erdafitinib; Exposure–response analyses; FGFR inhibitor; Metastatic urothelial carcinoma; Pharmacodynamically guided individual dose titration.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Transitional Cell / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Quinoxalines / administration & dosage*
  • Quinoxalines / adverse effects
  • Receptors, Fibroblast Growth Factor / metabolism
  • Survival Rate
  • Urinary Bladder Neoplasms / drug therapy*


  • Protein Kinase Inhibitors
  • Pyrazoles
  • Quinoxalines
  • Receptors, Fibroblast Growth Factor
  • erdafitinib

Associated data

  • ClinicalTrials.gov/NCT02365597