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

• Published in: Cancer chemotherapy and pharmacology 2022-02, Vol.89 (2), p.151-164
• Main Authors: Dosne, Anne-Gaëlle, Valade, Elodie, Goeyvaerts, Nele, De Porre, Peter, Avadhani, Anjali, O’Hagan, Anne, Li, Lilian Y., Ouellet, Daniele, Perez Ruixo, Juan Jose
• Format: Article
• Language: English
• Subjects: Adverse events; Aged; Biomarkers; Bladder cancer; Cancer Research; Carcinoma, Transitional Cell - drug therapy; Dosage; Dose-Response Relationship, Drug; Exposure; Female; Fibroblast growth factor receptors; Humans; Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; NCT; NCT02365597; Oncology; Original; Original Article; Patients; Pharmacology; Pharmacology/Toxicology; 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; Regression analysis; Safety; Survival; Survival Rate; Titration; Tumors; Urinary Bladder Neoplasms - drug therapy; Urothelial carcinoma
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04381-4

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.