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Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma
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 alteratio...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807442/ https://www.ncbi.nlm.nih.gov/pubmed/34977972 http://dx.doi.org/10.1007/s00280-021-04381-4 |
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author | Dosne, Anne-Gaëlle Valade, Elodie Goeyvaerts, Nele De Porre, Peter Avadhani, Anjali O’Hagan, Anne Li, Lilian Y. Ouellet, Daniele Perez Ruixo, Juan Jose |
author_facet | Dosne, Anne-Gaëlle Valade, Elodie Goeyvaerts, Nele De Porre, Peter Avadhani, Anjali O’Hagan, Anne Li, Lilian Y. Ouellet, Daniele Perez Ruixo, Juan Jose |
author_sort | Dosne, Anne-Gaëlle |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-021-04381-4. |
format | Online Article Text |
id | pubmed-8807442 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-88074422022-02-23 Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma Dosne, Anne-Gaëlle Valade, Elodie Goeyvaerts, Nele De Porre, Peter Avadhani, Anjali O’Hagan, Anne Li, Lilian Y. Ouellet, Daniele Perez Ruixo, Juan Jose Cancer Chemother Pharmacol Original Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-021-04381-4. Springer Berlin Heidelberg 2022-01-03 2022 /pmc/articles/PMC8807442/ /pubmed/34977972 http://dx.doi.org/10.1007/s00280-021-04381-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Dosne, Anne-Gaëlle Valade, Elodie Goeyvaerts, Nele De Porre, Peter Avadhani, Anjali O’Hagan, Anne Li, Lilian Y. Ouellet, Daniele Perez Ruixo, Juan Jose Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title | Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title_full | Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title_fullStr | Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title_full_unstemmed | Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title_short | Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
title_sort | exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807442/ https://www.ncbi.nlm.nih.gov/pubmed/34977972 http://dx.doi.org/10.1007/s00280-021-04381-4 |
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