Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma.
Cancer Chemother Pharmacol
; 89(2): 151-164, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34977972
ABSTRACT
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Quinoxalinas
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Neoplasias da Bexiga Urinária
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Carcinoma de Células de Transição
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Inibidores de Proteínas Quinases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article