Janssen Research and Development, Beerse, Belgium.
Janssen Research and Development, Spring House, PA, USA.
Cancer Chemother Pharmacol. 2022 Feb;89(2):151-164. doi: 10.1007/s00280-021-04381-4. Epub 2022 Jan 3.
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.
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.
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.
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.
NCT02365597.
在接受 FGFR 改变的局部晚期或转移性尿路上皮癌患者中，进行了探索疗效和安全性终点与血清磷酸盐（PO4）浓度之间关系的暴露-反应分析，血清 PO4 浓度是一种潜在的疗效和安全性生物标志物。
使用 Cox 比例风险或逻辑回归模型，对两项 FGFR 抑制剂 erdafitinib 的 2 期研究（NCT02365597）中两种剂量方案的数据进行了分析，分别为 6mg/天和 8mg/天，并根据血清 PO4 水平进行药效学指导的滴定。疗效终点为总生存期（OS）、无进展生存期（PFS）和客观缓解率（ORR）。安全性终点为 FGFR 抑制剂的典型不良事件。
对 156 例患者（6mg=68 例；8mg=88 例）进行了暴露-疗效分析，结果显示，在最初 6 周内血清 PO4 水平较高的患者 OS 更好（每毫克/分升 PO4 风险比为 0.57[95%CI 0.46-0.72]；p=0.01），PFS 更好（每毫克/分升 PO4 风险比为 0.80[0.67-0.94]；p=0.01），ORR 更高（每毫克/分升 PO4 比值比为 1.38[1.02-1.86]；p=0.04）。对 177 例患者（6mg=78 例；8mg=99 例）进行了暴露-安全性分析，结果表明，与靶外脱靶效应相关的某些不良事件的发生率随着 PO4 的升高而显著上升。
血清 PO4 水平与疗效/安全性结果之间的探索性关系支持使用药效学指导的剂量滴定来优化 erdafitinib 的治疗获益/风险比。
NCT02365597。
