Pfizer, San Diego, California, USA.
The Healthcare Business of Merck KGaA, Darmstadt, Germany.
CPT Pharmacometrics Syst Pharmacol. 2022 Apr;11(4):458-468. doi: 10.1002/psp4.12771. Epub 2022 Feb 27.
Avelumab is an anti-PD-L1 monoclonal antibody approved as monotherapy for Merkel cell carcinoma (MCC) and urothelial carcinoma (UC), and in combination with axitinib for advanced renal cell carcinoma (aRCC). Although initially approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), avelumab was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (PopPK), exposure-efficacy, and exposure-safety modeling in MCC and UC. Here, through modeling and simulation, we provide justification for a flat-dose regimen of avelumab plus axitinib in aRCC. Simulated exposure metrics from the previous monotherapy PopPK model (1827 patients) for both weight-based and flat-dose regimens were compared with exposure metrics from treatment-naive patients with aRCC who received avelumab plus axitinib (488 patients). The aRCC population exposures were derived from a fit-for-purpose PopPK model developed using data from monotherapy and combination studies and the existing base structural PopPK model. Exposure-response relationships for safety were analyzed, including grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions, and TEAE any-grade immune-related adverse events (irAEs). Weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to the flat-dose regimen reference exposures in the monotherapy population. Increased avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or any-grade IRRs, although there was a weak association with an increased probability of any-grade irAEs. Overall, models in aRCC suggest that the avelumab 800-mg Q2W flat-dose regimen would provide similar benefits compared with weight-based dosing with no meaningful change in the probability of AEs.
avelumab 是一种抗 PD-L1 单克隆抗体，已被批准用于 Merkel 细胞癌 (MCC) 和尿路上皮癌 (UC) 的单药治疗，以及与 axitinib 联合用于晚期肾细胞癌 (aRCC)。尽管最初基于体重剂量 (10mg/kg 静脉内 [IV] 每 2 周 [Q2W]) 批准使用，但根据 MCC 和 UC 的群体药代动力学 (PopPK)、暴露-疗效和暴露-安全性建模，avelumab 随后被批准用于固定剂量 (800mg IV Q2W)。在这里，我们通过建模和模拟，为 aRCC 中avelumab 加 axitinib 的固定剂量方案提供了合理性。来自先前单药治疗 PopPK 模型 (1827 例患者) 的体重和固定剂量方案的模拟暴露指标与接受 avelumab 加 axitinib 的治疗初治 aRCC 患者的暴露指标进行了比较 (488 例患者)。aRCC 人群的暴露量来自于使用单药和联合研究以及现有基础结构 PopPK 模型的数据开发的专用 PopPK 模型。分析了安全性的暴露-反应关系，包括 3 级及以上治疗后出现的不良事件 (TEAE)、任何级别与输注相关的反应以及任何级别免疫相关不良事件 (irAE)。在 aRCC 人群中，avelumab 的体重剂量方案产生的 PK 暴露与单药治疗人群中的固定剂量方案参考暴露相似。avelumab 暴露增加与 3 级及以上 TEAEs 或任何级别 IRR 的发生概率增加无关，尽管与任何级别 irAE 的发生概率增加有微弱关联。总体而言，aRCC 中的模型表明，avelumab 800mg Q2W 固定剂量方案与基于体重的剂量方案相比，提供了相似的疗效，而不良事件的发生概率没有明显变化。
