University of Washington and Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
Royal Marsden Hospital and Institute of Cancer Research, London, UK.
Cancer Chemother Pharmacol. 2019 Jan;83(1):191-199. doi: 10.1007/s00280-018-3723-4. Epub 2018 Nov 8.
Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety.
PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (C) and the average concentration throughout treatment (C). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles.
PFS and OS were described by models with an exponential hazard function and inhibitory E functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (EC50 = 82.0 µg/mL, EC50 = 179 µg/mL) and OS (EC50 = 66.1 µg/mL, EC50 = 134 µg/mL) corresponded to the median and 25th percentile of C/C in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels.
PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.
奥拉单抗是一种针对 PDGFRα 的重组人 IgG1 单克隆抗体。奥拉单抗联合多柔比星在一项开放标签、随机的软组织肉瘤（STS）Ⅱ期试验中，较多柔比星改善了生存。我们对无进展生存期（PFS）、总生存期（OS）和安全性的奥拉单抗暴露-反应关系进行了描述。
使用生存时间模型对纳入Ⅱ期研究的 133 例患者的 PFS 和 OS 数据进行分析。使用第 1 周期（C）后血清谷浓度和整个治疗期间的平均浓度（C）来探索奥拉单抗对 PFS/OS 的影响。比较不同奥拉单抗暴露四分位数的治疗相关不良事件（TEAEs）发生率。
无论采用哪种 PK 终点，PFS 和 OS 均由具有指数风险函数和抑制 E 函数的模型描述，这些模型描述了奥拉单抗的作用。PFS（EC50=82.0μg/ml，EC50=179μg/ml）和 OS（EC50=66.1μg/ml，EC50=134μg/ml）的奥拉单抗 EC50 值分别对应于研究中的中位值和 25%分位数。OS 和 PFS 的风险比最大预测改善约为 75%和 60%。随着奥拉单抗血清水平的升高，TEAEs 发生率没有变化。
在整个四分位数范围内，TEAEs 发生率没有变化，PFS/OS 获益。在 OS 中达到了最大获益，在上三个四分位数中，在奥拉单抗血清暴露的下四分位数中可能出现疾病早期进展。这些结果促使在正在进行的 STS Ⅲ期试验中采用了负荷剂量策略。
