Li Lili, Qu Jianye, Song Ming, Zhao Qun, Yang Yonghua, Tan Xi, Hu Yanyan, Li Jing, Lin Yunfei, Feng Hui, Yao Sheng, Keegan Patricia, Chen Meixia
Shanghai Junshi Biosciences, Shanghai, China.
TopAlliance Biosciences, Rockville, MD, United States.
Front Pharmacol. 2023 Jan 13;13:1069818. doi: 10.3389/fphar.2022.1069818. eCollection 2022.
Flat dosing regimen has recently been approved for programmed death receptor-1 (PD-1) inhibitors including toripalimab, nivolumab and pembrolizumab. The objective of this study is to provide pharmacological evidence for a flat dosing regimen of toripalimab by assessing the efficacy and safety profile of a 240 mg Q3W flat dose relative to the currently approved 3 mg/kg Q2W. A population pharmacokinetic (PopPK) model was established based on 1,014 evaluable patients in 13 clinical studies. The exposure-objective response rate (ORR, n = 234) and exposure-safety (n = 152) analyses were performed by logistic regression. Three safety endpoints including grade ≥ 3 adverse events (AEs), treatment-related grade ≥ 3 AEs, and AEs leading to study drug discontinuation were evaluated. Progression-free survival (PFS, n = 234) was evaluated using a Cox proportional hazard model with the Kaplan-Meier survival curve. The PK profiles of toripalimab are best described by a two-compartment model with time-varying clearance characterized by a sigmoidal maximum effect (E) function. Simulations for the first dose and steady-state exposures for the 240 mg Q3W dosing regimen were comparable to those for the 3 mg/kg Q2W dosing regimen with 95% exposure coverage ranging from 88% to 96%. The exposure-safety analysis showed that the probability of an adverse event occurring did not increase with increases in toripalimab exposure. A flat exposure-response relationship for ORR was identified. The Kaplan-Meier survival curve showed that exposure was a predictor for PFS; however, no difference in treatment benefit was demonstrated across exposure quantiles using a Cox proportional hazard model. This study revealed that toripalimab exposure of 240 mg Q3W dosing regimen was comparable to 3 mg/kg Q2W dosing regimen. The safety and efficacy E-R results of 240 mg Q3W is flat. Hence, the 240 mg Q3W dosing regimen is determined to be a preferred therapeutic dosage for toripalimab due to the convenience of flat dose.
固定剂量给药方案最近已被批准用于包括特瑞普利单抗、纳武利尤单抗和帕博利珠单抗在内的程序性死亡受体-1（PD-1）抑制剂。本研究的目的是通过评估相对于目前批准的3mg/kg Q2W剂量，240mg Q3W固定剂量的疗效和安全性，为特瑞普利单抗的固定剂量给药方案提供药理学证据。基于13项临床研究中的1014例可评估患者建立了群体药代动力学（PopPK）模型。通过逻辑回归进行暴露-客观缓解率（ORR，n = 234）和暴露-安全性（n = 152）分析。评估了三个安全终点，包括≥3级不良事件（AE）、治疗相关≥3级AE以及导致研究药物停用的AE。使用Cox比例风险模型和Kaplan-Meier生存曲线评估无进展生存期（PFS，n = 234）。特瑞普利单抗的药代动力学特征最好用具有时变清除率的二室模型来描述，该时变清除率由S形最大效应（E）函数表征。240mg Q3W给药方案的首剂和稳态暴露模拟与3mg/kg Q2W给药方案相当，95%暴露覆盖范围为88%至96%。暴露-安全性分析表明，不良事件发生的概率不会随着特瑞普利单抗暴露的增加而增加。确定了ORR的固定暴露-反应关系。Kaplan-Meier生存曲线表明暴露是PFS的预测指标；然而，使用Cox比例风险模型在各暴露分位数间未显示出治疗获益的差异。本研究表明，240mg Q3W给药方案的特瑞普利单抗暴露与3mg/kg Q2W给药方案相当。240mg Q3W的安全性和疗效E-R结果是固定的。因此，由于固定剂量的便利性，240mg Q3W给药方案被确定为特瑞普利单抗的首选治疗剂量。
