Zhao Yue, Li Li, Ma Jessica, Roy Amit, Bello Akintunde, Sheng Jennifer, Hamuro Lora
Bristol Myers Squibb, Princeton, New Jersey, USA.
Clinical Pharmacology and Pharmacometrics, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey, 08543, USA.
AAPS J. 2025 Apr 25;27(4):79. doi: 10.1208/s12248-025-01069-y.
Immunogenicity to biotherapeutics can lead to antidrug antibodies (ADAs) that have potential to alter pharmacokinetics (PK), efficacy, and safety. Here we provide an extensive model-informed immunogenicity assessments of nivolumab monotherapy and in combination with ipilimumab across multiple clinical trials. ADA was evaluated as both a binary and semiquantitative covariate, incorporating ADA titers to account for intensity over time. Data from 28 clinical trials, including 7,820 subjects with 2,770 ADA titer measurements, were analyzed using population pharmacokinetic (popPK) modeling. Nivolumab ADA incidence rate was higher for combination therapy (~ 32%) compared to monotherapy (~ 16%). ADA increased nivolumab clearance (CL) by 20-80% depending on titer. Nivolumab ADA impact on efficacy and safety was evaluated in melanoma and non-small cell lung cancer (NSCLC) patients. Despite the occurrence of nivolumab ADA being associated with lower nivolumab exposures, objective response rates (ORR) were similar in ADA-positive and negative patients, and ADA titer was not a significant predictor of response. An overall survival (OS) landmark analysis at 3 months suggested similar OS for NSCLC but lower OS for melanoma for ADA-positive vs negative patients mainly due to the imbalanced patient baseline characteristics. Propensity score matching and multivariable Cox Proportional-Hazards analysis indicated no ADA impact on OS. Additionally, there were no associations between ADA and acute hypersensitivities or immune mediated safety events. This model-based approach underscores the importance of accounting for ADA dynamics in clinical development and supports no significant association between ADA presence and clinical efficacy or safety, even with higher ADA incidence in combination therapy.
生物治疗药物的免疫原性可导致抗药物抗体（ADA）的产生，这些抗体有可能改变药代动力学（PK）、疗效和安全性。在此，我们通过多项临床试验，对纳武利尤单抗单药治疗以及与伊匹木单抗联合治疗进行了广泛的基于模型的免疫原性评估。ADA被评估为二元和半定量协变量，纳入ADA滴度以考虑随时间的强度变化。使用群体药代动力学（popPK）模型分析了来自28项临床试验的数据，包括7820名受试者的2770次ADA滴度测量。联合治疗的纳武利尤单抗ADA发生率（约32%）高于单药治疗（约16%）。ADA使纳武利尤单抗清除率（CL）根据滴度增加20 - 80%。在黑色素瘤和非小细胞肺癌（NSCLC）患者中评估了纳武利尤单抗ADA对疗效和安全性的影响。尽管纳武利尤单抗ADA的出现与较低的纳武利尤单抗暴露相关，但ADA阳性和阴性患者的客观缓解率（ORR）相似，且ADA滴度不是反应的显著预测因素。3个月时的总生存（OS）标志性分析表明，NSCLC患者中ADA阳性和阴性患者的OS相似，但黑色素瘤患者中ADA阳性患者的OS低于阴性患者，主要是由于患者基线特征不平衡。倾向评分匹配和多变量Cox比例风险分析表明ADA对OS无影响。此外，ADA与急性超敏反应或免疫介导的安全事件之间无关联。这种基于模型的方法强调了在临床开发中考虑ADA动态变化的重要性，并支持即使联合治疗中ADA发生率较高，ADA的存在与临床疗效或安全性之间也无显著关联。
