Model-Informed Immunogenicity Assessment of Nivolumab as Monotherapy and in Combination with Ipilimumab.

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.