The Relationship Between Pre-Operative Ipilimumab and Nivolumab Pharmacokinetics and Treatment Outcome in Locoregionally Advanced Urothelial Cancer.

Patients with locoregionally advanced urothelial cancer (UC) received three pre-operative cycles of ipilimumab and nivolumab in the NABUCCO trial, across three cohorts with different dosing combinations. This study aimed to define the pharmacokinetics (PK) of both drugs in this population and to assess the relationship between the PK and treatment response. Ipilimumab and nivolumab serum concentrations were measured in 139 samples of 52 patients. A population PK model was developed for both drugs using nonlinear mixed-effects modeling. This model was used to examine baseline clearance (CL₀)- and exposure-response relationships, with pathological response at surgery as efficacy parameter. A logistic regression model was constructed to quantify these relationships. The developed population PK model adequately described ipilimumab and nivolumab observations. Individual CL₀ estimates of both drugs were correlated (correlation coefficient = 0.57). Among patients in the lowest quartile of CL₀ of both drugs, twelve out of thirteen patients were responders. In the logistic regression model, a relatively low nivolumab CL₀ and high ipilimumab exposure were successfully related to treatment response. The model predicted probability of response was higher for high-dose ipilimumab (3 mg/kg) compared to low-dose ipilimumab (1 mg/kg) (54% vs. 29%, respectively), and was in line with NABUCCO trial outcomes. These results support the hypothesis that for ipilimumab, an exposure-response relationship exists, while this is not the case for nivolumab. Further confirmation of these relationships is warranted, given the limited number of patients included in the analysis.