(S-047) Population Pharmacokinetics and Exposure-Response Analysis of Nivolumab in Combination with Ipilimumab in Participants with First-Line Unresectable or Advanced Hepatocellular Carcinoma to Support Benefit-Risk Assessment

Izumi Hamada – Bristol Myers Squibb; Jian Shi – Bristol Myers Squibb; Ada Zhuang – Bristol Myers Squibb; Kelly Maxwell – Simulations Plus; Yassine Lyauk – Simulations Plus; Julie Passarell – Simulations Plus; Elizabeth Ludwig – Simulations Plus; Paul Statkevich – Bristol Myers Squibb; Li Zhu – Bristol Myers Squibb; Anna Kondic – Bristol Myers Squibb; Yue Zhao – Bristol Myers Squibb

Objectives: The population pharmacokinetics (popPK) and exposure-response (ER) analysis of nivolumab (nivo) and ipilimumab (ipi) were conducted to support the benefit-risk assessment of nivo 1mg/kg + ipi 3mg/kg Q3W for up to 4 doses followed by nivo 240 mg Q2W or 480 mg Q4W as a novel IO/IO first-line (1L) therapy in subjects with unresectable or advanced hepatocellular carcinoma (HCC).

Methods: The popPK analysis was conducted based on a previous model1 using a pooled dataset (2893 subjects from 9 clinical studies for nivo and 2735 subjects from 11 clinical studies for ipi) incorporating additional data from 1L HCC subjects administered nivo and ipi in combination in Study CA2099DW. Nivo and ipi PK were well described with linear two-compartment models with zero-order IV infusion, first-order elimination, and time-varying clearance (CL). The updated nivo model included the effect of subject type (defined by tumor type and line of therapy) on CL and time to attain 50% of the maximal change in CL from baseline (T50). The effect of subject type on CL was assessed in the updated ipi model. The robustness of the final models was validated using prediction-corrected visual predictive checks (pcVPCs). The empirical Bayes estimates (EBEs) of individual PK parameters and exposures were obtained to assess the impact of combination therapy and immunogenicity on nivo PK; line of therapy and ethnicity on nivo and ipi PK, and the alternative nivo maintenance dose (240mg Q2W), which was not evaluated in the study. The ER relationships for efficacy as measured by overall survival (OS) and safety as measured by time to first grade 2+ immune-mediated adverse event (Gr2+ IMAEs) were assessed using Kaplan-Meier plots in 1L HCC subjects.

Results: The final popPK models adequately characterized nivo and ipi PK across all subject types, including 1L HCC. Nivo baseline CL (CL0) and exposures were similar across lines of therapy in HCC subjects. Nivo monotherapy had higher exposure (geometric mean difference [∆GM] ≤46.6%) vs. combination; non-Japanese Asians had higher exposure (∆GM ≤51.0%) vs. non-Asians. Subjects with positive anti-drug antibody (ADA) status had higher CL0 and lower exposure (∆GM ≤ 39.1%) compared to those with negative ADA. These differences in exposures were not expected to be clinically relevant given the flat/shallow E-R relationships within the studied dose range2. Nivo maintenance dose of 240 mg Q2W provided comparable exposures to the tested 480 mg Q4W dose. Ipi CL0 and exposures were comparable across line of therapy (∆GM ≤28.3%) and ethnicity. Kaplan-Meier curves for OS showed no trend across nivo exposure (Cavg1) Quartiles 2-4. There was no trend observed between OS and ipi exposure quartiles. Higher nivo/ipi exposures were associated with an increased probability of Gr2+ IMAEs, consistent with the previous findings across tumor types3-4.

Conclusions: The analyses supporting the benefit-risk assessment of the nivo/ipi combination in 1L HCC subjects demonstrated comparable exposures across subgroups, with no clinically meaningful differences. These findings justified the proposed dosing regimen and supported the extension of the nivo/ipi combination into the 1L setting as a well-characterized treatment option for advanced HCC.

Citations: [1] Report: Updated population pharmacokinetics of nivolumab and ipilimumab when administered in combination to subjects with melanoma, nonsmall cell lung cancer, renal cell carcinoma, small cell lung cancer, hepatocellular carcinoma, and colorectal cancer. Bristol Myers Squibb Company; 2020.
[2] Nivolumab (BMS-936558) Investigator Brochure, Version No. 16. Bristol-Myers Squibb Company; 2017.
[3] Report: Exposure-response analyses in subjects with hepatocellular cancer treated with nivolumab monotherapy or in combination with ipilimumab. Bristol Myers Squibb Company; 2019.
[4] Report: Exposure-response analysis of efficacy and safety for nivolumab and ipilimumab when administered in combination in subjects with unresectable malignant pleural mesothelioma. Bristol Myers Squibb Company; 2020.

Keywords: PopPK, E-R