Population Pharmacokinetic and Exposure-Response Analyses of Nivolumab in Combination with Ipilimumab to Support Dosing Regimen in Subjects with First-Line MSI-H/dMMR Metastatic Colorectal Cancer
Authors: Shi Jian , Zhou Jian , Shah Zeel , Zhuang Ada , Maxwell Kelly , Bonnefois Guillaume , Passarell Julie , Ludwig Elizabeth , Statkevich Paul , Kondic Anna , Zhu Li , Zhao Yue 
Published: February 2025

Objectives: This study aims to support the proposed dosing regimen for nivolumab (nivo) and ipilimumab (ipi) when administered in combination (nivo 240 mg + ipi 1 mg/kg Q3W x 4 doses, then nivo 240 mg Q2W or 480 mg Q4W) in subjects with 1L MSI-H/dMMR metastatic colorectal cancer (CRC) by characterizing the PK and E-R of nivo and ipi.Methods: Nivo/ipi PK has been extensively characterized in multiple tumor types, including 2L+ CRC. The adequacy of the previously developed popPK models was validated through pcVPC plots to confirm that nivo/ipi PK is adequately described in 1L and 2L+ CRC subjects from studies CheckMate8HW (a phase 3 randomized trial of nivo, nivo + ipi, or chemotherapy in subjects with MSI-H/dMMR metastatic CRC; NCT04008030) and CheckMate142 (a phase 2 trial of nivo or nivo combinations, in recurrent and metastatic MSI-H and non-MSI-H CRC; NCT02060188). The empirical Bayes estimates (EBEs) of individual PK parameters were obtained using PK data from both studies and previously estimated PK parameters. The EBEs were then used to assess the impact of line of therapy, combination therapy, ethnicity (Chinese vs non-Chinese Asian vs non-Asian, Japanese vs non-Japanese Asian vs non-Asian), and immunogenicity on PK. The EBEs were also used to compare the exposures with an alternative maintenance nivo dose, and simulate exposures for E-R analyses. The relationships between nivo/ipi exposures (Cavg1) and efficacy (PFS)/safety (Gr2+ IMAEs) were characterized graphically. Results: The pcVPC plots confirmed that the models adequately characterized the nivo/ipi PK data in CRC subjects. Individual nivo CL0 and exposures in CRC subjects were comparable across lines of therapy, combination therapy vs nivo monotherapy, ethnicity (Chinese vs non-Chinese Asian vs non-Asian), and anti-drug antibody status (geometric means [GMs] differences ≤ 22.4%). Japanese 1L CRC subjects exhibited lower nivo CL0 and higher exposures (GMs up to 43.9%) compared to non-Asian 1L CRC subjects possibly due to the lower body weight in Japanese subjects compared to non-Asian subjects; however, due to the flat E-R relationship for safety, these differences are not expected to be clinically relevant. The nivo maintenance dose of 240 mg Q2W provided comparable exposures to 480 mg Q4W in 1L CRC subjects. Similarly, individual ipi CL0 and exposures in CRC subjects were comparable across lines of therapy and ethnicity (GMs differences ≤ 21.8%). Kaplan-Meier curves of PFS and Gr2+ IMAEs, stratified by nivo/ipi exposure quartiles (Cavg1), showed no clear trend for E-R relationships in 1L CRC subjects. Conclusions: The PK and E-R of nivo and ipi were characterized in 1L CRC subjects and the results are consistent with previous findings across various tumor types. Pharmacometric analysis remains a critical tool in drug development, providing strong support for dose selection/justification, alternate posologies, and other decision-making.Citations: NA