Population Pharmacokinetic and Exposure-Response Analyses of Neoadjuvant Nivolumab plus Chemotherapy, followed by Adjuvant Treatment with Nivolumab in Subjects with Resectable Stage II-IIIB NSCLC
Authors: Tendolkar Amol , Kondic Anna , Ludwig Elizabeth , Ma Xiaotang (Jessica) , Maxwell Kelly , Passarell Julie , Statkevich Paul , Taneja Amit , Zhao Yue , Zhu Li 
Published: February 2025

Objectives: To characterize PK of neoadjuvant (NADJ) nivolumab (NIVO) in combination with chemotherapy (CHEMO) followed by adjuvant (ADJ) NIVO as monotherapy, and to characterize the relationship of event-free survival (EFS) and pathologic complete response (pCR) with NIVO exposure measure corresponding to NADJ treatment (TRT), in early-stage non-small cell lung cancer (ES NSCLC). Methods: Two separate population PK (PopPK) analyses were conducted for NADJ and ADJ TRTs, assessing the effect of disease stage and TRT on NIVO clearance (CL). The analysis also evaluated if NIVO CL was best described with a time-varying or stationary CL during ADJ TRT. Individual NIVO concentration-time profiles were simulated using individual EBE of parameter values with the full models and the planned dosing regimens. Simulated individual measures of NIVO exposure (Cmin, Cavg, Cmax following first dose, and steady state) were summarized for NIVO NADJ (360 mg Q3W with CHEMO) and ADJ (480 mg Q4W monotherapy) TRTs.Exposure-response (ER) relationships were evaluated using Kaplan-Meier (K-M) curves for efficacy (EFS) and safety (time to first grade 2 or higher immune-mediated adverse events [Gr2+IMAE]) endpoints over time for each exposure quartile. pCR was explored graphically by comparing the observed probability by exposure quartiles. Results: PK of NIVO in NADJ and ADJ NSCLC was consistent with previous findings in 2L+ NSCLC [1]. Full ADJ model included an EMAX term indicating time-varying CL, which better described the data compared to stationary CL. The pcVPC plots confirmed that both NADJ and ADJ full models adequately characterized the longitudinal serum concentration data in NSCLC subjects. No clinically meaningful differences in CL were observed at baseline or steady state across subject types including NADJ NSCLC, ADJ NSCLC, and 1L NSCLC compared to 2L+ NSCLC (GM differences ≤ 20.7%). Predicted NIVO exposures (Cavg1 and Cavgss) in NADJ subjects were comparable by ethnicity and anti-drug antibody status. Model-predicted NIVO exposures in NADJ and ADJ NSCLC were similar to those in advanced NSCLC subject types.ER relationship between efficacy (EFS & pCR) or safety (Gr2+IMAE) and NIVO exposure (Cavg1 from NADJ period) indicated that NIVO in the NADJ and ADJ TRTs was associated with higher efficacy and higher risk of Gr2+IMAE compared to the standard 4 three-week cycles of CHEMO in the NADJ TRT, as measured by the K-M curves in resectable ES NSCLC subjects. The ER analyses showed overlapping probabilities over time for each exposure quartile, indicating no clear ER relationship. Conclusions: NIVO PopPK models in NADJ and ADJ ES NSCLC are robust and further extend the previous PK characterization of NIVO as monotherapy or in combination with CHEMO to subjects treated for 1L and 2L+ NSCLC, MEL, and other tumor types.The ER analyses indicated that there was no differentiation in the observed efficacy or safety relationships based on the exposure quartiles of NIVO.Citations: [1] Nivolumab Investigator Brochure, V22. BMS; 2023. DCN 930038243.