1274PA prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients

Abstract Background Nivolumab is currently administered in a weight-based or fixed-flat dosing regimen. Approved fixed-flat dosing regimens have been solely based on simulations from dose-finding clinical trials. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported, suggesting that nivolumab dosing needs further optimization. In this study, we determined nivolumab pharmacokinetics (PK) and assessed the relationship between nivolumab clearance (CL) and tumor response in patients with NSCLC, melanoma, and renal cell cancer (RCC). Methods In this prospective observational cohort study (MULTOMAB trial; Dutch Trial Registry NL6828), individual estimates of nivolumab CL and the impact of baseline covariates were determined using population-PK (PPK) modeling. The study was approved by the independent ethics committee (MEC 16-011). All patients provided written informed consent. Stratified by tumor type, CL was related to best overall response (RECIST v1.1) using ANOVA and post-hoc samples t-test. Results In total 1,715 nivolumab serum concentrations were analyzed from 221 patients who were treated with monotherapy nivolumab (NSCLC n = 158; melanoma n = 48; RCC n = 14; mesothelioma n = 1). The baseline parameters gender, body surface area (BSA), and serum albumin had a significant effect on nivolumab CL and were internally validated in the PPK model. Women had 22% lower CL than men, Patients with BSA > 2.2 m2 or with baseline albumin 20% higher CL than the population mean. For NSCLC, CL was 42% higher in patients with progressive disease (mean: 0.24; 95%CI: 0.22-0.27 L/day) compared to patients with partial/complete response (0.17; 0.15-0.19). Although a similar trend was observed in RCC, no CL-response relationship was observed in melanoma patients. Conclusions We generated the first real-world PPK model of nivolumab, in which covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab CL. A significant CL-response relationship was observed in patients with NSCLC, but not in patients with melanoma. Individualized dosing regimens might therefore increase nivolumab efficacy in patients with NSCLC. Clinical trial identification MULTOMAB trial; Dutch Trial Registry NL6828. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A.A.M. Van der Veldt: Advisory / Consultancy: BMS. J.G. Aerts: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.