Abstract
BackgroundNivolumab 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). MethodsIn 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. ResultsIn 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 <37.5g/L had >20% higher CL than the population mean. For NSCLC, CL was 42% higher in patients with progressive disease (mean: 0.24; 95%CI: 0.22-0.27L/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. ConclusionsWe 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 identificationMULTOMAB trial; Dutch Trial Registry NL6828. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA.A.M. Van der Veldt: Advisory / Consultancy: BMS. J.G. Aerts: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.
Highlights
Nivolumab is administered in a weight-based or fixed-flat dosing regimen
A total of 221 nivolumab-treated cancer patients were included in the Population pharmacokinetic (PPK) model (Mi and Mf ): non-small cell lung cancer (NSCLC) (71.4%), melanoma (21.7%), renal cell cancer (RCC) (6.3%), and one mesothelioma patient
For immune checkpoint inhibitors, approved flat dosing regimens for nivolumab have been solely based on simulations from dose-finding clinical trials
Summary
Nivolumab is administered in a weight-based or fixed-flat dosing regimen. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC). Nivolumab monotherapy has been approved for several indications, including advanced and metastatic melanoma [1], advanced clear-cell renal cell cancer (RCC), and metastatic non-small-cell lung cancer (NSCLC) [2, 3]. Nivolumab is administered in different schedules including 3 mg/kg Q2W, 240 mg flat dosing Q2W, and 480 mg flat dosing Q4W. Population pharmacokinetic (PPK) modeling of data from approximately 100 clinical trials was used to simulate nivolumab concentrations and to compare flat dosing regimens (240 mg Q2W, 480 mg Q4W) with 3 mg/kg Q2W dosing [7, 8]. It is noteworthy that a previous model-based PPK analysis resulted in significant but not clinically relevant covariate effects, of which gender and body weight were the most important [9]
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