Abstract
BackgroundNivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. 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).MethodsIn this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type.ResultsTwo-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m2 and < 37.5 g/L, respectively. For NSCLC, drug clearance 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 (mean: 0.17; 95% CI: 0.15–0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma.ConclusionsBased on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.
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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