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

Daan P Hurkmans, Edwin A Basak, Tanja Van Dijk, Darlene Mercieca, Marco W J Schreurs, Annemarie J M Wijkhuijs, Sander Bins, Esther Oomen-de Hoop, Reno Debets, Markus Joerger, Arlette Odink, Astrid A M Van Der Veldt, Cor H Van Der Leest, Joachim G J V Aerts, Ron H J Mathijssen & Stijn L W Koolen

abstract

BACKGROUND
Nivolumab 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).

METHODS
In 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.

RESULTS
Two-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 > 2.2m 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.

CONCLUSIONS
Based 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.
   
citation Hurkmans D P, Basak E A, Van Dijk T, Mercieca D, Schreurs M W J, Wijkhuijs A J M, Bins S, Hoop E O D, Debets R, Joerger M, Odink A, Van Der Veldt A A M, Van Der Leest C H, Aerts J G J V, Mathijssen R H J, Koolen S L W. A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients. J Immunother Cancer 2019; 7:192.
   
type journal paper/review (English)
date of publishing 19-07-2019
journal title J Immunother Cancer (7/1)
ISSN electronic 2051-1426
pages 192
PubMed 31324223
DOI 10.1186/s40425-019-0669-y