Evaluation of the interindividual variability in plasma nivolumab level in non-small-lung cancer outpatients: preliminary results

Abstract

Background: Nivolumab, an anti PD-1 inhibitor, has been approved for the treatment of previously treated advanced or metastatic non-small-cell-lung cancer (NSCLC). The response rate is about 20% with nivolumab. The inter-patient variability in clinical outcomes to nivolumab is large and could be influenced by its pharmacokinetics. However, no data is currently available about the inter-patient variability in plasma exposure to nivolumab in NSCLC outpatients. The aim was to investigate the inter-patient variability in plasma level of nivolumab from 27 NSCLC outpatients. Methods: NSCLC patients were treated with nivolumab (3 mg/kg) every two weeks. Blood samples were collected just before the infusion on days 0 (baseline), 14, 28 and 42 after treatment start. Plasma trough levels (Cmin) of nivolumab were assayed with home-made ELISA. Univariate linear regression models were performed in order to explain the inter-patient variability in nivolumab Cmin on day 42. Multivariate model included all variables which were significant at the 10% level in the univariate analyses. Results: The calibration for nivolumab assay was linear in the range 5-100 μg/mL. Intra- and interday imprecision for three internal quality controls (5, 20 and 75 μg/mL) were less than 9 and 12%, respectively. The median age of the cohort was 68 years (range 41-84) and the sex ratio (female/male) 1.27. The median dose of nivolumab was 207 mg (range 147-288). No nivolumab was detected in baseline samples. The mean nivolumab Cmin was 17.3 ± 4.8 μg/mL (CV = 27.8%), 25.0 ± 9.7 μg/mL (CV = 38.8%) and 33.0 ± 12.9 μg/mL (CV = 39.1%) on days 14, 28 and 42, respectively. A significant variation in nivolumab Cmin was observed over the time (one-way Anova test, p < 0.001). In the multivariate linear regression analysis, nivolumab Cmin on day 42 was independently associated with IgG level (β = -3.25; p = 0.0022) and ALAT (β = 0.45; p = 0.042). Conclusions: These preliminary results highlight a large inter-patient variability in nivolumab Cmin in NSCLC outpatients. Further PK/PD investigations are warranted to identify the influence of this pharmacokinetic variability on clinical outcomes.