A 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 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 2 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0669-y) contains supplementary material, which is available to authorized users.

Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients?

“…Hypoalbuminemia is a well-recognized marker of cachexia and elevated protein turnover secondary to chronic systemic inflammatory conditions, as observed in many cancer indications. In contrast with other studies [12,24], we failed to identify albuminemia as an independent variability factor of nivolumab pharmacokinetics, probably because of the low interindividual variability in albuminemia. Depending on the time course of tumor size, inflammation status and ADAs production, nivolumab clearance may vary more or less.…”

Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors

“…5 7 8 15-17 Interestingly, an exposure-response relationship was found across tumor types, which was hypothesized to be the result of the interpatient variability of drug clearance (CL). [18][19][20] Indeed, it was observed that patients with a faster drug CL had impaired survival outcomes, irrespective of pembrolizumab dosing. 20 Population PK modeling of PD-1 ICIs has previously been performed on data from phase I-III trials [21][22][23][24] and for nivolumab also on real-world data.…”

“…20 Population PK modeling of PD-1 ICIs has previously been performed on data from phase I-III trials [21][22][23][24] and for nivolumab also on real-world data. 19 These previous studies described the pembrolizumab PK Open access using two-compartment models with linear elimination or non-linear time-varying elimination. 23 Population PK parameters were similar among different PD-1 agents.…”

Characterizing Exposure–Response Relationship for Therapeutic Monoclonal Antibodies in Immuno‐Oncology and Beyond: Challenges, Perspectives, and Prospects

“…Similarly, for trastuzumab, a postmarketing study at a dose higher than the approved dose did not confirm a better response 21 . There was also confusion in the literature on whether a higher dose of nivolumab should be considered due to an apparent E–R relationship 22–24 …”