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

Abstract

BackgroundDosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I–III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting.MethodsAdvanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs).Results588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and −1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(Vd; 0.34). A significant inverse CL–OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07–2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade >3 irAEs (p=0.70).ConclusionsHigh interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on Vd). A strong inverse CL–OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.

Population pharmacokinetic models of anti-PD-1 mAbs in patients with multiple tumor types: A systematic review

“…Using the NIH study quality assessment tool, fourteen analyses had a good quality rating. Table 1 summarizes the characteristics of the included analyses, among which seven referred to nivolumab ( 21 , 22 , 28 – 32 ), four referred to pembrolizumab ( 20 , 23 , 33 , 34 ), one referred to cemiplimab ( 35 ), one referred to camrelizumab ( 36 ), and one referred to dostarlimab ( 37 ). The median (range) number of patients used to develop the PPK model was 1,137 (122–6,848) in fourteen analyses, with eight analyses (nivolumab 6/7, pembrolizumab 2/4) ( 21 , 28 – 34 ) involving more than 1,000 subjects.…”

“…The median (range) number of patients used to develop the PPK model was 1,137 (122–6,848) in fourteen analyses, with eight analyses (nivolumab 6/7, pembrolizumab 2/4) ( 21 , 28 – 34 ) involving more than 1,000 subjects. The data sources of twelve analyses were gathered from different clinical trials (nivolumab 6/7, pembrolizumab 3/4, cemiplimab 1/1, camrelizumab 1/1, and dostarlimab 1/1) ( 20 , 21 , 28 – 37 ), and two analyses were prospectively collected from a real-life patient cohort (nivolumab 1/7, pembrolizumab 1/4) ( 22 , 23 ). All fourteen analyses used internal evaluation to assess the model, of which nine analyses (nivolumab 4/7, pembrolizumab 3/4, cemiplimab 1/1, and camrelizumab 1/1) used three or more methods of internal evaluation ( 21 – 23 , 28 , 32 – 36 ).…”

“…found that the CL of nivolumab decreased with improving disease dynamics over time, and complete responders had the largest reduction in CL, while patients with disease progression showed the smallest reduction or even increased CL ( 19 ). Studies of other anti-PD-1 mAbs have also shown that the efficacy of treatment outcomes correlated negatively with CL ( 20 – 23 ). In such cases, employing the PPK model can describe the typical pharmacokinetic parameters of the target population, attempt to determine the measurable factors affecting the PK of anti-PD-1 mAbs, and identify the magnitude of these effects ( 24 ).…”

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

“…TDMbased therapeutic guidance is becoming widely utilized in clinical practice for patients losing response to anti-TNF agents for inflammatory bowel diseases 27 . We and others showed that the trough levels of ICI mAb can be a biomarker for cancer immunotherapy 3,4,[8][9][10] , this is of particular importance given the relatively low predictive capability of current biomarkers such as anti-PD-L1 IHC and TMB 14 . Therefore, development of a universal platform for quantitative analysis of mAbs is essential to streamline the PK study, TDM for effective use of mAbs, and biomarker discovery.…”

“…Monitoring of mAb levels is critical for drug development to ensure safety and efficacy of mAbs [3][4][5] . Therapeutic drug monitoring (TDM), used for small molecule drugs, has been applied to adjust the doses of mAbs for patients with chronic inflammatory immune disease 6,7 In addition, we and others have demonstrated that the trough levels of ICIs may serve as a potential biomarker for the effectiveness of cancer immunotherapy [8][9][10][11][12][13] .…”