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

J Immunother Cancer. 2021 Jun;9(6):e002344. doi: 10.1136/jitc-2021-002344.

Abstract

Background: Dosing 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.

Methods: Advanced-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).

Results: 588 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).

Conclusions: High 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.

Keywords: costimulatory and inhibitory t-cell receptors; lung neoplasms; melanoma; pharmacokinetics; urologic neoplasms.

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / pharmacokinetics
  • Body Surface Area
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Transitional Cell / blood
  • Carcinoma, Transitional Cell / drug therapy
  • Female
  • Humans
  • L-Lactate Dehydrogenase / blood*
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy
  • Mesothelioma, Malignant / blood
  • Mesothelioma, Malignant / drug therapy
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Prognosis
  • Prospective Studies
  • Serum Albumin, Human / metabolism*
  • Survival Analysis
  • Treatment Outcome
  • Urinary Bladder Neoplasms / blood
  • Urinary Bladder Neoplasms / drug therapy

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • pembrolizumab
  • L-Lactate Dehydrogenase
  • Serum Albumin, Human