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

Our plain-English summary of Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors, by D.P. Hurkmans, S.D.T. Sassen, K. de Joode, et al (Journal for Immunotherapy of Cancer, 2021).

The study

• Authors: D.P. Hurkmans, S.D.T. Sassen, K. de Joode, L. Putter, E.A. Basak, A.J.M. Wijkhuijs, M. Joerger, R. Debets, B.C.P. Koch, C.H. Van der Leest, M.W.J. Schreurs, A.A.M. van der Veldt, J.G.J.V. Aerts, R.H.J. Mathijssen, S.L.W. Koolen
• Journal: Journal for Immunotherapy of Cancer
• Published: 2021;9(6)
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This prospective Dutch study measured blood levels of the immunotherapy drug pembrolizumab in 122 patients with advanced solid tumors. They were treated between March 2016 and December 2018 at two hospitals. They included 42 with non-small-cell lung cancer, 51 with melanoma, 15 with urothelial cell cancer and 13 with malignant pleural mesothelioma. From 588 blood samples, the authors modelled how fast the drug was cleared. Body surface area and albumin affected clearance; LDH affected distribution volume. With clearance ranked in quartiles from lowest to highest, higher clearance was associated with shorter overall survival across all patients after adjustment (HR 1.58; 95% CI 1.20 to 2.08). By tumor type, the HR was 3.29 (95% CI 1.08 to 10.09) for the 13 mesothelioma patients and 1.69 (95% CI 1.07 to 2.68) for non-small-cell lung cancer. For melanoma and urothelial cancer the association was not statistically significant. Clearance did not differ significantly between patients with and without severe immune-related side effects (p=0.70). The authors suggested that personalized dosing be explored. They cautioned about possible confounding by disease severity and small subgroups.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective real-world observational cohort study with serial blood sampling and population pharmacokinetic modelling
• Who was studied: 122 patients with advanced-stage solid tumors treated with pembrolizumab monotherapy between March 2016 and December 2018 at Erasmus University Medical Center (Rotterdam) and Amphia Hospital (Breda), the Netherlands. Tumor types: non-small-cell lung cancer 42, melanoma 51, urothelial cell cancer 15, malignant pleural mesothelioma 13, small-cell lung cancer 1.
• Exposure: Pembrolizumab given as a 30-minute infusion every 3 weeks, either 2 mg/kg (weight-based) or 200 mg (fixed dose). Blood was drawn before each dose to measure trough drug levels. The study did not examine asbestos exposure.
• Main results:
  • In a one-compartment drug model built from 588 samples, body surface area (covariate estimate 1.46) and serum albumin (covariate estimate -1.43) had a significant effect on drug clearance.
  • Serum LDH at baseline had a significant effect on the drug's volume of distribution (0.34, 95% CI 0.20 to 0.48). Malignant pleural mesothelioma (on volume) and urothelial cell cancer (on clearance) also remained in the final model.
  • All patients: with drug clearance analysed as ordered quartiles (Q1 lowest to Q4 highest), higher clearance was associated with worse overall survival after correction for tumor type and prognostic factors (HR 1.58; 95% CI 1.20 to 2.08; p=0.001).
  • All patients: higher clearance quartile was also associated with worse progression-free survival in the multivariate analysis (HR 1.56; 95% CI 1.17 to 2.07; p=0.002).
  • With clearance analysed as ordered quartiles and after correction for patient factors, higher clearance was associated with worse overall survival in non-small-cell lung cancer (n=42; HR 1.69; 95% CI 1.07 to 2.68; p=0.024) and in malignant pleural mesothelioma (n=13; HR 3.29; 95% CI 1.08 to 10.09; p=0.037).
  • The association between clearance and overall survival was not statistically significant in melanoma (HR 1.31; 95% CI 0.85 to 2.04; p=0.22) or urothelial cell cancer (univariate HR 1.30; 95% CI 0.75 to 2.25; p=0.34).
  • Severe immune-related adverse events (grade 3 or 4) occurred in 21 patients (17%).
  • No statistically significant difference in drug clearance was observed between patients with severe immune-related adverse events and those without or with low-grade events (mean clearance 0.29 vs 0.30 L/day, p=0.70).
• The authors' conclusion: The authors concluded that variability in pembrolizumab handling between patients is determined by body surface area and serum albumin (on clearance) and LDH (on distribution volume). They reported a strong inverse clearance-survival relationship in non-small-cell lung cancer and malignant pleural mesothelioma, which was not seen in melanoma or urothelial cancer. They suggested that personalized dosing should be prospectively explored.
• Limitations the authors state:
  • The link between clearance and outcome may be confounded by baseline prognostic factors or disease severity.
  • Patient cohorts were small, so subgroup analyses by tumor type should be interpreted with care.
  • Fixed and weight-based dosing could not be compared, because the dose scheme followed local protocols that differed between departments.
  • 122 patients is a small cohort compared with earlier models based on trial data.
  • Only trough levels were measured, so a two-compartment model with separate central and peripheral volumes could not be estimated.

Topics

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), Monoclonal Antibody, Overall Survival, Immune-Related Adverse Events, Lung Cancer, Pleural Mesothelioma, Lactate Dehydrogenase (LDH).

Related studies

• Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study — A. Marabelle, M. Fakih, et al. (2020)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study — T.A. Yap, K. Nakagawa, et al. (2021)
• A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors — J.P. Sharman, J.J. Wheler, et al. (2019)
• Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors — J.J. Luke, F. Barlesi, et al. (2021)
• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)

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