Dose dependence of treatment-related adverse events for immune checkpoint inhibitor therapies: a model-based meta-analysis

Oncoimmunology. 2020 May 21;9(1):1748982. doi: 10.1080/2162402X.2020.1748982.

Abstract

Programmed cell death-1 (PD-1) and/or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitor (ICI) treatments are associated with adverse events (AEs), which may be dependent on ICI dose. Applying a model-based meta-analysis to evaluate safety data from published clinical trials from 2005 to 2018, we analyzed the dose/exposure dependence of ICI treatment-related AE (trAE) and immune-mediated AE (imAE) rates. Unlike with PD-1 inhibitor monotherapy, CTLA-4 inhibitor monotherapy exhibited a dose/exposure dependence on most AE types evaluated. Furthermore, combination therapy with PD-1 inhibitor significantly strengthened the dependence of trAE and imAE rates on CTLA-4 inhibitor dose/exposure.

Keywords: Adverse events; immune checkpoint inhibitor; meta-analysis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • B7-H1 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / antagonists & inhibitors
  • Clinical Trials as Topic
  • Combined Modality Therapy
  • Dose-Response Relationship, Immunologic
  • Humans
  • Immune Checkpoint Inhibitors* / administration & dosage
  • Immune Checkpoint Inhibitors* / adverse effects
  • Neoplasms* / immunology
  • Neoplasms* / therapy

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immune Checkpoint Inhibitors

Grants and funding

This work was supported by AstraZeneca.