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

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

Abbreviations

AE	=	Adverse event
ASCO	=	American Society of Clinical Oncology
CI	=	Confidence interval
CTLA-4	=	Cytotoxic T lymphocyte–associated antigen 4
ESMO	=	European Society for Medical Oncology
IC50	=	Half maximal inhibitory concentration
ICI	=	Immune checkpoint inhibitor
imAE	=	Immune-mediated adverse event
NSCLC	=	Non-small cell lung cancer
PD-1	=	Programmed cell death-1
PD-L1	=	Programmed cell death ligand-1
PI	=	Prediction interval
PK	=	Pharmacokinetics
PRISMA	=	Preferred Reporting Items for Systematic Reviews and Meta-Analyses
trAE	=	Treatment-related adverse event

Acknowledgments

The authors thank Eric Masson, Kald Abdallah, and Andrea Vergara-Silva for scientific discussions on this work. We thank Artem Dolgun for help with data programming. Editorial support was provided by Liam Gillies, PhD, of Cactus Communications, and was funded by AstraZeneca.

Author contributions

All authors were involved in the concept and design of the study and data collection. BS, YK, AO, and KP conducted the analysis. All authors actively participated in manuscript development. All authors reviewed the manuscript drafts and approved the submission of the manuscript to this journal.

Declarations

Ethics approval and consent to participate: Not applicable

Availability of data and materials: Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Disclosure statement

BS, YK, AO, and KP are employees of M&S Decisions LLC, Moscow, Russia, which received funding from AstraZeneca to conduct this research and analysis; LC, GM, SA, RP, GD, GK, and GH are all employees of AstraZeneca.

Supplementary Material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work was supported by AstraZeneca.