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

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

Boris Shulgin  1 , Yuri Kosinsky  1 , Andrey Omelchenko  1 , Lulu Chu  2 , Ganesh Mugundu  3 , Sergey Aksenov  3 , Rodrigo Pimentel  4 , Garrett DeYulia  4 , Geoffrey Kim  5 , Kirill Peskov  1   6 , Gabriel Helmlinger  7
Affiliations
Review

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

Boris Shulgin et al. Oncoimmunology. .

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.

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Conflict of interest 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.

Figures

Figure 1.
Figure 1.
Forest plots of grade 3/4 AEs for (a) CTLA-4 inhibitors and (b) CTLA-4 inhibitor + PD-1 inhibitor.
Figure 2.
Figure 2.
Dependencies of grade AEs upon ICI drug dose/exposure for (a) total trAEs, (b) gastrointestinal imAEs, and (c) hepatic imAEs.
Figure 3.
Figure 3.
Dependencies of AEs on ICI dose/exposure and baseline characteristics.
See this image and copyright information in PMC

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