Content area
Full Text
Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20-40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure-response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure-response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.
1 Introduction
Immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of melanoma, nonsmall cell lung cancer (NSCLC), urothelial carcinoma and a variety of other malignancies [1-4]. At present, six ICIs have been approved by the US Food and Drug Administration (FDA), of which five ICIs also received market authorization by the European Medicines Agency (EMA).
Immune checkpoints comprise a group of regulatory surface proteins that are entrenched within the immune system and are crucial to prevent autoimmune responses [5]. ICIs target these immune checkpoints in order to stimulate T-cell-mediated killing of tumor cells (Fig. 1) [6]. Current immune checkpoints targeted by ICIs include cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), the programmed death 1 (PD-1) receptor and the programmed cell death-ligand 1 (PD-L1) [5, 7]. In addition to these proteins, other co-stimulatory and co-inhibitory receptors are being targeted in clinical trials, such as GITR, OX40, 4-1BB, LAG-3 and TIM-3 [8]. In the current review, we focus only on those ICIs that received regulatory approval.
Although ICIs play a crucial role in the treatment of various malignancies, limited attention has been attributed to treatment optimization and individualization of ICIs. Variation in both exposure and individual response may allow to further...