Review
Not all immune-checkpoint inhibitors are created equal: Meta-analysis and systematic review of immune-related adverse events in cancer trials

https://doi.org/10.1016/j.critrevonc.2017.09.002Get rights and content

Abstract

Background

Targeting immune checkpoints is a novel approach in cancer therapy. This strategy may trigger immune related adverse events (irAE). We hypothesize that the incidence of irAE will be greater in patients receiving immune checkpoint inhibitors (ICI) targeting only immune cells compared to those that also target tumor cells (PD-L1). In addition, we compared the specific irAE profile and overall response rate (ORR) for each ICI by target(s).

Materials and methods

We reviewed all ICI cancer clinical trials (90; 174 arms) that reported irAE and were published through MEDLINE. 114 arms from 73 trials were eligible for this meta-analysis (including 11,328 patients). We collected and compared arm-specific data including ICI target, number of patients with irAE of any grade, grade 3+ and grade 5, specific irAE, and ORR. The R package “meta” was used to conduct a meta-analysis to calculate and compare the percentage of patients with irAE and ORR.

Results

The incidence (% of patients) of any grade irAE per ICI target was reported for 40 arms (3418 patients) treated with ICI. Most arms (80%) and patients (53%) studied were on phase 1/2 clinical trials. Patients were treated for solid malignancy on 39 arms (97%), mainly melanoma (40%). Two arms included ICI combinations. The incidence of any grade irAE was higher in patients who received ICI targeting CTLA-4 (53.8%) than PD-1 (26.5%) and PD-L1 ICI (17.1%) (P < 0.001). Comparative specific irAE rates were calculated for each ICI target.

Conclusions

Our systematic review supported our mechanistic-driven hypothesis. We encourage investigators to report the incidence of irAE in future ICI combination trials.

Introduction

The immune system plays an important role in maintaining checks and balance to protect the host from exogenous pathogens by distinguishing “self” from “non-self” (Postow et al., 2015a, Wolchok and Saenger, 2008). However, differentiating between malignant and benign cells is a challenge. The immune system and tumor cells exist in a dynamic state of equilibrium between two extremes (known as immune-editing): the elimination of the tumor by the immune system (T-cell activation) and the ability of the tumor to evade the immune response and proliferate unchecked (tolerance) (Kirkwood et al., 2008). This system involves both stimulatory and inhibitory signals to maintain immune tolerance. Without the latter, the body may eliminate the tumor but will likely develop autoimmune diseases that will destroy self tissues.

In recent years, the blockade of immune inhibitory signals using immune checkpoint inhibitors (ICI) has been approved as a strategy to treat a variety of malignancies such as melanoma (Hodi et al., 2010, Eggermont et al., 2015, Robert et al., 2015a, Weber et al., 2015, Postow et al., 2015b), lung (Borghaei et al., 2015, Garon et al., 2015), head and neck (Seiwert et al., 2016, Ferris et al., 2016), renal cell (Motzer et al., 2015, McDermott et al., 2016) and urothelial (Rosenberg et al., 2016) cancers, as well Hodgkin lymphoma (Ansell et al., 2015). This strategy consists of using one (Hodi et al., 2010, Eggermont et al., 2015, Robert et al., 2015a, Weber et al., 2015, Postow et al., 2015b, Borghaei et al., 2015, Garon et al., 2015, Motzer et al., 2015, Rosenberg et al., 2016, Ansell et al., 2015, McDermott et al., 2016, Ferris et al., 2016, Seiwert et al., 2016) or two (Postow et al., 2015b, Larkin et al., 2015, Antonia et al., 2016) monoclonal antibodies to target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand (PD-L1) to alleviate tumor-induced immunosuppression of T cells thereby enhancing antitumor effects (Pardoll, 2012). Promising trials are being developed for other cancers (e.g., breast cancer (Spellman and Tang, 2016)) for treatment with ICI.

Immune-related toxicities (irAEs) are a unique aspect of the ICI toxicity profile. These irAEs can affect dermatologic, gastrointestinal, hepatic, pancreatic, pulmonary, renal, endocrine, neurologic, hematologic, ophthalmologic, cardiac, and musculoskeletal organs as well cause infusion-related reactions. The overall and organ-specific irAEs profile differs among ICI classes and depends on the mechanism of action and target(s) inhibition (Fig. 1a and b). The intensity of irAEs can range from mild and manageable in the outpatient setting to severe and life threatening if diagnosed late or not treated aggressively and promptly with appropriate measures.

CTLA-4 is expressed exclusively on T-cells and regulates the amplitude of early T-cell activation. PD-1 is another well-characterized immune checkpoint receptor found on B-lymphocytes, NK cells, and also on T-cells after activation (Keir et al., 2008). CTLA-4, PD-1, and PDL-1 are all inhibitory molecules of the immune system. Whereas CTLA-4 is primarily involved in T-cell activation, PD-1 acts in peripheral tissues and the tumor microenvironment to limit effector T-cell function (Ribas, 2012). PD-L1 differs from PD-1 in its expression on the effector or target cells rather than the regulatory T cells that express CTLA-4 (Wolchok and Saenger, 2008, Ribas, 2012). We predict that inhibiting the function of CTLA-4, PD-1, or PD-L1 will result in a respective decrease in the degree of autoimmunity, since fewer activating T-regulatory cells and more non-T and target tumor cells are involved. Our hypothesis is to confirm that ICI targeting CTLA-4 induce more irAEs than ICI targeting PD-1 (Larkin et al., 2015) and that the latter induce more irAEs than ICI targeting PD-L1. Our objective was to compare, by immune checkpoint target(s) inhibition, the incidence of global irAEs, the incidence and nature of organ-specific irAEs, and the efficacy in terms of response rate through a meta-analysis and systematic review of the literature.

Section snippets

Search strategy and sources (identification)

A systematic literature search was performed up to December 2016 in the MEDLINE database to identify relevant clinical trials conducted in humans using immune checkpoint inhibitor (ICI) to treat cancer (Fig. 2). We identified appropriate anti-CTLA-4 ICI trials using the keywords ipilimumab or tremelimumab, and anti-PD-1 ICI trials using the keywords nivolumab, pembrolizumab, and pidizilumab (CT-011). We used keywords durvalumab, atezolizumab, and avelumab to search for appropriate anti-PD-L1

Literature search

We identified 253 articles reporting ICI clinical trials through MEDLINE searches (Fig. 2). Among these studies, 163 were excluded after reading the title, abstract, and, if necessary, reading the manuscript. Studies were excluded because authors did not report number or incidence of global irAEs (any grade and grade 3 and above), they were duplicate studies, biomarker studies or reviews, not a clinical trial or EAP, or were a non-cancer study. The screening process left us with 90 studies with

Discussion

To our knowledge, this is the first systematic review and meta-analysis comparing overall and organ-specific irAEs in patients with cancers treated with ICI monotherapies and combinations based on their mechanism of actions. In our study, we showed a pathophysiologic explanation as to why irAEs are more likely to occur with CTLA-4 compared to PD-1 blockade, confirming what is known in melanoma, and demonstrated that irAES are more likely to occur with CTLA-4 and PD-1 ICI than PD-L1 blockade.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Disclosures

No disclosures.

Funding

Georgia Cancer Center at Augusta University - United States.

Authors contribution

  • Conceptualization: Formulation of overarching research goals and aims: B El Osta, R Sadek, SC Tang.

  • Methodology: Development or design of methodology; creation of models: B El Osta, F Hu, R Sadek.

  • Software: Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components: F Hu, R Sadek.

  • Validation: Verification, whether as a part of the activity or separate, of the overall replication/reproducibility

Acknowledgement

Department of Hematology / Medical Oncology - Atlanta VA Medical Center, Decatur, GA (Contents do not represent the views of the DoVA or the US Government). The authors thank Dr. Anthea Hammond for editing the manuscript.

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