Meta-analysis of immune-related adverse events of immune checkpoint inhibitor therapy in cancer patients

Abstract

Background: Immune checkpoint inhibitors (ICIs) have significant clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the incidence of immune-related adverse events (irAEs) of up to 50% has prevented their widespread use. With the increase in the use of ICIs alone or as combination therapy, clinicians are required to have a better understanding of irAEs and be able to manage them systematically. In this study, we aimed to assess the incidence of irAEs associated with ICIs.

Methods: We searched PubMed, Embase, and the Web of Science databases, and also included relevant literature references to widen our search. The relevant data with inclusion criteria were performed using RevMan 3.6.0 for meta-analysis. We undertook a systematic literature search which included published data up to December 2019.

Results: Overall, 147 articles and 23 761 cancer patients with 11 different ICI treatment-related (grade 1-5 and 3-5) irAEs were included in the study. There were 46 articles on pembrolizumab (6598 patients), 27 on nivolumab (3576 patients), 13 on atezolizumab (2787 patients), 12 on avelumab (3213 patients), 10 on durvalumab (1780 patients), 22 on ipilimumab (4067 patients), eight on tremelimumab (1158 patients), three on JS001 (223 patients), four on camrelizumab (SHR-1210) (178 patients), one on sintilimab (96 patients), and one on cemiplimab (85 patients). Grade 1-5 irAEs were: cytotoxic T lymphocyte antigen 4 (CTLA-4) (82.87%), programmed cell death 1 (PD-1) (71.89%), and programmed cell death ligand-1 (PD-L1) (58.95%). Subgroup analysis was: Avelumab (44.53%), durvalumab (66.63%), pembrolizumab (67.25%), atezolizumab (68.77%), nivolumab (76.25%), Ipilimumab (82.18%), and tremelimumab (86.78%). Grade 3-5 irAEs were: CTLA-4 (27.22%), PD-1(17.29%), and PD-L1(17.29%). Subgroup analysis was: Avelumab (5.86%), durvalumab (13.43%), atezolizumab (14.45%), nivolumab (15.72%), pembrolizumab (16.58%), tremelimumab (22.04%), and ipilimumab (28.27%).

Conclusions: This meta-analysis confirmed that anti-PD-1 and anti-PD-L1 inhibitors had a lower incidence of irAEs compared with anti-CTLA-4 inhibitors.

Keywords: Cancer; immune checkpoint inhibitor (ICI); immune-related adverse events (irAEs).

Figure 1

Flowchart of study selection and design.

Figure 2

(a) Forest plot of conventional therapy; and (b) CTLA‐4 for grade 1–5 adverse events (AEs).

Figure 3

Forest plot of PD‐1 for grade 1–5 adverse events (AEs).

Figure 4

Forest plot of PD‐L1 for grade 1–5 adverse events (AEs).

Figure 5

(a) Forest plot of atezolizumab; (b) avelumab; and (c) durvalumab or grade 1–5 adverse events (AEs).

Figure 6

(a) Forest plot of ipilimumab; and (b) nivolumab for grade 1–5 adverse events (AEs).

Figure 7

(a) Forest plot of pembrolizumab; and (b) tremelimumab for grade 1–5 adverse events (AEs).

Figure 8

Funnel plot of PD‐1 for grade 1–5 adverse events (AEs).

Figure 9

Forest plot of conventional therapy for grade 3–5 adverse events (AEs).

Figure 10

(a) Forest plot of CTLA‐4; and (b) PD‐1 for grade 3–5 adverse events (AEs).

Figure 11

(a) Forest plot of PD‐L1; and (b) atezolizumab for grade 3–5 adverse events (AEs).

Figure 12

(a) Forest plot of avelumab; and (b) durvalumab for grade 3–5 adverse events (AEs).

Figure 13

(a) Forest plot of ipilimumab; and (b) nivolumab for grade 3–5 adverse events (AEs).

Figure 14

Forest plot of pembrolizumab for grade 3–5 adverse events (AEs).

Figure 15

Forest plot of tremelimumab for grade 3–5 adverse events (AEs).