Treatment-Related Adverse Events with PD-1 or PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

Abstract

Objective: to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. Methods: randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed. Results: a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85–2.96), rash (RR: 1.53, 95% CI: 1.25–1.87), ALT elevation (RR 1.54, 95% CI 1.23–1.92), AST elevation (AST: RR 1.49, 95% CI 1.20–1.85), hepatitis (RR: 3.54, 95% CI: 1.96–6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00–6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21–1.48), dyspnea (RR:1.23, 95% CI: 1.12–1.35) and chest pain (RR: 1.26, 95% CI: 1.07–1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13–2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10–1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45–0.70) compared with that of chemotherapy. Conclusions: our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration.

PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events

“…The true spectrum of irAE across clinical trials and the mechanisms by which these events are induced have been conjectural until now. Wang et al 11 clarify that while the incidence of all-grade toxic effects is about 66%, the incidence of grade 3 or higher AEs is about 15%, and the incidence of all-grade irAEs is 7% to 10%. In at least some patients, irAEs occur as a result of immunogenic responses to shared antigens in both tumor tissue and native skin as shown by Berner et al 12 However, several questions remain unanswered.…”

“…Wang et al 11 report on a meta-analysis of 125 randomized clinical trials involving 20 128 patients who received PD-1 or PD-L1 inhibitors for a variety of cancers. Although melanoma (n = 16), lung (n = 26), and genitourinary (n = 22) cancers predominated this list, gastrointestinal tumors, hematologic cancers, and other cancers also were evaluated.…”

Efficacy and adverse events of immune checkpoint inhibitors in esophageal cancer patients: Challenges and perspectives for immunotherapy

“…Although immunotherapy remains a promising trend for cancer treatment, its associated irAEs have become a concern in the clinic, as some patients develop immunotherapy-related pancreatitis, hyperamylasemia, immune-related myocardial infarction, or even fatal myocarditis after receiving immunotherapy. 25,26 Interstitial pneumonia and myocarditis are correlated with a poor prognosis. 24,26 Typical irAEs involve multiple organs and systems including skin rashes, severe exfoliative dermatitis, acute myocardial infarction, severe bradycardia, and severe interstitial pneumonia.…”

Dezocine Has the Potential to Regulate the Clinical and Biological Features of Tumors

“… 24 PD-1/PDL-1 inhibitors, mainly upregulating the function of cytotoxic T cells (CD8+ cells), promote the apoptosis of tumor cells but can also promote angiogenesis, induce capillary syndrome, decrease its antitumor effects and reduce the analgesic effect of morphine. 28 , 29 Antidepressant treatment may promote tumor proliferation 30 and increase the expression of vascular growth factor (VEGF), which may facilitate the treatment of depression, but VEGF promotes tumor growth and metastasis. 31 …”