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.
Highlights
In recent years, cancer patients gained increasingly significant benefits from immunotherapy, due to its remarkable clinical efficacy and durable response [1]
Case series, single-arm cohort studies, reviews and meeting abstracts, but we had no restriction on cancer type; (2) type of interventions: participants were treated with a single-agent PD-1 or PD-L1 inhibitor in treatment group; (3) type of outcomes: we focused on treatment-related adverse events, so the included studies should display reported tabulated data on treatment-related adverse events in clinicaltrail.gov or in the full article; (4) published in English
Subgroup analysis demonstrated PD-L1 inhibitors associated with higher risk of fever (RR: 1.56, 95% confidence interval (95% CI): 1.24–1.97; see Figure S9) and headache (RR: 1.55, 95% CI: 1.19–2.91; see Figure S10) For PD-L1 inhibitors versus PD-1 inhibitors, the risk of ALT elevation and AST elevation were both higher (RR: 2.10 versus 1.48; 2.34 versus 1.39, respectively)
Summary
Cancer patients gained increasingly significant benefits from immunotherapy, due to its remarkable clinical efficacy and durable response [1]. In China, a number of PD1 or PD-L1 inhibitors successfully entered the Medicare list, such as sintilimab, tislelizumab, and camrelizumab for the treatment of metastatic colorectal cancer, nonsmall cell lung cancer, Hodgkin’s lymphoma, and metastatic melanoma. In nonsmall-cell lung cancer, immune checkpoint inhibitors show very robust efficacy over docetaxel in overall survival, whether combined with chemotherapy or not [4,5,6]. The combination of PD-1/PD-L1 immune checkpoint inhibitors with first-line chemotherapy provide a significant benefit for extensive-stage small cell lung cancer in overall survival, progression-free survival and objective response rate [7]
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