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Treatment-Related Adverse Events with PD-1 or PD-L1 Inhibitors: A Systematic Review and Meta-Analysis
Yixi Zhang1, Bin La2, Baosheng Liang1
1Department of Biostatistics, School of Public Health, Peking University, Beijing 100191, China.
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.
Insights
This meta-analysis reveals that PD-1/PD-L1 inhibitors increase the risk of immune-related adverse events like rash and hepatitis. Respiratory and musculoskeletal issues, including cough and arthralgia, also warrant attention during cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Immune checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are crucial in cancer therapy.
- Understanding the full spectrum of treatment-related adverse events is essential for patient safety and treatment optimization.
Purpose of the Study:
- To systematically evaluate the risk of various treatment-related adverse events associated with PD-1 or PD-L1 inhibitors in cancer patients.
- To compare the incidence of adverse events across different organ systems and severity grades.
Main Methods:
- A meta-analysis was conducted on randomized controlled trials (RCTs) published between January 2019 and May 2021.
- Data from 41 RCTs involving PD-1/PD-L1 inhibitors were analyzed to determine risk ratios (RR) and 95% confidence intervals (95% CI) for adverse events compared to control groups.
Main Results:
- PD-1/PD-L1 inhibitors significantly increased the risk of immune-related adverse events such as pruritus, rash, elevated ALT/AST, hepatitis, and hypothyroidism.
- Increased risks were also observed for respiratory events (cough, dyspnea, chest pain) and musculoskeletal issues (arthralgia).
- Dyspnea was a high-risk event across all grades and severe grades (≥3).
Conclusions:
- PD-1/PD-L1 inhibitors are associated with a wide range of adverse events affecting multiple organ systems.
- Clinicians should monitor for common immune-related events as well as respiratory and musculoskeletal adverse events, including cough, dyspnea, arthralgia, and myalgia.
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