Risk of Immune-Related Pneumonitis with PD-1/PD-L1 Inhibitors in Different Cancer Types and Treatment Regimens: A Systematic Review and Meta-Analysis of 22 Randomized Controlled Trials

Background: Pneumonitis, the specific toxicity associated with PD-1/PD-L1 inhibitors, is severe and potentially life-threatening, and its incidence and severity are poorly understood among different tumor types or treatment methods. This meta-analysis was performed to compare the incidence and severity of pneumonitis among different tumor types and treatment regimens. Methods: MEDLINE and Embase were retrieved until September 2021. Meta-analysis of the risk of pneumonitis was calculated using a fixed-effect model. Pooled analysis of the incidence of pneumonitis in different tumor types was performed using a metaprop function. Results: Twenty two randomized controlled trials (RCTs) (n = 10,700) were included for pool analysis, and eighteen RCTs (n = 8,852) were eligible for meta-analysis. For all-grade pneumonitis, the risk of the combination therapy (PD-1/PD-L1 plus CTLA-4 inhibitor) was 3.62 times significantly higher than that of monotherapy, and 4.06 and 1.78 times significantly higher than that of chemotherapy and placebo than monotherapy. The incidence of pneumonitis was not significantly different between PD-1/PD-L1 inhibitor versus ipilimumab or between low doses versus high doses. For high-grade (grade ≥3) pneumonitis, the risk in PD-1/PD-L1 inhibitors alone was 3.62 times significantly higher than chemotherapy. No significant difference was found in the incidence of pneumonitis between combination versus monotherapy, monotherapy versus placebo, combination versus ipilimumab alone, monotherapy versus ipilimumab alone, or low doses versus high doses. Conclusions: Compared with chemotherapy, PD-1/PD-L1 inhibitor monotherapy may cause more treatment-related pneumonitis. Increasing the dose of PD-1/PD-L1 inhibitor does not significantly increase the incidence of pneumonitis. Compared with the monotherapy, combination therapy does not increase the incidence of pneumonitis significantly.